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SECTION III

APPLIED BIOCHEMISTRY

CHAPTER 10 METABOLISM AND VITAMINS/MINERALSCo-authors/Editors: Maria L Valencik and Cynthia C Mastick

Uni vers i ty of Neva da School of Medi ci ne, Depa rtment of Bi ochemi s try, Reno, NV

Meta bol i c Rol es of Ma jor Bi ochemi ca l Mol ecul es

Integra ti on a nd Regul a ti on of Meta bol i s m

Hormona l Control of Meta bol i s m

Vi ta mi ns a nd Mi nera l s

Revi ew Ques ti ons

OVERVIEW

The i ntegra ti on of meta bol i s m i s a s tory of s uppl y a nd dema nd Food i s i nges ted to s uppl y energy but mus t be converted to the ca rbohydra te,

l i pi d, a nd a mi no a ci d forms the body ca n us e, pri ma ri l y gl ucos e a nd fa tty a ci ds Indi vi dua l cel l s then convert the fuel s to us a bl e energy,

a denos i ne tri phos pha te (ATP) a nd ni coti na mi de a deni ne di nucl eoti de (NADH) The body dema nds energy to functi on but i ndi vi dua l orga ns

a nd ti s s ues requi re pa rti cul a r s ources of energy under va ryi ng condi ti ons

To convert cons umed food i nto the needed energy, the body us es a va ri ety of orga ns , ea ch wi th uni que meta bol i c profi l es , to i ntegra te a ndregul a te the us e a nd s tora ge of energy Speci fi c regul a tory poi nts of bi ochemi ca l pa thwa ys provi de i mmedi a te control of the us a ge,

convers i on, or s tora ge of food energy Va ri ous hormones ca n a l s o regul a te thes e bi ochemi ca l pa thwa ys to provi de l onger term control of foodconvers i on a nd energy us a ge Es s enti a l to both of thes e proces s es i s the ma i ntena nce of gl ucos e homeos ta s i s Fi na l l y, vi ta mi ns a nd mi nera l s

s erve i mporta nt functi ons a s cofa ctors i n ma ny of thes e meta bol i c rea cti ons Thei r defi ci ency or exces s ca n l ea d to numerous di s ea s e s ta tes

METABOLIC ROLES OF MAJOR BIOCHEMICAL MOLECULES

The fi rs t cons i dera ti on i s the ma jor s ources of energy tha t ca n be us ed by the body, the nutri ents requi red for thei r meta bol i s m, a nd the

bi ochemi ca l pa thwa ys tha t i ntegra te them

Amino acids (Cha pter 1, Fi gure 10-1) provi de s evera l ma jor bi ochemi ca l functi ons , i ncl udi ng s ervi ng a s (1) the bui l di ng bl ocks of protei ns ; (2)the precurs ors of hormones , neurotra ns mi tters , a nd other i mporta nt s i gna l i ng mol ecul es (s uch a s ni trous oxi de); a nd (3) contri butors to thepuri ne a nd pyri mi -di ne components of nucl ei c a ci ds , co-enzymes [NADH a nd fl a vi n a deni ne di nucl eoti de (FADH2)], a nd other funda menta l

bi ol ogi ca l mol ecul es Addi ti ona l l y, exces s a mi no a ci ds ca n enter the ci tri c a ci d cycl e a nd ca n be us ed to genera te or s tore bi ol ogi ca l energy(Cha pter 5) Furthermore, the meta bol i s m of s ome a mi no a ci ds ca n be funnel ed i nto gl ucos e s ynthes i s (gl uconeogenes i s ) duri ng food

depri va ti on

Figure 10-1 Summary of Amino Acid Metabolism [Reproduced wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l

Publ i s hers (P) Ltd., 2009.]

Carbohydrates (Cha pter 2, Fi gure 10-2) perform a funda menta l rol e a s the pri ma ry energy-producti on s ource for the huma n body Gl ycol ys i s

a nd the s ubs equent meta bol i c pa thwa ys form the pri ma ry energy mol ecul es ATP, NADH, a nd FADH2 vi a the oxi da ti on of gl ucos e a nd other

ca rbohydra tes (Cha pter 6) Stora ge of ca rbohydra tes a s gl ycogen offers a rea di l y a va i l a bl e s ource of energy when di eta ry ca rbohydra te i nta ke i s

l ow (Cha pter 2) Ca rbohydra tes a re a l s o i mporta nt i n the s ynthes i s of ni coti na mi de a deni ne di nucl eoti de phos pha te (NADPH) (Cha pter 6) a ndnucl ei c a ci ds (Cha pter 4)

Figure 10-2 Transport and Fate of Major Carbohydrates and Amino Acids [Reproduced wi th permi s s i on from Murra y RA, et a l : Ha rper’s Il l us tra ted

Bi ochemi s try, 28th edi ti on, McGra w-Hi l l , 2009.]

Lipids (Cha pter 3, Fi gure 10-3) a re nonpol a r bi omol ecul es In mos t ti s s ues , they s erve a pri ma ry s tructura l rol e a s the components of

bi ol ogi ca l membra nes , crea ti ng a l i pi d bi l a yer vi a thei r hydrophobi c a nd hydrophi l i c enti ti es (Cha pters 7 a nd 8) Thei r rol es i n membra nes a swel l a s i n pa thol ogi ca l proces s es s uch a s a theros cl eros i s (Cha pter 16) ha ve ra i s ed the a wa renes s of s a tura ted, mono-uns a tura ted, a nd pol y-uns a tura ted forms wi th rega rd to thei r rol e i n di et However, i n a di pos e ti s s ue, tri gl yceri des a re the ma jor s tora ge form of bi ol ogi ca l energy

a nd thei r oxi da ti on yi el ds more energy per ca rbon tha n ca rbohydra tes (Cha pter 7) Li pol ys i s of tri gl yceri des mobi l i zes fa tty a ci ds tha t genera teenergy through β-oxi da ti on a nd produces the s ubs tra tes neces s a ry for ketone body (a cetoa ceta te a nd β-hydroxybutyra te) s ynthes i s , a n

es s enti a l fuel s ource duri ng prol onged s ta rva ti on Oxi da ti on of both fa tty a ci ds a nd ketone bodi es s pa res gl ucos e by preventi ng i ts oxi da ti on.The cons umpti on of di eta ry chol es terol a nd fa ts ha s a l a rge i mpa ct on l i pi d meta bol i s m through the genera ti on of pl a s ma l i poprotei ns[chyl omi crons a nd l ow-dens i ty l i poprotei n (LDL) vi a very-l ow-dens i ty l i poprotei n (VLDL)] The res ul ta nt el eva ti on of ha rmful l i pi ds /l i poprotei ns(dys l i pi demi a ) ha s nega ti ve meta bol i c cons equences tha t di rectl y i mpa ct hea l th a nd di s ea s e throughout a l l s oci oeconomi c cl a s s es of modern

s oci ety

Figure 10-3 Transport and Fate of Major Lipid Substrates and Metabolites FFA, free fa tty a ci ds ; LPL, l i poprotei n l i pa s e; MG, monoa cyl gl ycerol ; TG,

tri a cyl gl ycerol ; a nd VLDL, very-l ow-dens i ty l i poprotei n [Reproduced wi th permi s s i on from Murra y RA, et a l : Ha rper’s Il l us tra ted Bi ochemi s try,28th edi ti on, McGra w-Hi l l , 2009.]

Vitamins, both l i pi d a nd nonl i pi d deri ved, s erve i mporta nt rol es a s cofa ctors i n meta bol i c pa thwa ys a nd rea cti ons (s ee end of thi s cha pter).

Severa l di s ea s es , i ncl udi ng s curvy, ri ckets , a nd Werni cke–Kors a koff s yndrome, res ul t di rectl y from defi ci enci es of vi ta mi ns or, a s i n perni ci ous

a nemi a , from the body’s i na bi l i ty to properl y a bs orb them Minerals, i ncl udi ng s odi um, pota s s i um, chl ori de, ca l ci um, phos pha te, i ron, a nd

others , pl a y ma jor rol es i n the regul a ti on of meta bol i c enzymes i nvol ved i n di ges ti on, i n the us e a nd/or s tora ge of food meta bol i tes , a nd i nthe el i mi na ti on of wa s te products

Even more i mporta nt i s the i ntegra ti on of meta bol i s m of thes e mol ecul es i n the huma n body a nd how regul a ti on ca n be ma i nta i ned by

i nterrel a ti ons hi ps between thei r a na bol i c a nd ca ta bol i c meta bol i s m In thi s rega rd, the body’s a bi l i ty to s ens e energy l evel s , res pond tohormone s i gna l i ng, a nd upregul a te a nd downregul a te pa rti cul a r meta bol i c pa thwa ys i s pa ra mount for the body to ma i nta i n the proper a ndcontrol l ed l evel of meta bol i c functi on a nd for the myri a d of s tructura l a nd functi ona l proces s es to occur, whi ch a l l ow l i fe

INTEGRATION AND REGULATION OF METABOLISMATP, a s s oci a ted wi th ma gnes i um (Mg2+) for s ta bi l i ty, i s the pri ma ry form of bi ol ogi ca l energy uti l i zed by the huma n body (Fi gure 10-4)

Figure 10-4 Adenosine Triphosphate Structure with Its Magnesium Cofactor [Reproduced wi th permi s s i on from Murra y RA, et a l : Ha rper’s Il l us tra ted

Bi ochemi s try, 28th edi ti on, McGra w-Hi l l , 2009.]

As s uch, the ca ta bol i c oxi da ti on of ca rbohydra tes (gl ycol ys i s , ci tri c a ci d cycl e, a nd oxi da ti ve phos phoryl a ti on), fa tty a ci ds / l i pi ds /ketonebodi es (fa tty a ci d degra da ti on), a nd a mi no a ci ds a l l l ea d eventua l l y to the producti on of ATP In contra s t, a na bol i c meta bol i c proces s es(gl uconeogenes i s , gl ycogen s ynthes i s , l i pi d s ynthes i s , tri gl yceri de s ynthes i s , a nd a mi no a ci d s ynthes i s ) cons ume ATP, NADH, a nd/or NADPH to

s tore energy (gl ucos e), to s tore energy, or to bui l d es s enti a l bi omol ecul es Coupl ed to a l l of thes e proces s es i s the need to el i mi na te wa s teproducts , i ncl udi ng CO2 (exha l a ti on, a ci d–ba s e ba l a nce), rea cti ve a nd/or free-ra di ca l s peci es (a nti oxi da nts ), a nd urea (urea cycl e) Thes econcepts a re s umma ri zed i n Fi gure 10-5

Figure 10-5 Interrelationship Between Proteins, Carbohydrates, and Fats ATP, a denos i ne tri phos pha te; CoA, coenzyme A [Ada pted wi th permi s s i on

from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l Publ i s hers (P) Ltd., 2009.]

Thes e meta bol i c pa thwa ys a re i nti ma tel y l i nked a t s evera l poi nts i n bi ochemi ca l pa thwa ys , but a re a l s o s epa ra ted i nto di s ti nct

compa rtments a nd/or orga nel l es (e.g., cytopl a s m vers us mi tochondri a vers us nucl eus , etc.) to a l l ow the neces s a ry regul a ti on a nd control Addi ti ona l l y, ea ch orga n ha s uni que meta bol i c needs a nd functi ons a s s umma ri zed i n Fi gure 10-6 Thes e functi ons a nd needs mus t becoordi na ted i n a va ri ety of orga ns to ma i nta i n a cons ta nt s uppl y of energy whi l e pres ervi ng s ome energy for the future The body a ccompl i s hesthi s goa l by us i ng the nervous s ys tem a nd hormona l s i gna l s to di fferenti a l l y s ti mul a te a nd i nhi bi t bi ochemi ca l pa thwa ys wi thi n va ri ousorga ns i n res pons e to s uppl y a nd dema nd The ma i n s i gna l s us ed to regul a te meta bol i s m a re i ns ul i n, gl uca gon, ca techol a mi nes ,

gl ucocorti coi ds , a nd growth hormone (i n chi l dren)

Figure 10-6 Integration of Metabolism Among Major Organs [Ada pted wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers

Medi ca l Publ i s hers (P) Ltd., 2009.]

The rema i nder of thi s cha pter wi l l focus on the meta bol i s m i n three ma jor ti s s ues , the l i ver, a di pos e ti s s ue, a nd s kel eta l mus cl e (Fi gure

10-6) The l i ver a cti vel y provi des the qui ck fuel (gl ucos e) your body needs , wherea s a di pos e ti s s ue provi des l ong-term energy s tora ge Fi na l l y,

s kel eta l mus cl e a nd the res t of your body cons ta ntl y dema nd thi s energy For exa mpl e, the bra i n cons umes a pproxi ma tel y 90 g of gl ucos e i n a

da y, 20% of the a vera ge di et

The s uppl y a nd dema nd of energy mus t be conti nuous l y provi ded vi a di eta ry i nta ke or brea kdown of s tores to ba l a nce wi th the energyrequi rements of res pi ra ti on, tra ns port, moti l i ty, a nd s ynthes i s of cel l s a nd ti s s ues (Fi gure 10-7) Overa l l , the a vera ge a dul t us es a pproxi ma tel y

24 kca l of energy per ki l ogra m of body ma s s to i ns ure proper hea l th a nd to ma i nta i n proper wei ght

Figure 10-7 Factors Affecting Blood Glucose [Reproduced wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l

Publ i s hers (P) Ltd., 2009.]

Severa l key bi omol ecul es (gl ucos e-6-phos pha te or G6-P, pyruva te, a nd a cetyl coenzyme A or a cetyl -CoA) l i nk the bi ochemi ca l pa thwa ys for

ca rbohydra tes , l i pi ds , a nd a mi no a ci ds / protei ns a nd the pa thwa ys they funnel i nto a re ti ghtl y regul a ted a nd ti s s ue s peci fi c (Fi gure 10-8)

G6-P, pyruva te, a nd a cetyl -CoA l i nk the a na bol i c a nd ca ta bol i c pa thwa ys of ca rbohydra te meta bol i s m to ma i nta i n a cons ta nt s uppl y of energy to

ma i nta i n homeos ta s i s under cons ta ntl y cha ngi ng condi ti ons The pa rti cul a r pa thwa ys a nd regul a ti on a l s o depend on the s peci fi c functi ons

a nd needs of ea ch ti s s ue type

Figure 108 Summary of Important Control Points of Metabolism The three i mporta nt i ntermedi a ri es , gl ucos e6phos pha te, pyruva te, a nd a cetyl

-CoA a re i ndi ca ted Meta bol i c pa thwa ys of i mporta nce a re i ndi ca ted i n red See text for ful l di s cus s i on ATP, a denos i ne tri phos pha te; -CoA,coenzyme A; NADPH, ni coti na mi de a deni ne di nucl eoti de phos pha te [Ada pted wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypeeBrothers Medi ca l Publ i s hers (P) Ltd., 2009.]

GLUCOSE-6-PHOSPHATE Meta bol i c regul a ti on a t thi s fi rs t bra nch poi nt, G6-P, i s cl ea rl y i l l us tra ted i n the l i ver (Fi gure 10-8) After the i nges ti on of ca rbohydra tes , gl ucos e

ta ken up by the l i ver i s converted to G6-P by gl ucoki na s e Thi s phos phoryl a ti on us es one ATP mol ecul e a nd tra ps the gl ucos e wi thi n l i ver cel l s

(hepa tocytes ) Subs equentl y, G6-P i s meta bol i zed vi a one of the fol l owi ng three pa thwa ys : (a ) glycogenesis—the s tora ge of ca rbohydra tes a s

gl ycogen, (b) glycolysis—the producti on of ATP, or (c) the pentose phosphate pathway—the producti on of NADPH a nd/ or fi ve-ca rbon (pentos e)

s uga rs (Cha pter 6, Fi gure 10-8) The pa thwa y chos en depends upon the a cti va ti on s ta te of key enzymes (glycogen synthase a nd

phosphofructokinase-1), s ubs tra te a va i l a bi l i ty (G6-P, ATP, a nd NADP+), a nd a l l os teri c effectors [ATP, a denos i ne monophos pha te (AMP), fructos e2,6-bi s phos pha te (F2,6BP), hydrogen i ons (H+), a nd ci tra te] The key enzymes i n gl ycogenes i s a nd gl ycol ys i s a re predomi na ntl y regul a ted by

hormone-s ti mul a ted, cova l ent modi fi ca ti on (phosphorylation), wherea s the a l l os teri c effectors fi ne-tune the fl ow of ca rbons through thes e

pa thwa ys In contra s t, the pentos e phos pha te pa thwa y i s pri ma ri l y regul a ted by the a va i l a bi l i ty of G6-P a nd NADP+ (Cha pter 6)

In the wel l -fed s ta te, when ATP a nd ci tra te concentra ti ons a re hi gh, phosphofructokinase-1 i s a l l os teri ca l l y i nhi bi ted, s l owi ng down the commi tted s tep of gl ycol ys i s (the producti on of fructose 1,6-bisphosphate) l ea di ng to i ncrea s ed concentra ti ons of G6-P The i ncrea s ed

concentra ti on of G6-P ca n s ti mul a te ca rbohydra te s tora ge i n two wa ys Fi rs t, G6-P i s a pos i ti ve a l l os teri c effector of glycogen synthase, l ea di ng

to the forma ti on of gl ycogen Second, G6-P i ndi rectl y i nhi bi ts glycogen phosphorylase thereby i nhi bi ti ng glycogenolysis (gl ycogen degra da ti on).

Al terna ti vel y, when the ra ti o of NADP+ to NADPH i s hi gh, G6-P ca n be s huttl ed i nto the pentos e phos pha te pa thwa y to genera te NADPH

(reducti ve energy) Thi s reduci ng power i s us ed to s ynthes i ze a va ri ety of bi omol ecul es s uch a s , fa tty a ci ds , chol es terol , nucl eoti des a nd othercofa ctors a s needed Under condi ti ons where the ra ti o of NADP+ to NADPH i s l ow, the pentos e pa thwa y wi l l not opera te rega rdl es s of theconcentra ti on of G6-P

The producti on of gl ycogen i n the l i ver i s further control l ed by the hormones , i ns ul i n a nd gl uca gon (s ee bel ow), a nd the res ul ti ng

phos phoryl a ti on or dephos phoryl a ti on of gl ycogen s yntha s e Degra da ti on of gl ycogen i s decrea s ed concomi ta ntl y by counterregul a tory

dephos phoryl a ti on or phos phoryl a ti on of gl ycogen phos phoryl a s e Ea ti ng brea kfa s t, a fter a n overni ght fa s t, s ti mul a tes gl ycogen s ynthes i s(a nd i nhi bi ts gl ycogen brea kdown) i n prepa ra ti on for the next peri od of fa s ti ng Thi s repl eni s hment i s control l ed by the fa vora bl e hi gh ra ti o of

i ns ul i n to gl uca gon, l ea di ng to a cti va ti on of gl ycogen s yntha s e a cti vi ty a nd decrea s ed gl ycogen phos phoryl a s e a cti vi ty Under thes e condi ti ons ,the dema nd for de novo s ynthes i s of l i pi d wi l l ri s e a fter the gl ycogen i s repl a ced, us i ng ca rbons from exces s di eta ry ca rbohydra te (to

s ynthes i ze fa tty a ci ds ) Addi ti ona l l y, i f chol es terol bi os ynthes i s i s a cti ve, exces s a cetyl Co A from fa tty a ci d ca ta bol i s m ca n be s ynthes i zed i ntochol es terol Once l i pi d bi os ynthes i s commences , the uti l i za ti on of NADPH i ncrea s es the NADP+/NADPH ra ti o fa vori ng fl ux through the pentos ephos pha te pa thwa y

After a mea l , the key regul a tor tha t res ta rts gl ycol ys i s i n l i ver i s F2,6BP F2,6BP concentra ti on i s control l ed by a bifunctional enzyme tha t

i ncl udes both ki na s e a nd phos pha ta s e a cti ve s i tes Under condi ti ons of a hi gh ra ti o of i ns ul i n to gl uca gon, the bi functi ona l enzyme

(phosphofructokinase-2/fructose 2,6-bisphosphatase) i s dephos phoryl a ted, l ea di ng to s ti mul a ti on of phos phofructoki na s e-2 The res ul ti ng F2,6BP

formed a l l os teri ca l l y a cti va tes phos phofructoki na s e-1 a nd hence i ncrea s es gl ycol ys i s whi l e s i mul ta neous l y i nhi bi ti ng fructos e 1,6

bi s phos pha ta s e, therefore s hutti ng down gl uconeogenes i s Fol l owi ng food depri va ti on, thes e events a re revers ed wi th a hi gh ra ti o of

gl uca gon to i ns ul i n, fa vori ng phos phoryl a ti on of the bi functi ona l enzyme s ti mul a ti ng the fructos e 2,6-bi s phos pha ta s e a cti vi ty a nd l ea di ng todecrea s ed phos phofructoki na s e-1 a cti vi ty

PYRUVATE The s econd ma jor bra nch poi nt i n the i ntegra ti on of meta bol i s m i s a t pyruvate (Cha pter 6, Fi gure 10-8) Pyruva te ca n be converted i nto four

di fferent s ubs tra tes : l a cta te, a l a ni ne, oxa l o-a ceta te, a nd a cetyl -CoA, dependi ng upon the energy needs of a cel l Therefore, i t i s a n i mporta nt

i ntegra ti on poi nt where ca rbons a re s huttl ed between energy s tora ge, energy genera ti on, a nd/or bi os yntheti c rea cti ons In the l i ver, pyruva te

ca n undergo oxi da ti ve deca rboxyl a ti on to enter the ci tri c a ci d cycl e a nd ul ti ma tel y genera te ATP when energy l evel s a re l ow Speci fi ca l l y, l ow

energy l evel s i nhi bi t the a cti vi ty of a n i mporta nt regul a tory enzyme, pyruvate dehydrogenase kinase Thi s i nhi bi ti on prevents phos phoryl a ti on of

the pyruva te dehydrogena s e compl ex to a n i na cti ve s ta te Furthermore, thi s ki na s e i s i nhi bi ted by NAD, pyruva te, a nd s ul fhydryl form of CoA(non-a cetyl a ted), s ubs tra tes of pyruva te dehydrogena s e Therefore, when s ubs tra tes a re pl enti ful , pyruva te i s oxi da ti vel y deca rboxyl a ted to

a cetyl -CoA In the l i ver, pyruva te i s a l s o the poi nt where l a cta te a nd a l a ni ne (s ee bel ow) ca n be a cti vel y funnel ed i nto ei ther the ci tri c a ci dcycl e or gl uconeogenes i s vi a pyruva te ca rboxyl a ti on to oxa l oa ceti c a ci d (Cha pter 6) when l i ver gl ycogen or bl ood gl ucos e l evel s a re l ow Duri ng

s ta rva ti on, gl uconeogenes i s ca n produce up to 160 g of gl ucos e i n a da y, ha l f of thi s from a mi no a ci ds Ha l f of thi s gl ucos e wi l l be us ed by thebra i n As bl ood gl ucos e l evel s s ta bi l i ze a nd gl uconeogenes i s i s no l onger requi red, oxa l oa ceta te ca n re-enter the gl ycol yti c pa thwa y a tphos phoenol pyruva te or s huttl e ba ck i nto the mi tochondri a , a s ma l a te, to be us ed i n the ci tri c a ci d cycl e If energy i s a bunda nt, hi gh NADH

a nd a cetyl -CoA concentra ti ons a cti va te pyruva te dehydrogena s e ki na s e a nd a l s o s erve a s a l l os teri c i nhi bi tors of enzyma ti c a cti vi ti es wi thi nthe PDH compl ex Thi s effecti vel y turns off the pyruva te dehydrogena s e compl ex by phos phoryl a ti on a nd a l l os teri c control a nd s huts down the

ci tri c a ci d cycl e Hi gh ATP a nd a cetyl -CoA concentra ti ons a l s o s ti mul a te pyruvate carboxylase, the fi rs t s tep of gl uconeogenes i s (hormone

regul a ti on of gl uconeogenes i s i s even more i mporta nt; s ee bel ow)

Skel eta l mus cl e i l l us tra tes a nother i mporta nt wa y tha t pyruva te ca n be meta bol i zed (Fi gure 10-9) If oxygen l evel s a re l ow a nd anaerobic respiration becomes i mporta nt (s uch a s duri ng a qui ck s pri nt), pyruva te ca n be converted to lactate by lactate dehydrogenase wi th a n oxi da ti on of

one NADH to NAD+, the l a tter bei ng es s enti a l for s us ta i ni ng gl ycol ys i s In thi s s cena ri o, ATP i s s ol el y deri ved from a na erobi c gl ycol ys i s La cta te

ca n s ubs equentl y be converted ba ck to gl ucos e for energy producti on vi a the Cori cycle (i n the l i ver); when l a cta te concentra ti ons get too hi gh,

feedba ck i nhi bi ti on bl ocks further convers i on of pyruva te to l a cta te Hi gh l a cta te concentra ti ons a l s o crea te the s ens a ti on of “burni ng” i nmus cl es , whi ch s erves a s a s i gna l to the body to l i mi t further us e of thes e mus cl es Furthermore, pyruva te ca n a l s o be converted i n mus cl e

ti s s ue to the a mi no a ci d alanine vi a the alanine transaminase rea cti on In a ma nner a na l ogous to the Cori cycl e, the alanine cycle then converts

thi s a l a ni ne ba ck to pyruva te i n the l i ver where i t i s us ed to produce new gl ucos e vi a gl uconeogenes i s a s a s ource of energy for a na erobi c

gl ycol ys i s i n mus cl e Once oxygen l evel s a re res tored i n s kel eta l mus cl e, producti on of ATP vi a ci tri c a ci d cycl e/oxi da ti ve phos phoryl a ti onres umes

Figure 10-9 The Lactic Acid (Cori) and Glucose–Alanine Cycles Ca rbons from gl ucos e meta bol i s m i n mus cl e a re recycl ed to the l i ver ei ther a s l a cta te

or a l a ni ne for reconvers i on to gl ucos e Hence, when thes e cycl es opera te gl ucos e ca rbons a re s pa red [Ada pted wi th permi s s i on from Murra y

RA, et a l : Ha rper’s Il l us tra ted Bi ochemi s try, 28th edi ti on, McGra w-Hi l l , 2009.]

ACETYL-COA Acetyl-CoA i s the thi rd bra nch poi nt of pri ma ry meta bol i c control , a nd coordi na tes ca rbohydra te, ketone, a nd fa t/l i pi d pa thwa ys (Cha pter 6,

Fi gures 10-8 a nd 10-10) Acetyl -CoA i s a s ubs tra te for the ci tri c a ci d cycl e a nd ca n be oxi di zed to genera te energy However, when energy l evel s

a re hi gh (hi gh NADH/ NAD+ ra ti o), NADH i nhi bi ts the ci tri c a ci d cycl e a t the i s oci tra te dehydrogena s e a nd α-ketogl uta ra te dehydrogena s e s teps Accumul a ti on of FADH2 a l s o occurs , l ea di ng to a n i ncrea s e i n s ucci nyl -CoA tha t i nhi bi ts the cycl e a s wel l Hormones a l s o pl a y a key, l ongerterm rol e i n the regul a ti on of fa tty a ci d s ynthes i s a nd degra da ti on (s ee bel ow) Acetyl -CoA i s a l s o requi red for producti on of the

neurotra ns mi tter a cetyl chol i ne (s ee bel ow a nd Cha pter 19)

Figure 10-10 Overview of Acetyl-CoA Metabolism ATP, a denos i ne tri phos pha te; CoA, coenzyme A; TCA, tri ca rboxyl i c a ci d [Ada pted wi th permi s s i on

from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l Publ i s hers (P) Ltd., 2009.]

In the fed s ta te, exces s a cetyl -CoA ca n be di rected towa rd s ynthes i s of chol es terol a nd/or fa ts /tri a cyl gl ycerol s i n the l i ver Duri ng s ta rva ti on,

fa tty a ci d oxi da ti on s uppl i es energy for hepa tocytes to dri ve gl uconeogenes i s Furthermore, a ny exces s a cetyl -CoA genera ted wi l l be us ed forthe s ynthes i s of ketone bodi es The ketones ca nnot be oxi di zed by the l i ver a nd a re exported a nd us ed a s a n a l terna te fuel for the bra i n,hea rt, a nd mus cl es In fa ct, duri ng fa s ti ng/s ta rva ti on, the bra i n wi l l be hea vi l y rel i a nt on ketone bodi es , us i ng them for up to 70% of i ts energyrequi rements , es peci a l l y i n prol onged s ta rva ti on Hormones a l s o regul a te ketone body s ynthes i s (s ee bel ow)

In both nutri ti ona l ci rcums ta nces , a cetyl -CoA ma y a cti va te pyruvate carboxylase, a l though for di fferent purpos es In the fed s ta te, pyruva te

ca rboxyl a s e converts pyruva te to oxa l oa ce-ta te, whi ch condens es wi th a cetyl -CoA produci ng ci tra te, the fi rs t product of the ci tri c a ci d cycl e The

ci tra te i s tra ns ported to the cytopl a s m for fa tty a ci d s ynthes i s Hi gh ci tra te a cti va tes acetyl-CoA carboxylase to promote the forma ti on of fa tty

a ci ds (Cha pter 7) Ci tra te, when too hi gh, i nhi bi ts phos phofructoki na s e-1, thus bl ocki ng gl ycol ys i s to prevent unneces s a ry meta bol i s m of more

gl ucos e to pyruva te The G6-P tha t ba cks up ca n be cycl ed through the pentos e pa thwa y to provi de NADPH for fa tty a ci d s ynthes i s , a s des cri bed

a bove, or ma y be di rected towa rd gl ycogen s ynthes i s In the s ta rva ti on s ta te, hi gh a cetyl -CoA from oxi da ti on of fa tty a ci ds s ti mul a tes pyruva te

ca rboxyl a s e to promote gl uconeogenes i s

Low concentra ti ons of citrate a nd the other i ntermedi a tes of the ci tri c a ci d cycl e a s wel l a s l ow ATP/NADH/FADH 2 promote conti nua ti on ofthe ci tri c a ci d cycl e a nd oxi da ti ve phos phoryl a ti on The ci tri c a ci d cycl e i ntermedi a tes ca n a l s o be us ed for the producti on of a mi no a ci ds or a s

a n energy s ource (Cha pter 5) Low ci tra te/hi gh pa l mi toyl -CoA (from l i pol ys i s ) concentra ti ons prevent fa tty a ci d s ynthes i s The res ul ta nt

decrea s e of malonyl-CoA, a n a l l os teri c i nhi bi tor of ca rni ti ne pa l mi toyl tra ns fera s e 1 (CPT1), fa vors forma ti on of pa l mi toyl ca rni ti ne by CPT1, wi th

s ubs equent tra ns port a cros s the mi tochondri a l membra ne a nd oxi da ti on i n the mi tochondri a

HORMONAL CONTROL OF METABOLISM

The coordi na ti on of meta bol i c pa thwa ys to a chi eve thi s es s enti a l ba l a nce pri ma ri l y depends on hormone; nerve a nd s i gna l i ng pa thwa ys ,

i ncl udi ng i ns ul i n, gl uca gon, ca techol a mi nes (Cha pter 19), gl ucocorti coi ds (s l ower, s tres s -rel a ted cha nges ); a nd cytoki nes Erra nt control l ea ds

to di s ea s e s ta tes i f gl ucos e l evel s a re hi gh (di a betes mel l i tus or DM) or l ow (hypogl ycemi a ) a nd, i f too l ow, even dea th due to coma

INSULIN

Ins ul i n (Fi gure 10-11) i s the a na bol i c hormone of the wel l -fed s ta te a nd a n i mporta nt s i gna l to s ti mul a te s tora ge of exces s nutri ents a s

gl ycogen a nd tri gl yceri des (fa t i n a di pos e ti s s ue)

Figure 10-11 Preproinsulin Processing Preproi ns ul i n (top) i s compos ed of a l ea der s equence (bl ue), A (green) a nd B (yel l ow) i ns ul i n cha i ns , a nd C

(red) pepti de Remova l of the l ea der s equence produces proi ns ul i n (bottom l eft) Cl ea va ge of C-pepti de from proi ns ul i n l ea ds to the

producti on of a cti ve i ns ul i n Beca us e C-pepti de i s produced i n equa l a mounts to i ns ul i n, i t ha s become a n i mporta nt mea s ure of i ns ul i nproducti on [Ada pted wi th permi s s i on from Ki bbl e JD a nd Ha l s ey CR: The Bi g Pi cture: Medi ca l Phys i ol ogy, 1s t edi ti on, McGra w-Hi l l , 2009.]

The a cti on of i ns ul i n (Fi gure 10-12) i s experi enced by three ma i n ta rgets , the l i ver, a di pos e ti s s ue, a nd s tri a ted mus cl e The s ynthes i s a ndrel ea s e of i ns ul i n i s s ti mul a ted by gl ucos e a nd potenti a ted by a mi no a ci ds In the l i ver, i ns ul i n s ti mul a tes gl ycogenes i s (gl ycogen s ynthes i s ),

fa tty a ci d s ynthes i s , gl ycol ys i s , a nd the pentos e phos pha te pa thwa y In the a di pos e ti s s ue, i t s ti mul a tes gl ucos e a nd fa tty a ci d upta ke a ndtri gl yceri de s ynthes i s (energy s tora ge) Si mi l a rl y, i n s kel eta l mus cl e, i t s ti mul a tes gl ucos e upta ke, gl ycogenes i s , a nd protei n s ynthes i s It i snoteworthy tha t i ns ul i n does not i nfl uence gl ucos e meta bol i s m i n ei ther the bra i n or red bl ood cel l s

Figure 10-12 Metabolic Systems Affected by Insulin [Ada pted wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l

Publ i s hers (P) Ltd., 2009.]

The rel ea s e of i ns ul i n from the pa ncrea ti c β-cel l s (Fi gure 10-13) i s the res ul t of i ncrea s ed bl ood gl ucos e concentra ti ons Gl ucos e enters theβ-cel l s vi a the gl ucos e tra ns porter 2 (GLUT2) (pa s s i ve tra ns port) The GLUT2 ha s a wea k a ffi ni ty for gl ucos e s o tha t i t fa vors gl ucos e upta ke onl y

a fter a mea l , when bl ood gl ucos e l evel s a re hi gh, ra ther tha n i n the fa s ted s ta te Fol l owi ng gl ucos e oxi da ti on, the i ncrea s ed ATP

concentra ti on s ti mul a tes K+ cha nnel s a nd depol a ri zes the cel l membra ne Thi s depol a ri za ti on opens vol ta ge-ga ted Ca2+ cha nnel s Other

s i gna l s rel a ted to producti on of i nos i tol tri s phos pha te, a s econd mes s enger, s ti mul a te Ca2+ rel ea s e from the endopl a s mi c reti cul um,

res ul ti ng i n hi gh i ntercel l ul a r Ca2+ concentra ti on a nd tri ggeri ng the rel ea s e of i ns ul i n

Figure 10-13 Regulation of Secretion of Insulin via Glucose Pa ncrea ti c β-cel l s a re i nduced to s ecrete i ns ul i n by (1) the upta ke of gl ucos e a nd i ts

oxi da ti ve meta bol i s m i n mi tochondri a , whi ch produces i ncrea s ed concentra ti on of ATP (2) Increa s ed ATP ca us es cl os ure of the ATP-s ens i ti ve K+cha nnel s , l ea di ng to depol a ri za ti on (3) The depol a ri za ti on of the cel l ca us es i n i nfl ux of Ca2+ from vol ta ge-ga ted Ca2+ cha nnel s (4) The

i ncrea s ed Ca2+ a l ong wi th IP3 a nd other s i gna l i ng i nduces further rel ea s e of Ca2+ from the endopl a s mi c reti cul um (ER), whi ch prompts

exocytos i s of i ns ul i n, produced i n the ER, a nd s ubs equentl y proces s ed a nd rel ea s ed from s ecretory gra nul es of the Gol gi a ppa ra tus ATP,

a denos i ne tri phos pha te; GLUT2, gl ucos e tra ns porter 2; IP3, i nos i tol tri s phos pha te [Ada pted wi th permi s s i on from Ki bbl e JD a nd Ha l s ey CR: The

Bi g Pi cture: Medi ca l Phys i ol ogy, 1s t edi ti on, McGra w-Hi l l , 2009.]

Ins ul i n a ffects the meta bol i s m of cel l s tha t ha ve i ns ul i n receptors : l i ver cel l s (hepa tocytes ), fa t cel l s (a di pocytes ), a nd mus cl e cel l s (Ta bl e10-1) The bra i n a nd red bl ood cel l s a re not a ffected by i ns ul i n Ins ul i n works vi a a tyros i ne ki na s e receptor, whi ch phos phoryl a tes ta rgetprotei ns tha t l ea d to a number of meta bol i c effects One effect i s the ra pi d tra ns l oca ti on of a gl ucos e tra ns porter 4, GLUT4, from ves i cl es to thecel l s urfa ce of s kel eta l a nd ca rdi a c mus cl e a nd fa t cel l s , i ncrea s i ng gl ucos e tra ns port i nto thes e cel l s Ins ul i n a l s o regul a tes meta bol i c

enzymes s uch a s gl ycogen s yntha s e a nd phos phoryl a s e through a cti va ti on of type I phos pha ta s e a nd dephos phoryl a ti on.

TABLE 10-1 Ins ul i n Effects on Meta bol i s m

GLUCAGON

Gl uca gon (Fi gure 10-14) i s the hormone of fa s ti ng produced by pa ncrea ti c α-cel l s , a dja cent to the i ns ul i n-produci ng α-cel l s Gl uca gon s i gna l s

vi a G-protei n coupl ed receptors a nd the s econda ry mes s enger mol ecul e cycl i c AMP In contra s t to ma ny ma mma l s , gl uca gon a cts a l mos texcl us i vel y on the l i ver i n huma ns (Ta bl e 10-2) Pri ma ri l y, i t s ti mul a tes gl ycogenol ys i s , gl uconeogenes i s , a nd fa tty a ci d oxi da ti on Gl uca gon

l evel s i ncrea s e two-to threefol d i n res pons e to hypogl ycemi a , a nd the l i ver begi ns producti on of gl ucos e from gl ycogen Duri ng ti mes of hi gh

bl ood gl ucos e, gl uca gon i s reduced to ha l f of i ts norma l l evel Gl uca gon a l s o s ti mul a tes the rel ea s e of i ns ul i n, thereby a l l owi ng i ns ul i

n-s enn-s i ti ve cel l n-s to ta ke up the rel ea n-s ed gl ucon-s e The del i ca te ba l a nce of gl uca gon a nd i nn-s ul i n l evel n-s i n-s how the body ma i nta i nn-s gl ucon-s ehomeos ta s i s under va ryi ng condi ti ons

Figure 10-14 Preproglucagon Preprogl uca gon, produced by pa ncrea ti c α-cel l s , i s proces s ed to a cti ve gl uca gon (ora nge) [Ada pted wi th

permi s s i on from Ki bbl e JD a nd Ha l s ey CR: The Bi g Pi cture: Medi ca l Phys i ol ogy, 1s t edi ti on, McGra w-Hi l l , 2009.]

TABLE 10-2 Gl uca gon Effects on Meta bol i s m

CATECHOLAMINES

Ca techol a mi nes , i ncl udi ng norepi nephri ne a nd epi nephri ne, the l a tter bei ng pri ma ri l y the hormone res pons i bl e for the “fi ght or fl i ght”res pons e to externa l s tres s es , ca n provi de a l mos t i mmedi a te (wi thi n s econds ) regul a ti on of meta bol i s m (Fi gure 10-15) Speci fi ca l l y, they

s ti mul a te gl ycogenol ys i s a nd gl ycol ys i s for the producti on of ATP i n the mus cl e At the s a me ti me, they i nhi bi t gl ycol ys i s i n the l i ver a nd

s ti mul a te gl ycogenol ys i s to provi de gl ucos e for the bl ood More recentl y, s yna pti ca l l y rel ea s ed ca techol a mi nes ha ve emerged a s the ma i nphys i ol ogi ca l pa thwa y for the a cti va ti on of l i pol ys i s under condi ti ons of fa s ti ng (a condi ti on of chroni c s tres s ) The effects of epi nephri ne onmeta bol i s m a re s umma ri zed i n Ta bl e 10-3

Figure 10-15 Integrated Control of Blood Glucose Concentration [Ada pted wi th permi s s i on from Ki bbl e JD a nd Ha l s ey CR: The Bi g Pi cture: Medi ca l

Phys i ol ogy, 1s t edi ti on, McGra w-Hi l l , 2009.]

TABLE 10-3 Epi nephri ne Effects on Meta bol i s m

GLUCOCORTICOIDS Corti s ol , a glucocorticoid, i s a chroni c s tres s hormone tha t a l s o regul a tes meta bol i s m but i n the ti me fra me of hours to da ys Wi th prol onged

s tres s , the hypotha l a mus i ncrea s es s ecreti on of corti cotrophi n-rel ea s i ng fa ctor, whi ch s ubs equentl y l ea ds to producti on a nd s ecreti on of

a drenocorti cotropi c hormone from the a nteri or pi tui ta ry gl a nd a nd then corti s ol from the a drena l gl a nds Corti s ol ha s much of the s a me

i nfl uence on meta bol i s m a s epi nephri ne but functi ons vi a a cti va ti on of tra ns cri pti on a nd tra ns l a ti on of genes ra ther tha n modul a ti on ofenzyme a cti vi ty Under condi ti ons where i ns ul i n decl i nes a nd/ or corti s ol l evel s ri s e, corti s ol s ti mul a tes tra ns cri pti on of l i pa s es i nvol ved i n

l i pogenes i s (gl ucos e s pa ri ng), enzymes i nvol ved i n gl uconeogenes i s a nd gl ycogenes i s i n the l i ver, a nd i n the brea kdown of mus cl e protei n.The net effect i s res tored bl ood gl ucos e a nd l a rger gl ycogen s tores i n the l i ver However, thi s i ncrea s e i s a t the expens e of mus cl e a nd bone

a nd ul ti ma tel y i mpa i rs i mmunol ogi ca l functi on

DIABETES MELLITUS (DM)

DM i s a condi ti on cha ra cteri zed by ei ther the tota l l a ck of i ns ul i n (Type 1) or res i s ta nce of peri phera l ti s s ues to the effects of i ns ul i n (Type 2).

Both di s ea s es l a ck the s i gna l i ng effect of i ns ul i n i n the pres ence of norma l or hi gh gl uca gon a nd other meta bol i c s i gna l s (Fi gure 10-16) The

di s ea s e of DM i s due to the i mba l a nce i n ca rbohydra te meta bol i s m a nd i ts effects on other meta bol i c pa thwa ys

Figure 10-16 Metabolic Events Occurring in Diabetes Mellitus Overvi ew of effects i ncurred by the defi ci ency of i ns ul i n a nd exces s gl uca gon,

i ncl udi ng thos e on gl ucos e, protei ns /a mi no a ci ds , a nd l i pi ds Al l effects l ea d to dehydra ti on a nd the condi ti on of di a beti c ketoa ci dos i s , whi ch

ca n be fa ta l [Reproduced wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l Publ i s hers (P) Ltd., 2009.]

In type 1 DM, a utoi mmune des tructi on of the pa ncrea ti c β-cel l s l ea ds to a compl ete l os s of i ns ul i n producti on Al though the l i ver ca n ma ke

gl ucos e, gl ycogen s ynthes i s i s i mpeded In the a bs ence of i ns ul i n, gl uconeogenes i s i s unres tra i ned, el eva ti ng bl ood gl ucos e (Fi gure 10-17).However, mus cl e a nd fa t cel l s ca nnot ta ke up a va i l a bl e bl ood gl ucos e vi a the GLUT4 Thus , the body i s una bl e to cl ea r the el eva ted bl ood

gl ucos e, a nd the peri phera l ti s s ues (mus cl e a nd fa t) a re s ta rved for gl ucos e even when pres ent a t very hi gh l evel s i n the bl ood Furthermore,

i n the a bs ence of i ns ul i n, gl uca gon s ecreti on i s uncoupl ed from the bl ood gl ucos e l evel s (i ns ul i n i s a n i mporta nt phys i ol ogi ca l regul a tor of

gl uca gon s ecreti on) Unoppos ed gl uca gon, together wi th the other counter regul a tory hormones (ca techol a mi nes , corti s ol , a nd growth

hormone), i nhi bi ts gl ycogen s ynthes i s a nd s ti mul a tes gl uconeogenes i s , gl ycogenol ys i s , a nd l i pol ys i s Increa s ed l i pol ys i s l ea ds to el eva ti on of

free fatty acids i n the bl ood s trea m Thes e fa tty a ci d mol ecul es a re pa rtl y ta ken up by l i ver a nd i ncorpora ted i nto lipoproteins to i ncrea s e VLDL

a nd LDL l evel s , a ri s k fa ctor for hea rt di s ea s e Ketone bodies a re a l s o produced beca us e of the exces s of l i pol ys i s , whi ch ca nnot be i nhi bi ted i n

the a bs ence of i ns ul i n Thi s ca n res ul t i n the da ngerous condi ti on ketoa ci dos i s , i f the ketone body l evel becomes too el eva ted The onl y

a va i l a bl e trea tment i s the i njecti on of exogenous i ns ul i n i nto the body However, even wi th opti ma l control , the da ma gi ng effects of el eva ted

gl ucos e a nd l i pi ds eventua l l y l ea d to medi ca l compl i ca ti ons

Figure 10-17 Type 1 Diabetes Mellitus The effect of thi s di s ea s e on orga ns a nd ma jor meta bol i c pa thwa ys i s i l l us tra ted The a bs ence of i ns ul i n

i n type 1 di a betes i nhi bi ts (red ba rs ) the upta ke/convers i on of gl ucos e by mus cl e a nd a di pos e ti s s ue, l ea di ng to a n i ncrea s e i n gl ucos e (red

a rrow) s ynonymous wi th the di s ea s e Upta ke of fa tty a ci ds from tri a cyl gl ycerol s by a di pos e ti s s ue i s a l s o i nhi bi ted (red ba rs ), l ea di ng to a n

i ncrea s e i n i ts l evel s (red a rrow) Res ul ti ng cha nges i n meta bol i s m l ea d to i ncrea s ed fa tty a ci ds a nd ketone bodi es (red a rrows ), the l a tter ofwhi ch contri butes to di a beti c ketoa ci dos i s s een i n type 1 di a beti c pa ti ents See the text for further di s cus s i on VLDL, very-l ow-dens i ty

l i poprotei n [Ada pted wi th permi s s i on from Ka tzung BG, et a l : Ba s i c a nd Cl i ni ca l Pha rma col ogy, 11th edi ti on, McGra w-Hi l l , 2009.]

Diabetes and the Polyol Pathway DM i s a di s ea s e wi th the ha l l ma rk of el eva ted bl ood gl ucos e Al though the mecha ni s m i s not compl etel y

a greed, the hi gh gl ucos e l evel s a re s peci fi ca l l y detri menta l to the kidneys, retina, a nd nerves beca us e of thei r a bi l i ty to tra ns port gl ucos e

wi thout the a i d of i ns ul i n In thes e ti s s ues , exces s gl ucos e enters the sorbitol–aldolase reductase pathway (a l s o known a s the polyol pathway) where i t i s reduced to s orbi tol a nd then fructos e, oxi di zi ng NADPH to NADP+ a nd reduci ng NAD+ to NADH, duri ng the enzyma ti c rea cti ons

Reproduced wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l Publ i s hers (P) Ltd., 2009

When gl ucos e concentra ti ons a re norma l , thi s pa thwa y i s mi ni ma l l y a cti ve beca us e of l ow a ffi ni ty of gl ucos e for the enzyme aldolase reductase However, when gl ucos e l evel s a re hi gh, thi s rea cti on i s more promi nent The res ul ti ng decrea s e i n NADPH a nd i ncrea s e i n NADH

a ffects other enzyma ti c rea cti ons tha t us e thes e mol ecul es a s cofa ctors NADPH i s requi red for producti on of reduced glutathione a nd ni tri c oxi de requi red for detoxi fi ca ti on of reactive oxygen species Lowered NAD+ a l s o l ea ds to a ddi ti ona l rea cti ve oxygen s peci es , a nd producti on of

inositol (s i gna l i ng, i ncl udi ng i ns ul i n receptor) i s a l s o decrea s ed The effects of l owered NADPH a nd NAD+ res ul t i n conti nua l da ma ge tothos e ti s s ues where the pol yol pa thwa y i s mos t promi nent, ca us i ng ki dney, eye, a nd nerve probl ems s een i n ma ny di a beti c pa ti ents

Type 2 DM i s cha ra cteri zed by the producti on of i ns ul i n but res i s ta nce of i ts effects on ta rget ti s s ues As a res ul t of thi s res i s ta nce, thehuma n body a cts a s i f there i s a rel a ti ve defi ci ency of i ns ul i n, even when pres ent a t hi gh l evel s (Fi gure 10-18) The di s ea s e s ha res ma ny tra i ts

wi th type 1 DM As i n type 1, gl uconeogenes i s i s unres tra i ned, a nd mus cl e a nd fa t cel l s do not ta ke up gl ucos e vi a the GLUT4 As a res ul t, hi gh

l evel s of bl ood gl ucos e a re pres ent However, the l i ver s ti l l ca n ma ke gl ycogen, a nd l i pol ys i s i s kept i n check beca us e of decrea s ed butpres ent i ns ul i n However, pl a s ma l i poprotei ns a re typi ca l l y el eva ted, often a s a cons equence of obes i ty a nd poor nutri ti on Ketoa ci dos i s i snot a common s equel a to type 2 DM However, i t ca n occur i n type 2 DM pa ti ents under condi ti ons of a ddi ti ona l meta bol i c s tres s a nd a fter

pa ncrea ti c fa i l ure l ea ds to decrea s ed producti on a nd s ecreti on of i ns ul i n Some ol der peopl e wi th type 2 DM ma y experi ence a di fferent

s eri ous condi ti on ca l l ed Hyperosmolar hyperglycemic nonketotic syndrome (HHNS), a condi ti on i n whi ch the body tri es to get ri d of exces s s uga r by

pa s s i ng i t i nto the uri ne HHNS i s us ua l l y brought on by a n i l l nes s , i nfecti on, or other fa ctors

Figure 10-18 Type 2 Diabetes Mellitus The effect of thi s di s ea s e on orga ns a nd ma jor meta bol i c pa thwa ys i s i l l us tra ted Ins ul i n res i s ta nce i n

type 2 di a betes i nhi bi ts (red ba rs ) the upta ke/convers i on of gl ucos e by mus cl e a nd a di pos e ti s s ue, l ea di ng to a n i ncrea s e i n gl ucos e (red

a rrow) s ynonymous wi th the di s ea s e Upta ke of fa tty a ci ds from tri a cyl gl ycerol s by a di pos e ti s s ue i s a l s o i nhi bi ted (red ba rs ), l ea di ng to

i ncrea s e i n i ts l evel s (red a rrow) Unl i ke type 1 di a betes , fa tty a ci ds a nd ketone bodi es a re not i ncrea s ed (not s hown) a nd di a beti c

ketoa ci dos i s i s , therefore, ra re See the text for further di s cus s i on VLDL, very-l ow-dens i ty l i poprotei n [Ada pted wi th permi s s i on from Ka tzung

BG, et a l : Ba s i c a nd Cl i ni ca l Pha rma col ogy, 11th edi ti on, McGra w-Hi l l , 2009.]

DM and Advanced Glycation End Products: Increa s ed l evel s of s orbi tol a nd fructos e i n di a beti c pa ti ents l ea d to nons peci fi c a tta chment onto

protei ns of ca rbohydra te mol ecul es vi a ca rbohydra te–ni trogen l i nks (s ee the fi gure bel ow), for exa mpl e, l ys i ne a nd a rgi ni ne a mi no a ci ds ,

proporti ona l to the l evel of gl ucos e i n the body Thes e erroneous l y modi fi ed protei ns a re referred to a s advanced glycated (also known as glycosylation) endproducts (AGEs) The bes t known AGE i s hemogl obi n A1C i n ci rcul a ti ng red bl ood cel l s , whi ch forms the ba s i s for tes ti ng of

di a beti c control AGE protei ns a nd thei r brea kdown products ca us e oxi da nt da ma ge to the ki dney a nd a l s o i ncrea s e the producti on of

cytoki nes (e.g., tumor necros i s fa ctor-β), whi ch da ma ges the gl omerul us In a ddi ti on, they i ncrea s e the permeability of blood vessels, i ncrea s e oxidized LDL l evel s a nd i ncrea s e cytoki ne-rel a ted oxidative stress.

Ada pted wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l Publ i s hers (P) Ltd., 2009

AGE protei ns a l s o bi nd to a receptor for advanced glycation endproducts (RAGE) Acti va ti on of RAGE l ea ds to nuclear factor kappa B i nducti on of

s evera l i nfl a mma tory gene products res ul ti ng i n a chroni c i nfl a mma tory envi ronment Thi s l ong-term i nfl a mma ti on promotes s uch va ri ed

di s ea s e s ta tes a s a theros cl eros i s wi th a ccompa nyi ng hea rt a tta cks a nd s trokes Da ma ge to the nerves a nd reti na i s a l s o promi nent,

l ea di ng to diabetic neuropathy a nd retinopathy, the l a tter of whi ch often l ea ds to a voi da bl e bl i ndnes s

VITAMINS AND MINERALS

VITAMINS

Vi ta mi ns a nd mi nera l s s erve a s i mporta nt cofa ctors i n s evera l , es s enti a l enzyma ti c rea cti ons , i ncl udi ng protei n, ca rbohydra te, a nd fa tmeta bol i s m a s wel l a s the forma ti on of ti s s ues Vi ta mi ns a re us ua l l y di vi ded i nto fa t s ol ubl e (vi ta mi ns A, D, E, a nd K) a nd wa ter s ol ubl e(vi ta mi ns B a nd C)

Al though the huma n body or res i dent, benevol ent ba cteri a ca n produce s ome vi ta mi ns , mos t, a l ong wi th the requi red mi nera l s , a reobta i ned from the di et Some vi ta mi ns ca n a l s o be s tored i n the body for di fferent ti mes Defi ci enci es of pa rti cul a r vi ta mi ns i n the di et,therefore, often do not ma ni fes t thems el ves for a l engthy peri od of ti me Vi ta mi ns A, D, a nd B12, for exa mpl e, a re s tored i n l a rge enoughqua nti ti es s o tha t a bs ence i n the di et wi l l not be noti ced for months or yea rs Defi ci enci es i n vi ta mi ns a nd mi nera l s ma y l ea d to ti s s ue

da ma ge a nd/or a number of di s ea s es (e.g., beri beri , s curvy, ni ght bl i ndnes s , pel l a gra , a nd ri ckets ), ma ny of them bei ng fa ta l At the other end

of the s pectrum, exces s a mounts of l i pi d-s ol ubl e vi ta mi ns ca n be toxi c The contri buti on of vi ta mi ns duri ng feta l devel opment i s es peci a l l y

i mporta nt; exces s ma terna l vi ta mi n A duri ng pregna ncy ca n l ea d to s i gni fi ca nt bi rth defects Vi ta mi ns requi red by huma ns a re s umma ri zed i n

Ta bl e 10-4

TABLE 10-4 Summa ry of Vi ta mi ns

MINERALS

Mi nera l s , s peci fi ca l l y thos e es s enti a l a toms i n the huma n di et, a re s i mpl e chemi ca l el ements requi red for the exi s tence a nd s ubs i s tence of

l i fe The ba s i c chemi ca l el ements i ncl ude ca rbon, hydrogen, ni trogen, oxygen, phos pha te, a nd s ul fur Addi ti ona l mi nera l s tha t pl a y a s ma l l erbut s ti l l i mporta nt rol e a re s odi um, pota s s i um, ca l ci um, ma gnes i um, i odi ne, a nd zi nc Other mi nera l s a re requi red by the huma n body,

a l though the exa ct number of es s enti a l mi nera l s i s s ti l l controvers i a l A s umma ry of mi nera l s i mporta nt to bi ochemi ca l functi ons of thehuma n body i s i ncl uded i n Ta bl e 10-5

TABLE 10-5 Summa ry of Importa nt Mi nera l s

REVIEW QUESTIONS

1 Wha t a re the genera l meta bol i c rol es of the ma jor bi ochemi ca l mol ecul es —ca rbohydra tes , l i pi ds , a nd a mi no a ci ds ?

2 Wha t a re the pri ma ry meta bol i c contri buti ons of s ma l l i ntes ti ne, l i ver, a di pos e ti s s ue, pa ncrea s , a nd mus cl e?

3 Why a re gl ucos e-6-phos pha te, pyruva te, a nd a cetyl -CoA cons i dered pri ma ry i ntermedi a tes i n meta bol i s m of the ma jor bi ochemi ca l

mol ecul es ?

4 How does the concentra ti on of gl ucos e-6-phos pha te determi ne the fa te of gl ucos e a fter entry i nto the l i ver cel l or mus cl e cel l ?

5 Wha t i s the rol e of fructos e 2,6-bi s phos pha te i n the control of l i ver ca rbohydra te meta bol i s m?

6 Wha t fa ctors i n the fed a nd s ta rved s ta tes determi ne the fa te of pyruva te i n terms of i ts oxi da ti on, us e for gl ucos e s ynthes i s , or rol e i n

fa tty a ci d forma ti on? How do thes e fa ctors ba l a nce ea ch other?

7 Wha t fa ctors i n the fed a nd s ta rved s ta tes determi ne the fa te of a cetyl CoA i n l i ver i n terms of i ts oxi da ti on, us e for fa tty a ci d s ynthes i s , or

convers i on to ketone bodi es ? How do thes e fa ctors ba l a nce ea ch other?

8 How does the ra ti o of i ns ul i n to gl uca gon determi ne the ba l a nce of ca rbohydra te meta bol i s m i n the body i n terms of effects on meta bol i c

pa thwa ys i n s peci fi c ti s s ues ?

9 How does the ra ti o of i ns ul i n to gl uca gon determi ne the ba l a nce of fa t meta bol i s m i n the body i n terms of effects on meta bol i c pa thwa ys

i n s peci fi c ti s s ues ?

10 Wha t a re the key effects of epi nephri ne on meta bol i s m a nd how do thes e rel a te to the body’s needs i n the fi ght or fl i ght res pons e?

11 Wha t a re the rol es of gl ucocorti coi ds i n s tres s or s ta rva ti on?

12 Wha t a re the key meta bol i c di s turba nces a s s oci a ted wi th type 1 a nd type 2 di a betes ?

13 Wha t a re the fa t-s ol ubl e vi ta mi ns , thei r functi ons , a nd di s ea s es of defi ci ency?

14 Wha t a re the B vi ta mi ns , thei r functi ons , a nd di s ea s es of defi ci ency?

15 Wha t a re the functi ons of vi ta mi n C a nd di s ea s es of defi ci ency?

16 Wha t a re the functi ons of the fol l owi ng mi nera l s a nd the cons equences of thei r defi ci ency a nd/or exces s —s odi um, pota s s i um, ca l ci um,

ma gnes i um, phos phorus , i ron, a nd i odi ne?

CHAPTER 11 THE DIGESTIVE SYSTEMEditor: Kshama Jaiswal

Depa rtment of Surgery, Denver Hea l thMedi ca l Center, Denver, Col ora do

Summa ry of the Di ges ti ve Sys tem

Sma l l Intes ti ne (Duodenum, Jejunum, a nd Il eum)

La rge Intes ti ne/Anus

Revi ew Ques ti ons

OVERVIEW

The di ges ti ve or ga s troi ntes ti na l s ys tem i s roughl y defi ned a s the a na tomi ca l component from the mouth to the a nus , i ncl udi ng orga nsres pons i bl e for tra ns i t, mecha ni ca l brea kdown, di ges ti on a nd a bs orpti on of foods tuffs , a s wel l a s the effi ci ent el i mi na ti on of s ol i d wa s te.Incl uded a re the mouth a nd denti ti a , pha rynx a nd es opha gus , s toma ch, s ma l l i ntes ti ne, l i ver, ga l l bl a dder, pa ncrea s , l a rge i ntes ti ne, rectum,

a nd a nus As wi th the compl ex i ntegra ti on a nd control of meta bol i s m, the di ges ti ve s ys tem i s , i ts el f, under the i nfl uence of neurol ogi ca l a ndhormona l regul a ti on tha t both a cti va tes a nd i nhi bi ts ma ny of i ts compl ex a cti ons Mos t of thes e compl ex a cti ons a re, thems el ves , s i mpl e

bi ochemi ca l proces s es of protei ns , ca rbohydra tes , l i pi ds , a nd nucl eos i des / nucl eoti des to i ncl ude enzyme rea cti ons wi th a s s oci a ted

a cti va ti ng a nd i nhi bi tory mol ecul es , membra ne-s pa nni ng protei n cha nnel s , a nd pumps a l l l ea di ng to the producti on a nd s tora ge of energy

a nd es s enti a l bui l di ng bl ocks for current or future us e

SUMMARY OF THE DIGESTIVE SYSTEM

The di ges ti ve s ys tem i s the col l ecti on of orga ns res pons i bl e for the di ges ti on of i nges ted foods a nd l i qui ds (Fi gure 11-1) Thi s s ys tem i s

cl a s s i ca l l y cons i dered to s ta rt a t the mouth a nd conti nue vi a the es opha gus , s toma ch, s ma l l a nd l a rge i ntes ti nes , a nd end a t the rectum/a nus Bes i des thei r mecha ni ca l a nd enzyma ti c brea kdown of foods tuffs , cons i dera bl e contri buti ons towa rd di ges ti ons a re s uppl i ed from the l i ver

a nd pa ncrea s

Figure 11-1 Overview of the Digestive System Components of di ges ti on a nd tra ns port of food from the mouth to the rectum/a nus a re s hown,

i ncl udi ng a s umma ry of thei r contri buti ons a nd the a vera ge a mount of ti me for food to rea ch thei r l oca ti on a fter i nges ti on [Reproduced wi thpermi s s i on from Ki bbl e JD a nd Ha l s ey CR: The Bi g Pi cture: Medi ca l Phys i ol ogy, 1s t edi ti on, McGra w-Hi l l , 2009.]

MOUTH

Teeth provi de the i ni ti a l mecha ni ca l brea kdown of food vi a chewi ng or ma s ti ca ti on a nd, therefore, the forma ti on a nd hea l th of teeth i s

i mporta nt Protei ns s erve a s a n i mporta nt s tructura l component of teeth ena mel Li ke bone, teeth requi re the col l a gen-l i ke protei ns

amelogenin (over 90% compos ed of prol i ne, gl uta mi ne, a nd hi s ti di ne a mi no a ci ds ), ameloblastin, enamelin, a nd tuftelin (a phos phoryl a ted

gl ycoprotei n), whi ch orga ni ze, i ni ti a te, a nd di rect ca l ci um phos pha te crys ta l forma ti on a nd hel p a nchor teeth to the gums

The pos s i bl e brea kdown of ena mel i s equa l l y i mporta nt a nd i s a l s o dependent on bi ochemi ca l proces s es Denta l pl a que forma ti on a ndtooth deca y both rel y on enzyma ti c proces s es for forma ti on a s wel l a s preventi on Pl a que i s ca us ed ma i nl y by the norma l ora l ba cteri a

Streptococcus mutans, Lactobacillus acidophilus, Fusobacterium nucleatum, Actinomyces viscosus, a nd Nocardia spp When thes e orga ni s ms form a l a yer

on teeth, thos e cl os es t to the teeth exi s t i n a n oxygen-defi ci ent envi ronment a nd convert to a na erobi c res pi ra ti on for energy producti on Thi senzyma ti c proces s turns ca rbohydra tes i nto l a cti c a ci d from pyruva te (Cha pter 6) a nd res ul ts i n a pH of bel ow 5.5, l ea di ng to tooth deca y, thedemi nera l i za ti on proces s tha t ca us es ca vi ti es Gl ucos e, fructos e, a nd es peci a l l y s ucros e (common ta bl e s uga r) a re the ma i n ca rbohydra te

s ources

The mouth i s a l s o the l oca ti on for the s ta rt of the proces s es of ca rbohydra te, l i pi d, a nd protei n di ges ti on vi a i mporta nt enzymes conta i ned

i n s a l i va Sa l i va producti on, a l ong wi th feel i ngs of hunger a nd s a ti ety, i s control l ed by a va ri ety of neuro-bi ochemi ca l proces s es , whi ch s ta rt

wi th the i ni ti a l thoughts or cephalic phase of ea ti ng The phys i ca l pres ence a nd a ct of chewi ng a nd ta s ti ng food, known a s the oros ens ory or gustatory phase, el i ci ts further s i gna l s tha t enha nce s a l i va forma ti on a nd expres s i on The va ri ous fa ctors a ffecti ng hunger a nd s a ti ety a re

di s cus s ed i n Cha pter 19 Sa l i va a l s o tra ps mol ecul es produced by norma l ora l ba cteri a tha t a dds to the ta s te s ens a ti on of otherwi s e odorl es s

a nd ta s tel es s food compounds The hormone gustin, produced i n s a l i va a nd a n a cti va tor of a ca l modul i n-dependent cycl i c a denos i ne

monophos pha te (cAMP) phos phodi es tera s e (Cha pter 8), i s a l s o thought to pl a y a n i mporta nt pa rt i n ta s te bud forma ti on Di ges ti ve enzymesconta i ned i n s a l i va a nd thei r rol es i n di ges ti on a re l i s ted i n Ta bl e 11-1

TABLE 11-1 Compos i ti on of Sa l i va

“Meth Mouth”: Pa ti ents who a bus e methamphetamines a re prone to ma rked denta l deca y, known col l oqui a l l y a s “Meth Mouth.”

Metha mpheta mi ne a cts on the αadrenergic receptors of the va s cul a ture of the s a l i va ry gl a nds , ca us i ng va s ocons tri cti on a nd reduci ng s a l i va ry

fl ow, depri vi ng the ora l envi ronment of s a l i va ’s bufferi ng a cti vi ty to countera ct a ci di ty a nd prevent demi nera l i za ti on of ena mel

Metha mpheta mi ne-i nduced vomi ti ng a l s o expos es teeth to a ci ds In a ddi ti on, metha mpheta mi ne overs ti mul a tes the s ympa theti c nervous

s ys tem, eventua l l y depl eti ng norepi nephri ne a nd dopa mi ne a nd a l teri ng concentra ti ons of other centra l nervous s ys tem (CNS)

neurotra ns mi tters s uch a s s erotoni n, a cetyl chol i ne, a nd gl uta ma te Thi s reducti on i ncrea s es the dema nd for a denos i ne tri phos pha te (ATP);metha mpheta mi ne us ers ma y compens a te by cons umi ng more ca rbohydra tes i n the form of s uga rs a nd s ta rches Obs ervers s peci fi ca l l yreport a hi gh i nta ke of ca rbona ted s oft dri nks a mong meth us ers At the s a me ti me, us ers typi ca l l y a ba ndon ora l hygi ene In s hort,

metha mpheta mi ne us e encoura ges a n envi ronment tha t ma xi mi zes ca ri es ri s k—decrea s ed s a l i va , frequent expos ure to s uga r, a nd l a ck of

pl a que control

STOMACH

Stoma ch i s the l oca ti on of conti nued mecha ni ca l brea kdown of food vi a the a cti ons of i ts s mooth mus cl e l a yers but, perha ps more

i mporta ntl y, the s i te of the a cti va ti on a nd a cti vi ty of a number of regul a ted enzymes a nd expos ure to a ci d (pH 1–2) tha t i ni ti a tes meta bol i s m.The other ma i n functi on of the s toma ch i s the regul a ted a nd coordi na ted s ecreti on of hydrogen a toms a nd va ri ous di ges ti ve enzymes underthe control of the a utonomi c nervous s ys tem a nd s evera l hormones Thes e mol ecul es a re produced from a va ri ety of cel l types found i n

va ri ous pa rts of the s toma ch a s s hown i n Fi gure 11-2 a nd s umma ri zed bel ow Hormones tha t a ffect the s toma ch a re des cri bed i n Ta bl e 11-2

Figure 11-2 Hormone Production from the Stomach Speci fi c porti ons of the s toma ch a re res pons i bl e for producti on of hormones a s i l l us tra ted

a bove (s ee text for further des cri pti on) [Reproduced wi th permi s s i on from Ki bbl e JD a nd Ha l s ey CR: The Bi g Pi cture: Medi ca l Phys i ol ogy, 1s tedi ti on, McGra w-Hi l l , 2009.]

TABLE 11-2 Hormones Affecti ng the Stoma ch

1 Mucus (Neck) Cells Found i n a l l pa rts of the s toma ch, thes e cel l s produce a vi s cous mi xture of protecti ve enzymes a nd mucins, l a rge

gl ycoprotei ns (Cha pter 1), vi a s ti mul a ti on of a myristylated alanine-rich C kinase Muci ns ha ve l ow gl ycos yl a ti on on the a mi no a nd ca rboxy

termi na l ends but very hi gh l evel s of gl ycos yl a ti on (vi a s eri ne, threoni ne, a nd a s pa ra gi ne a mi no a ci ds ) i n the centra l pa rt of i ts a mi no a ci d

s equence Thes e muci n gl ycoprotei ns a re a l s o i nterl i nked by cys tei ne–cys tei ne di s ul fi de bonds (Cha pter 1) tha t form l a rge a ggrega te gel s

fi l l ed wi th wa ter a nd protected from enzymes by thei r dens e ca rbohydra te coa ti ng The s ecreted mucus provi des a protecti ve ba rri er a ga i ns tthe di ges ti ve enzymes a nd hi ghl y a ci di c condi ti ons found i n the s toma ch

2 Parietal (Oxyntic) Cells Found i n a l l pa rts of the s toma ch, pa ri eta l cel l s a re s ti mul a ted by the hormones histamine vi a the H2 receptor (Gs—

a denyl cycl a s e/cAMP) a nd gastrin vi a a CCK2 receptor [Gq—phos phol i pa s e C/i nos i tol tri phos pha te (IP3)/Ca2+] a s wel l a s by the va gus

(pa ra s ympa theti c) nerve vi a a cetyl chol i ne a nd the M3 receptor (Gq—phos phol i pa s e C/IP3/Ca2+) Sti mul a ti on of a denyl cycl a s e i s known to

s peci fi ca l l y a cti va te the H+/K+ ATPa s e a cti ve tra ns port cha nnel a nd ga s tri c a ci d producti on Thes e cel l s produce three ma i n components tha t

a re a s fol l ows :

a Gastric acid [ma i nl y hydrogen (H+) a nd chl ori de (Cl−) i ons ] vi a a uni que H + /K + ATPase active transport channel tha t pumps hydrogen i ons i nto

the s toma ch a ga i ns t a very hi gh concentra ti on gra di ent (a pprox 3 mi l l i on to 1) Ga s tri c a ci d functi ons i n protei n dena turi za ti on,

peps i nogen a cti va ti on (s ee bel ow), a nd i nhi bi ti on of ba cteri a l growth

b Bicarbonate ion (HCO 3 ) Excreted i nto the bl ood a s pa rt of the overa l l H+ pumpi ng mecha ni s m

c Intrinsic factor Requi red for i ntes ti na l a bs orpti on of vi ta mi n B12 (s ee Cha pter 10)

Achlorydia: The des tructi on or da ma ge of parietal cells l ea ds to a ma rked reducti on i n the producti on of ga s tri c a ci d, es s enti a l for the i ni ti a l

brea kdown of food a nd a cti va ti on of s toma ch enzymes (e.g., peps i n) Al though s evera l di s ea s e s ta tes a nd/or s urgi ca l i nterventi ons ca n

a ffect pa ri eta l cel l s , i mmune des tructi on of the cel l s l ea ds to the condi ti on of achlorydia/hypochloridia i n whi ch decrea s ed a mounts of

hydrochl ori c a ci d a re produced The res ul ti ng hi gher s toma ch pH l ea ds to s ymptoms of ga s troes opha gea l refl ux, pa i n a nd ful l nes s from

i na dequa te di ges ti on, a nd i ncrea s ed growth of ba cteri a , norma l l y l i mi ted by l ow pH, whi ch ca n l ea d to di a rrhea a nd decrea s ed a bs orpti on

of es s enti a l i ons (e.g., ma gnes i um a nd zi nc) a nd vi ta mi ns (e.g., C, K, B-compl ex), whi ch thems el ves l ea d to other di s ea s e s ta tes Trea tment

i s vi a s uppl ementa ti on wi th Betaine HCl, a form of hydrochl ori c a ci d, whi ch s urvi ves i nto the s toma ch, a nd a ny requi red vi ta mi ns a nd

mi nera l s

3 Chief (Zymogenic) Cells Produce pepsinogen, the proenzyme form of the i mporta nt enzyme pepsin, whi ch cl ea ves pepti de bonds , prefera bl y a t

hydrophobi c a nd a roma ti c [phenyl a l a ni ne (Phe), tryptopha n, a nd tyros i ne] a mi no a ci ds Sti mul a ti on of chi ef cel l s ecreti ons i s by the va gus

nerve, a ci di c condi ti ons per ga s tri c a ci d, or by the hormones ga s tri n or secretin (produced i n the duodenum) In i nfa ncy, Chi ef cel l s a l s o

produce the enzyme rennin, whi ch a i ds mi l k a bs orpti on by brea ki ng the Phe–methi oni ne pepti de bond i n mi l k protei n ka ppa -ca s ei n.

Secreti on of renni n i s s ti mul a ted by i nges ti on of mi l k by the huma n i nfa nt but the gene product i s turned off pa s t thi s s ta ge

4 Enterochromaffin-like Cells (ELCs) Found i n the ga s tri c gl a nds Thes e cel l s s ecreted hi s ta mi ne, whi ch a cti va tes pa ri eta l cel l s a nd ga s tri c a ci d

producti on ELCs a re, thems el ves , a cti va ted by the hormone ga s tri n, pi tui ta ry a denyl cycl a s e-a cti va ti ng pepti de, a nd va gus nerve ELCs a re

i nhi bi ted by somatostatin.

5 G Cells Found i n the a ntrum Secrete the hormone gastrin (s ee Ta bl e 11-2), whi ch both i ncrea s es the s ecreti on of a nd works a l ong wi th

hi s ta mi ne to s ti mul a te pa ri eta l cel l s to produce hydrochl ori c a ci d a nd Chi ef cel l s to produce peps i n Secreti on of ga s tri n i s i ncrea s ed by

pa ra s ympa theti c va gus nerve a cti vi ty vi a rel ea s e of gastrin-releasing peptide or by the pres ence of a mi no a ci ds i n the s toma ch.

6 Prostaglandin E 2 Bi ndi ng to i ts receptor s ti mul a tes s mooth mus cl e contra cti on of the ga s troi ntes ti na l tra ct a nd decrea s es pa ri eta l cel l

s ecreti on of ga s tri c a ci d whi l e i ncrea s i ng mucus producti on The a cti on i s vi a the Gi protei n receptor, whi ch i nhi bi ts the producti on of cAMP

by a denyl cycl a s e a nd, therefore, pa ri eta l cel l H+/K+ ATPa s e pump a cti vi ty

Misoprostol and Gastric Ulcers Misoprostol (s ee the fi gure), a s yntheti ca l l y produced prostaglandin E 1, i s s ometi mes us ed to prevent ga s tri c

ul cers beca us e of i ts a bi l i ty to i nhi bi t pa ri eta l cel l producti on of ga s tri c a ci d Mi s opros tol i s norma l l y us ed onl y for trea tment of or

prophyl a xi s a ga i ns t nons teroi da l a nti -i nfl a mma tory drug-i nduced pepti c ul cers beca us e other medi ca ti on cl a s s es (H2-receptor bl ocker a ndprotei n pump i nhi bi tors , PPIs ) a re more effecti ve for l ong-term ca re of a ci d refl ux a nd s i mi l a r di s orders

Reproduced wi th permi s s i on from Ka tzung BG, et a l : Ba s i c a nd Cl i ni ca l Pha rma col ogy, 11th edi ti on, McGra w-Hi l l , 2009

The a cti ons of ea ch of the a bove cel l types a nd, therefore, the envi ronment of the s toma ch a re control l ed by va gus nerve s i gna l s a s wel l a sthe hormones l i s ted bel ow Of note i s the fa ct tha t s evera l hormones tha t a ffect the s toma ch a re produced a nd a l s o a ct on orga ns outs i de the

s toma ch (e.g., s ma l l i ntes ti ne) to decrea s e s toma ch moti l i ty a nd/or di ges ti on (Fi gure 11-3) In thi s ma nner, the body not onl y “turns on” the

s toma ch when food i s pres ent but a l s o turns i t “off” when food ha s tra vel ed further a l ong the di ges ti ve tra ct

Figure 11-3 Hormone Production by the Digestive System Si tes of producti on of the fi ve ma jor ga s troi ntes ti na l hormones a l ong the l ength of the

ga s troi ntes ti na l tra ct The wi dth of the ba rs i ndi ca tes the rel a ti ve a bunda nce a t ea ch l oca ti on CCK, chol ecys toki ni n; GIP, ga s tri c i nhi bi torypepti de [Reproduced wi th permi s s i on from Ba rrett KE, et a l : Ga nong’s Revi ew of Medi ca l Phys i ol ogy, 23rd edi ti on, McGra w-Hi l l , 2010.]

Acid Reflux (Gastroesophageal Reflux Disease or GERD), Barrett’s esophagus, and the Vagus Nerve GERD a ffects a l a rge percenta ge of the

popul a ti on ei ther a cutel y or chroni ca l l y Untrea ted GERD ca n s ometi mes l ea d to preca ncerous cha nges i n the l ower pa rt of the es opha gus

ca l l ed Barrett’s esophagus, whi ch ca n progres s to potenti a l l y fa ta l adenocarcinoma of the es opha gus The s urgi ca l s everi ng of the va gus nerve (vagal nervectomy or vagotomy) wa s once us ed for trea tment due to thi s nerve’s promi nent rol e i n pa ri eta l a nd G cel l (producers of ga s tri n),

s ecretory a cti vi ty The procedure, a l though us ua l l y effecti ve for GERD a nd pepti c ul cer di s ea s e, a l s o ca rri ed a number of unwa nted s i deeffects beca us e of the i nnerva ti on of other orga ns by the va gus nerve unl es s ca reful a nd s el ecti ve s urgery wa s performed Ma ny trea tment

methods ha ve s i nce been devel oped, i ncl udi ng the H 2 blocker cl a s s of medi ca ti ons , whi ch i nhi bi t the promoti on of a ci d s ecreti on by

hi s ta mi ne a nd PPIs, whi ch bl ock the uni que H+/K+ ATPa s e pump found i n the s toma ch As a res ul t, a va gotomy i s now ra rel y performed forGERD trea tment

LIVER

The l i ver pl a ys mul ti pl e, cri ti ca l rol es (s ee Ta bl e 11-3) i n s uch di vers e functi ons a s a ma jor pa rt i n ca rbohydra te, protei n, a nd l i pi d

meta bol i s m/regul a ti on; s ynthes i s a nd s ecreti on of s evera l bl ood cl otti ng (coa gul a ti on) fa ctors ; s ynthes i s of bi l e; the degra da ti on of

hemogl obi n/bi l i rubi n from decompos i ng red bl ood cel l s (Fi gure 11-4); s ynthes i s a nd cl ea ra nce of chol es terol ; s tora ge of gl ycogen, vi ta mi ns , A,

D, B12, i ron, a nd copper; brea kdown a nd el i mi na ti on of a va ri ety of toxi c s ubs ta nces (i ncl udi ng a l cohol ); a nd the s ynthes i s of a va ri ety ofmol ecul es from a l bumi n to i ns ul i n-l i ke growth fa ctor 1 to a ngi otens i n (s ee Cha pters 12 a nd 16) Thes e functi ons a re ca rri ed out by

hepa tocytes , the functi ona l cel l s of the l i ver

TABLE 11-3 Summa ry of Li ver Functi ons

Figure 11-4 Degradation of Hemoglobin to Bilirubin Overvi ew of brea kdown i n the reti cul oendothel i a l s ys tem of heme mol ecul es tha t a re

rel ea s ed from decompos i ng red bl ood cel l s Steps produci ng bi l i verdi n a nd bi l i rubi n a re s hown The gra dua l brea kdown of heme res ul ts i n

s evera l i ntermedi a te products tha t crea te the col ors s een i n a n evol vi ng a nd hea l i ng brui s e NADPH, ni coti na mi de a deni ne di nucl eoti dephos pha te [Reproduced wi th permi s s i on from Ba rrett KE, et a l : Ga nong’s Revi ew of Medi ca l Phys i ol ogy, 23rd edi ti on, McGra w-Hi l l , 2010.]

Bilirubin Measurement and Disease: La bora tory mea s urement of bilirubin i s a l wa ys reported a s the conjugated (direct), unconjugated (indirect), a nd total bilirubin A dye us ed to detect bi l i rubi n qui ckl y produces a red-vi ol et a zobi l i rubi n compound wi th conjuga ted bi l i rubi ns ; thes e a re,

therefore, referred to a s “di rect” bi l i rubi n The a ddi ti on of etha nol to the s a mpl e ma kes a l l bi l i rubi ns (conjuga ted a nd unconjuga ted) rea ctqui ckl y wi th the dye a nd yi el ds “tota l bi l i rubi ns ” Unconjuga ted bi l i rubi n l evel s a re ca l cul a ted by s ubtra cti ng di rect bi l i rubi n from tota l

bi l i rubi n a nd a re, therefore, ca l l ed “i ndi rect” bi l i rubi n Urobilinogen i s mea s ured by the a ddi ti on of a rea gent conta i ni ng

p-di methyl a mi nobenza l dehyde, whi ch turns a da rk pi nk/red proporti ona l to the urobi l i nogen i n the tes t s a mpl e Urobi l i n does not rea ct wi ththi s compound a nd, therefore, us ua l l y onl y urobi l i nogen i s mea s ured Stercobl i n, found excl us i vel y i n feces , i s us ua l l y not mea s ured

Di s ea s es of the l i ver, ga l l bl a dder, a nd red bl ood cel l s a l l a ffect the a mount of unconjuga ted/conjuga ted bi l i rubi n a s wel l a s the

a mounts of res ul ta nt urobi l i nogen a nd s tercobi l i n Si mpl e obs erva ti ons a nd l a bora tory mea s urement of thes e mol ecul es ca n grea tl y a s s i s t

i n determi ni ng thes e di s ea s e s ta tes For exa mpl e, ga l l s tones , chroni c l i ver di s ea s e wi th ci rrhos i s , or other di s ea s es tha t bl ock or decrea s ethe s ecreti on of conjuga ted bi l i rubi n i nto the bi l e wi l l l ea d to a n i ncrea s ed l ea ka ge of bi l i rubi n from l i ver cel l s a nd a res ul ti ng ri s e i n uri ne

bi l i rubi n Thi s ri s e ca n both be mea s ured a nd s een i n uri ne by the res ul ti ng da rk a mber col or The l a ck of bi l i rubi n s ecreti on i nto the

i ntes ti ne wi l l a l s o decrea s e the a mount of s tercobi l i n crea ti ng whi te or pa l e feces Di s ea s es tha t ca us e i ncrea s ed brea kdown of red bl oodcel l s (e.g., hemol yti c a nemi a s ) wi l l i ncrea s e the a mount of unconju-ga ted bi l i rubi n i n bl ood tes ts ; however, a s the unconjuga ted form i s not

s ol ubl e i n wa ter, uri ne bi l i rubi n wi l l not i ncrea s e a nd uri ne col or wi l l rema i n the s a me However, the exces s heme from the des troyed red

bl ood cel l s wi l l i ncrea s e the a mount of urobi l i nogen/urobi l i n tha t ca n be mea s ured

In newborns , the i ni ti a l l a ck of l i ver enzymes res pons i bl e for conjuga ti on a nd i ntes ti na l ba cteri a , whi ch convert bi l i rubi n to urobi l i nogen,

ma y l ea d to the di s ea s es of hyperbilirubinemia a nd potenti a l l y l etha l kernicterus Thes e s a me condi ti ons a l s o l ea d to pa l er feces i n

newborns a nd el eva ted l evel s of bi l i rubi n crea te a yel l ow s ki n col or (ja undi ce)

LIPID METABOLISM IN THE LIVER The l i ver pl a ys a centra l rol e i n l i pi d meta bol i s m It i s the onl y orga n ca pa bl e of the di s pos a l of s i gni fi ca nt qua nti ti es of cholesterol, ei ther vi a

excreti on i nto the bi l e or by meta bol i s m to bi l e a ci ds , both of whi ch a re l os t to s ome degree i n the feces Di eta ry chol es terol , whi ch i s

pa cka ged i nto chyl omi crons i n the i ntes ti ne for tra ns port i n the bl ood, ul ti ma tel y ends up i n the l i ver where i t combi nes wi th the pool ofchol es terol s ynthes i zed from a cetyl coenzyme A deri ved from β-oxi da ti on of s a tura ted fa tty a ci ds a nd i s ei ther excreted vi a the bi l e a s bi l e

s a l ts or di s tri buted to other ti s s ues vi a low-density lipoprotein (LDL) In the fed s ta te, the l i ver converts exces s di eta ry gl ucos e to fa tty a ci ds tha t

a re es teri fi ed to gl ycerol (Cha pter 7) The res ul ti ng triglycerides a re pa cka ged, wi th chol es terol , i nto very-low-density lipoprotein (VLDL), whi ch i s

s ecreted i nto the bl ood to del i ver fa tty a ci ds pri ma ri l y to a di pos e cel l s a nd mus cl e Fi na l l y, bi l e s a l ts ma de i n the l i ver a re needed for the

a bs orpti on of di eta ry l i pi ds (e.g., tri gl yceri des a nd chol es terol ) a nd fa t-s ol ubl e vi ta mi ns

The l i ver i s the s ource of the l i poprotei n VLDL a nd mos t a pol i poprotei ns (a po) a nd i s a cti vel y i nvol ved i n the endogenous

tra ns port/meta bol i c pa thwa y of chol es terol a nd a s s oci a ted l i poprotei ns (hi gh-dens i ty l i poprotei n, LDL, a nd VLDL; s ee Cha pter 3) Its ma jorfuncti on i s to tra ns port the endogenous l y s ynthes i zed tri a cyl gl ycerol from the l i ver to extra hepa ti c ti s s ues VLDL s ecreted i nto the ci rcul a ti on

a l s o conta i ns a po B100 (a l s o s ynthes i zed i n l i ver) tha t i s requi red for the proper a s s embl y a nd export of VLDL pa rti cl es The s econd ma jorfuncti on of VLDL i s to ca rry l i ver-genera ted chol es terol es ters to peri phera l cel l s a fter i ts convers i on to LDL (s ee Cha pter 16) The further s teps

i n chol es terol tra ns port a nd del i very to peri phera l ti s s ues a re des cri bed i n Cha pter 16

GALL BLADDERThe ga l l bl a dder s erves to s tore a nd concentra te bile produced i n the l i ver Bi l e i s rel ea s ed i nto the duodenum a t the ampulla of Vater by s mooth

mus cl e contra cti on of the muscularis externa l a yer a nd rel a xa ti on of the Sphincter of Oddi Rel ea s e i s i n res pons e to s ecreti on of cholecystokinin

(CCK), the na me of a group of rel a ted pepti de hormones s ecreted from I-cel l s i n the duodenum wi th s i mi l a r s tructure to ga s tri n (s ee a bove).

CCK s ecreti on i s i ncrea s ed by entra nce of fa t- or protei n-conta i ni ng food i nto the duodenum but decrea s ed by the a cti ons of s oma tos ta ti n (s ee

a bove) Bi l e i s compos ed of wa ter, a va ri ety of i ons [Na+, K+, Ca2+, Cl−, a nd HCO3 (bi ca rbona te)], l i pi ds (fa tty a ci ds , phos phol i pi ds , a nd

chol es terol ), protei ns , a nd, mos t i mporta ntl y for di ges ti on, more tha n 30 g/l of a ni on forms of bi l e a ci ds (s ee Cha pter 3) As noted i n Cha pter 3,

gl yci ne- a nd ta uri ne-conjuga ted bi l e a ci ds a re the ma jor forms Thes e bi l e a ci ds ha ve detergent properti es ena bl i ng them to s urround a ndbrea k up tri gl yceri des a nd phos phol i pi ds fa t pa rti cl es i n food (Fi gure 11-5), a l l owi ng l i pi d-degra di ng enzymes (e.g., pa ncrea ti c l i pa s e) to a ct

Bi l e a ci ds a l s o promote i mproved a bs orpti on of fa ts , i ncl udi ng the fa t-s ol ubl e vi ta mi ns A, D, E, a nd K (Cha pters 3 a nd 10)

Figure 11-5 A–B Role of Bile Salts in Triglycerides Metabolism A Bi l e s a l ts form mi cel l es wi th fa tty a ci ds rel ea s ed from di eta ry tri gl yceri des by

pa ncrea ti c l i pa s e The hydrophobi c, cha rged s i de cha i n a nd hydroxyl (OH) groups of bi l e s a l t monomers (s ee Cha pter 3) a re wel l s ui ted for

mi cel l e forma ti on [Ada pted wi th permi s s i on from Ba rrett KE, et a l : Ga nong’s Revi ew of Medi ca l Phys i ol ogy, 23rd edi ti on, McGra w-Hi l l , 2010.] B.

Thes e mi cel l es promote i ncrea s ed degra da ti on of the tri a cyl gl ycerol , by the l i pa s e/col i pa s e compl ex, to two fa tty a ci ds a nd monoa cyl gl ycerolfol l owed by tra ns port of thes e products to the mucos a , a s pa rt of new mi cel l es , where they a re a bs orbed for rea s s embl y of tri a cyl gl ycerol s

Bes i des expres s i on of bi l e from the ga l l bl a dder, CCK s erves a n i mporta nt rol e i n s ti mul a ti ng the pa ncrea s to rel ea s e di ges ti ve enzymes ,

i ncl udi ng trypsin, chymotrypsin, pancreatic lipase, a nd pancreatic amylase, to a i d i n fa t a nd protei n di ges ti on CCK a l s o s l ows down s toma ch

emptyi ng to a l l ow proper di ges ti on of thes e food pa rti cl es a nd decrea s es the producti on of ga s tri c a ci d (s ee a bove) Fi na l l y, CCK s erves a s aneuropep-ti de regul a ti ng hunger/s a ti ety worki ng vi a CCK receptors found i n the CNS As di s cus s ed a bove, the CCK receptor a l s o bi nds ga s tri n

a nd functi ons vi a a G protei n-coupl ed s i gna l i ng proces s , whi ch a cti va tes phos phol i pa s e C wi th s ubs equent producti on of IP a nd Ca2+ In the

CNS, CCK works vi a regul a ti on of the a cti vi ty of dopa mi ne a nd pos s i bl y GABA (Cha pter 19) CCK a cti vi ty i s a l s o i nvol ved i n the a cti vi ty of opi oi ds

i n the CNS

Cholesterol Gallstones: The forma ti on of chol es terol ga l l s tones , one type of chol el i thi a s i s , occurs mos t often i n women ol der tha n 40 yea rs

who ha ve ha d s evera l pregna nci es Obes i ty i ncrea s es the ri s k Ga l l s tones a re a l s o i ncrea s ed i n women of Ca uca s i a n a nd Hi s pa ni c ori gi n.Thes e ri s k fa ctors a re s ometi mes des cri bed by the fi ve “Fs ”—fema l e, forty, ferti l e, fa t, a nd fa i r—but the mecha ni s m a ppea rs to be fa r morecompl i ca ted tha n thes e s i mpl e fa ctors Hi gh chol es terol a nd rel a ti vel y l ow bi l e s a l t l evel s a re known ri s k fa ctors a s wel l a s bi l e s ta s i s i nthe ga l l bl a dder due to i nfrequent, wea k, a nd i ncompl ete contra cti ons a nd emptyi ng of i ts contents Pa rti cul a r protei ns found i n bi l e ha ve

a l s o been noted to enha nce or i nhi bi t the preci pi ta ti on of chol es terol i nto s tones Interes ti ngl y, l evel s of the di eta ry s uppl ement

mel a toni n ma y a l s o pl a y a rol e i n ga l l s tone forma ti on a s , a mong ma ny s ugges ted functi ons , i t a l s o promotes l ower l evel s of chol es terol

a nd reduces oxi da ti on l evel s i n the ga l l bl a dder

PANCREAS

The pa ncrea s pl a ys a predomi na nt rol e i n the di ges ti on of fa ts a nd protei ns beca us e of the pa ncrea ti c jui ce a nd va ri ous di ges ti ve enzymes

tha t i t produces a nd s ecretes i nto the duodenum (exocrine functions), s ha ri ng the a mpul l a of Va ter wi th the common bi l e duct In a ddi ti on, the

pa ncrea s produces s evera l hormones (endocrine functions) The exocri ne functi ons occur i n the pancreatic acini, s ma l l cl us ters of cel l s a nd ducts

One functi on of thes e a ci ni i s the producti on of bi ca rbona te i ons (HCO3), under control of the hormone secretin, for a l ka l i ni za ti on of the a ci d

contents l ea vi ng the s toma ch (Fi gure 11-6)

Figure 11-6 Mechanism for Production of Bicarbonate Ions (HCO 3 ) by the Pancreas Ach, a cetyl chol i ne [Reproduced wi th permi s s i on from Ki bbl e JD

a nd Ha l s ey CR: The Bi g Pi cture: Medi ca l Phys i ol ogy, 1s t edi ti on, McGra w-Hi l l , 2009.]

A s econd functi on, ma i nl y under the control of CCK, i s the s ynthes i s a nd s ecreti on of enzyme protea s es , i ncl udi ng the proenzymes

tryps i nogen a nd chymotryps i nogen a s wel l a s pa ncrea ti c l i pa s e, pa ncrea ti c a myl a s e, phos phol i pa s e A2, l ys ophos phol i pa s e, a nd chol es terol

es tera s e (Ta bl e 11-4)

TABLE 11-4 Exocri ne Pa ncrea ti c Enzymes a nd Thei r Functi ons

As a n endocri ne orga n, the pa ncrea s produces a nd s ecretes s evera l hormones from fi ve di fferent cel l types formi ng the Is l ets of

La ngerha ns , s umma ri zed i n Ta bl e 11-5

TABLE 11-5 Endocri ne Pa ncrea ti c Hormones , Cel l s ource, a nd Functi ons

The endocri ne pa ncrea s i s regul a ted not onl y by other hormones but a l s o by the a utonomi c nervous s ys tem (Cha pter 19) Sympa theti c(a drenergi c) i nnerva ti on s peci fi ca l l y i ncrea s es α-cel l s ecreti ons whi l e decrea s i ng tha t from β-cel l s Pa ra s ympa theti c (mus ca ri ni c) i nnerva ti on

i ncrea s es s ecreti ons from both α- a nd β-cel l s

SMALL INTESTINE (DUODENUM, JEJUNUM, AND ILEUM)The small intestine i s the a pproxi ma tel y 16–20 ft l ong s ecti on of the di ges ti ve tra ct i n whi ch a ma jori ty of the di ges ti on of food a nd a bs orpti on

of nutri ents occurs The effecti ve functi ona l l ength of the s ma l l i ntes ti ne i s i ncrea s ed by a fa ctor of a bout 500 by fol ds / i nva gi na ti ons (plicae

circulares a nd ruga e) of the i ntes ti na l wa l l a nd a l s o the projecti ons (vi l l i ) of the enterocyte cel l borders whi ch l i ne i t The three di fferent pa rts

of the s ma l l i ntes ti ne—the duodenum, the jejunum, a nd the ileum—perform di fferent functi ons , dependi ng on the pres ence of di ges ti ve

enzymes a nd a bs orpti ve ca pa bi l i ti es of thei r pa rti cul a r cel l types (Fi gure 11-7)

Figure 11-7 Summary of Absorption by Small Intestine Abs orpti on of va ri ous nutri ents i s noted for the duodenum, jejunum, a nd i l eum.

[Reproduced wi th permi s s i on from Ki bbl e JD a nd Ha l s ey CR: The Bi g Pi cture: Medi ca l Phys i ol ogy, 1s t edi ti on, McGra w-Hi l l , 2009.]

Short Gut Syndrome: Short gut (bowel) syndrome res ul ts from ei ther congeni ta l or s urgi ca l l y ca us ed s horteni ng of the s ma l l i ntes ti ne wi th

res ul ti ng l os s of the es s enti a l di ges ti ve a nd a bs orpti ve functi ons Surgery for Crohn’s di s ea s e, ca ncers , tra uma , a nd ba ri a tri c (obes i ty)trea tments a re the pri ma ry ca us es Symptoms whi ch i ncl ude di a rrhea , pa i n, a nd s econda ry di s orders from l i mi ted vi ta mi n a nd nutri ent

a bs orpti on us ua l l y do not pres ent unl es s more tha n two-thi rds of the s ma l l i ntes ti ne (i e., l es s tha n 7 ft rema i ni ng) i s a ffected Some

pa ti ents ca n i mprove vi a enl a rgement a nd i ncrea s ed functi oni ng of the rema i ni ng i ntes ti na l l ength a nd/or s l owi ng of movement of foodthrough the i ntes ti ne to opti mi ze di ges ti on a nd a bs orpti on Trea tment i s s ymptoma ti c a nd by s uppl ementa ti on of requi red nutri ents ,

a l though s urgi ca l a ttempts a t i ntes ti na l l engtheni ng or tra ns pl a nt a re bei ng a ttempted

Infectious/Inflammatory Diseases of the Small Intestine: The cons ta nt expos ure of the di ges ti ve tra ct a nd, i n pa rti cul a r, the s ma l l i ntes ti ne to

i nges ted mi croorga ni s ms l ea ds to mul ti pl e occurrences of gastroenteritis or i nfl a mma ti on of the s toma ch a nd/or s ma l l i ntes ti ne Al though a

ma jori ty of ca us es a re vi ra l (e.g., rota vi rus ), va ri ous ba cteri a (e.g., Escherichia coli, Shigella, Salmonella, Campylobacter, Vibrio cholerae, a nd

Clostridium), protozoa n (e.g., Gi a rdi a ), a nd pa ra s i tes (e.g., Ascaris lumbricoides, fl a t-worms , a nd ta peworms ) ca n a l s o i nfect the s ma l l

i ntes ti ne Al l i nfecti ons l ea d to a cute cha nges i n the a bi l i ty of the i ntes ti na l l i ni ng to di ges t a nd a bs orb nutri ents a nd wa ter, l ea di ng to

a cute di a rrhea a nd nutri ent defi ci enci es

Di ges ti on a nd a bs orpti on of ea ch of the three pa rts of the s ma l l i ntes ti ne a re s umma ri zed i n Ta bl e 11-6

TABLE 11-6 Overvi ew of Functi ons of the Sma l l Intes ti ne

Pernicious Anemia: Pernicious anemia i s a decrea s e i n red bl ood cel l s count ca us ed by a decrea s e of a bs orbed vitamin B 12 due to the l a ck of

intrinsic factor Intri ns i c fa ctor i s norma l l y produced by the pa ri eta l cel l s of the s toma ch a nd i s es s enti a l i n a l l owi ng the a bs orpti on of thi s

es s enti a l vi ta mi n i n the i l eum The ca us e of perni ci ous a nemi a i s norma l l y by atrophic gastritis a nd res ul ti ng i mmune a tta ck a ga i ns t i ntri ns i c

fa ctor a nd thes e cel l s Ga s tri c bypa s s s urgery ca n a l s o ca us e a n a rti fi ci a l l y produced form of nonfuncti ona l pa ri eta l cel l s Symptoms i ncl ude

l os s or a l tera ti on of nerve s ens a ti on (paresthesia) us ua l l y i n the fi ngers a nd toes , i nfl a mma ti on of the tongue (glossitis), a nd wea knes s (s econda ry to the a nemi a ) a mong others Perni ci ous a nemi a i s one of the megaloblastic anemias, one ca us e of whi ch i s fol a te defi ci ency,

l ea di ng to defects i n red bl ood cel l s DNA s ynthes i s a nd a bnorma l l y enl a rged red bl ood cel l s Trea tment i s by ora l a nd s ubl i ngua l

s uppl ementa ti ons , both of whi ch a l l ow a bs orpti on of vi ta mi n B12 vi a l oca ti ons other tha n the i l eum, or by i njecti ons or other a bs orpti vemethods

LARGE INTESTINE/ANUS

The fi na l pa rt of the ga s troi ntes ti na l tra ct i s the a pproxi ma tel y 5 ft l ong, l a rge i ntes ti ne a nd a nus /rectum, whi ch ma i nl y s erves a s a l oca ti onfor conti nued, pa s s i ve wa ter rea bs orpti on, vi ta mi n a bs orpti on, a nd tra ns port of i ndi ges ti bl e food for el i mi na ti on a s feces (Fi gure 11-8) Ma ny

of thes e functi ons a re dependent on “gut fl ora ,” a va ri ety of from 300 to 1000 di fferent, s ymbi oti c ba cteri a l s peci es a nd four or more funga l

s peci es tha t l i ve i n the i ntes ti ne a nd a l l ow a l a rge number of bi ochemi ca l rea cti ons tha t a re es s enti a l to l i fe The Bacteroides genus of

ba cteri a a ppea rs to be mos t a bunda nt a nd pl a y a n es peci a l l y i mporta nt rol e

Figure 11-8 Summary of Functions of the Large Intestine Abs orpti on of wa ter a nd i ons by the a s cendi ng a nd proxi ma l tra ns vers e col on a nd s tora ge

a nd tra ns port of wa s te ma teri a l s by the di s ta l tra ns vers e, des cendi ng, a nd s i gmoi d col on a nd the rectum i s i l l us tra ted [Reproduced wi thpermi s s i on from Ki bbl e JD a nd Ha l s ey CR: The Bi g Pi cture: Medi ca l Phys i ol ogy, 1s t edi ti on, McGra w-Hi l l , 2009.]

One rol e of gut fl ora i s the fi na l di ges ti on of dietary fiber, s ta rches , a nd ca rbohydra tes tha t the huma n body ca nnot meta bol i ze, i ncl udi ng

l a ctos e i n l a ctos e-i ntol era nt i ndi vi dua l s Thes e pol ys a ccha ri de cha i ns a re converted to short-chain fatty acids (e.g., a ceti c a ci d, propi oni c a ci d, butyri c a ci d, l a cti c a ci d, a nd i s ova l eri c a ci d) by ba cteri a l fermentation a nd pa s s i vel y a bs orbed i nto the bl ood s trea m Indi ges ti bl e protei ns (e.g.,

col l a gen a nd el a s ti n) a re a l s o broken down by ba cteri a l fermenta ti on pa thwa ys Bi ca rbona te i ons s ecreted by the l a rge i ntes ti ne hel p toreduce a ci di ty produced by the fermenta ti on rea cti ons In a ddi ti on, s ymbi oti c, i ntes ti na l ba cteri a a l s o i ncrea s e the a bs orpti on of rema i ni ng

l i pi ds a nd mi nera l s s uch a s ca l ci um, ma gnes i um, a nd i ron Thes e ba cteri a l proces s es not onl y a l l ow uti l i za ti on of thes e energy s ources but

a l s o i ncrea s e wa ter a bs orpti on a nd reduce l evel s of da ngerous i ntes ti na l ba cteri a whi l e i ncrea s i ng growth of benefi ci a l ba cteri a

Gut fl ora a l s o a ugment l evel s of vitamin K a nd biotin (vitamin B 7 ), whi ch a re a bs orbed by the l a rge i ntes ti ne, a s a norma l by-product of thei r meta bol i s m Gut fl ora a re a l s o res pons i bl e for producti on of s ome modified (secondary) bile salts In a ddi ti on, thes e ba cteri a a re i mporta nt i n the devel opment a nd growth of es s enti a l , i ntes ti na l lymph tissue; the devel opment of antibodies to ha rmful pa thogens ; meta bol i s m a nd

el i mi na ti on of i nges ted carcinogens; the conti nued repl i ca ti on a nd growth of the cel l s l i ni ng the i ntes ti ne; a nd protecti ve cha nges i n the

expres s i on of cel l -s urfa ce mol ecul es on thes e cel l s

Antibiotic Use and Clostridium difficile: Gut fl ora provi des a number of es s enti a l functi ons , whi ch i ncl udes keepi ng the growth of unwa nted

ba cteri a a nd yea s t reduced Thi s a bi l i ty to prevent ha rmful s peci es from overproduci ng i n the huma n i ntes ti ne i s s ometi mes ca l l ed the

“ba rri er effect.” Anti bi oti cs us ed i n the trea tment of di s ea s es ca n s ometi mes a dvers el y a ffect thi s ba l a nce by i na dvertentl y reduci ng thenumber of hel pful gut fl ora The i ncrea s i ng us e of broa d-s pectrum a nti bi oti cs tha t el i mi na te mul ti pl e ba cteri a l s peci es , es peci a l l y the

fa mi l y of fluoroquinolones, ha s a ugmented thi s probl em.

One common ba cteri um tha t grows i n the l a rge i ntes ti ne i n the wa ke of overa ggres s i ve a nti bi oti c us e i s C difficile Overgrowth by thi s

orga ni s m a nd i ts rel ea s e of ha rmful toxi ns l ea ds to chroni c di a rrhea , bl oa ti ng, a nd a bdomi na l pa i n Thes e toxi ns a re bel i eved to i na cti va te

a fa mi l y of G-protei ns /GTPa s e receptors by a l teri ng es s enti a l recogni ti on a nd bi ndi ng s uga r res i dues on thei r s urfa ce Conti nued growth of

C difficile ca n l ea d to the s eri ous condi ti on of pseudomembranous colitis, a s evere i nfecti on of the col on Thi s di s ea s e res ul ts from ma rked

i nfl a mma ti on of the i ntes ti na l l i ni ng a nd a res ul ti ng membra ne-l i ke s tructure compos ed of fi bri n, l ymphocytes a nd monocytes , a nd dea d

a nd dyi ng l i ni ng cel l s Pa ti ents who ha ve been i n the hos pi ta l or nurs i ng homes a re i ncrea s i ngl y s us cepti bl e to thi s probl em due to

i ncrea s ed numbers of ba ckground Clostridium i n thei r i ntes ti nes Trea tment of the condi ti on i s ei ther by ces s a ti on of a nti bi oti c us e or wi th

the ora l us e of the a nti bi oti cs metronidazole or vancomycin.

REVIEW QUESTIONS

1 Wha t a re the genera l rol es of the mouth, s toma ch, l i ver, ga l l bl a dder, pa ncrea s , a nd s ma l l i ntes ti ne i n di ges ti on?

2 Wha t a re the ma jor di ges ti ve enzymes of s a l i va a nd the s peci fi c functi on of ea ch?

3 Wha t i s the rol e of mucus ?

4 Wha t a re the functi ons of the pa ri eta l (oxynti c) a nd Chi ef cel l s i n the s toma ch?

5 Wha t a re the functi ons of the ma jor di ges ti ve hormones a nd where i s ea ch produced?

6 Wha t a re the pri ma ry meta bol i c rol es of l i ver?

7 Wha t fa ctors rel a ted to cl otti ng a nd cl ot di s s ol uti on a re s ecreted by the l i ver a nd wha t a re thei r functi ons ?

8 Wha t tra ns port/ca rri er protei ns a re s ecreted by l i ver?

9 Wha t rol es does the l i ver pl a y i n l i pi d tra ns port a nd meta bol i s m, es peci a l l y wi th rega rd to chol es terol a nd a s s oci a ted l i poprotei ns ?

10 Wha t a re the functi ons of ea ch of the exocri ne pa ncrea ti c hormones ?

11 Wha t a re the functi ons of ea ch of the endocri ne pa ncrea ti c hormones a nd i n whi ch cel l type i s ea ch produced?

12 Wha t a re the ma i n functi ona l mol ecul es /gl a nds of ea ch s ecti on of the s ma l l i ntes ti ne?

13 Wha t i s i ntri ns i c fa ctor a nd the cons equence of i ts defi ci ency?

14 Wha t a re the ma i n functi ons of the l a rge i ntes ti ne?

CHAPTER 12 MUSCLES AND MOTILITYCo-author/Editor: Darren Campbell

Di vi s i on of Sports Medi ci ne,U.S Ai r Force Aca demy

The Ba s i c Components of Mus cl e

Exci ta ti on–Contra cti on Coupl i ng

Skel eta l Mus cl e

Ca rdi a c Mus cl e

Smooth Mus cl e

Energy Producti on a nd Us e i n Mus cl es

Mi crotubul e-Ba s ed Moti l i ty

Intermedi a te Fi l a ments

Nonmus cl e Cel l s

Revi ew Ques ti ons

OVERVIEW

Movement a nd i ts regul a ti on, on a mi cros copi c a nd/or ma cros copi c s ca l e, a re es s enti a l for huma n l i fe Mus cl e, compos ed of a cti n, myos i n,

a nd a va ri ety of s tructura l a nd regul a tory protei ns , i s one of the ma i n cel l /ti s s ue types i nvol ved i n thi s movement Skel eta l , ca rdi a c, a nd

s mooth mus cl es offer a coordi na ted a nd regul a ted mea ns to move the huma n body from pl a ce to pl a ce; i ntera ct wi th i ts s urroundi ngs ; keepnutri ents fl owi ng to a nd wa s te products fl owi ng from va ri ous cel l s ; or move nutri ents , bl ood, l ymph, a nd other mol ecul es Speci a l i zed protei ns

a nd the mea ns to provi de energy for thes e proces s es ha ve evol ved for pa rti cul a r ti s s ues a nd functi ons

Mi crotubul es wi th tubul i n, dynei n, a nd ki nes i n mol ecul es a nd a s s oci a ted s tructures s uch a s ci l i a , fl a gel l a , centri ol es , ba s a l bodi es ,

centromeres , a nd mi toti c s pi ndl es provi de a nother i mporta nt mecha ni s m for a va ri ety of cel l movements a nd i nterna l cel l functi ons tha t a ffect

a l l types of cel l s a nd a l l ow the di vi s i on of cel l s Intermedi a te fi l a ments (IFs ) a l s o s erve s evera l es s enti a l rol es of cel l moti l i ty Nonmus cl ecel l s uti l i ze a l l of thes e mecha ni s ms —a cti n/myos i n, mi crotubul e/dynei n/ki nes i n, a nd IFs —to a chi eve a wi de a rra y of functi ons throughoutthe huma n body

THE BASIC COMPONENTS OF MUSCLE

Mus cl e i s a n orga n tha t s peci a l i zes i n tra ns formi ng chemi ca l energy i nto mecha ni ca l work or movement The mus cul a r s ys tem compri s es a l lthe i ndi vi dua l a na tomi c mus cl es Mus cl e ti s s ue i s deri ved from the mes oderma l l a yer of embryol ogi c germ cel l s a nd i s di vi ded i nto three

ma i n types : s kel eta l mus cl e, ca rdi a c mus cl e, a nd s mooth mus cl e (Fi gure 12-1) The s tructure of thes e di fferent types of mus cl es i s s i mi l a r butthe a rchi tecture a nd regul a ti on a re often very di fferent, ma ki ng thei r functi ons uni que Nonmus cl e cel l s a re a fourth cel l type tha t uti l i zes

ma ny of the s a me protei ns a nd proces s es for moti l i ty

Figure 12-1 A–C The Three Types of Muscle Li ght mi crogra phs of ea ch type, a ccompa ni ed by l a bel ed dra wi ngs A Skel eta l mus cl e i s compos ed of

l a rge, el onga ted, mul ti nucl ea ted fi bers tha t s how s trong, qui ck, vol unta ry contra cti ons B Ca rdi a c mus cl e i s compos ed of i rregul a r bra nched cel l s bound together l ongi tudi na l l y by i nterca l a ted di s ks a nd s hows s trong, i nvol unta ry contra cti ons C Smooth mus cl e i s compos ed of

grouped, s pi ndl e-s ha ped cel l s wi th wea k, i nvol unta ry contra cti ons The dens i ty of i ntercel l ul a r pa cki ng s een refl ects the s ma l l a mount ofextra cel l ul a r connecti ve ti s s ue pres ent [Reproduced wi th permi s s i on from Mes cher AL: Junquei ra ’s Ba s i c Hi s tol ogy Text a nd Atl a s , 12thedi ti on, McGra w-Hi l l , 2010.]

There a re two ma jor protei ns i nvol ved i n contra cti on i n a l l types of mus cl e: actin a nd myosin Thes e protei ns convert chemi ca l energy i nto mecha ni ca l work through a n i ntera cti on wi th adenosine triphosphate (ATP) The tri ggeri ng a nd control of thi s proces s a re di fferent for ea ch mus cl e type Skel eta l , ca rdi a c, a nd s mooth mus cl es ha ve a repea ti ng uni t ca l l ed the sarcomere, conta i ni ng the mus cl e fi bers compos ed of a cti n

a nd myos i n a nd a cces s ory protei ns (s ee bel ow) Surroundi ng thes e mus cl e fi bers i s the equi va l ent of a pl a s ma membra ne ca l l ed the

sarcolemma Wi thi n the s a rcol emma i s the s a rcopl a s m conta i ni ng mi tochondri a a nd a sarcoplasmic reticulum (SR), the equi va l ent of a s mooth

endopl a s mi c reti cul um (SER) Li ke the SER i n other cel l types , the SR conta i ns ca l ci um i ons (Ca2+) es s enti a l for the i ni ti a ti on of mus cl e

a cti va ti on More s peci fi ca l l y, s peci a l i zed i nva gi na ti ons of the SR, ca l l ed transverse tubules (T-tubules), i nterdi gi ta te between the mus cl e fi bers

to provi de effi ci ent del i very of ca l ci um.

ACTIN The term actin des cri bes both the gl obul a r, s i ngl e a mi no a ci d (monomer) cha i n (G-actin) a nd the thin filament (F-actin) s tructure formed from two

pa ra l l el s tra nds of mul ti pl e G-a cti n mol ecul es , whi ch wi nd to form a doubl e hel i x s tructure (Fi gure 12-2A) Three ma jor cl a s s es of a cti n exi s t,

i ncl udi ng α-a cti n (found i n s kel eta l , ca rdi a c, a nd s mooth mus cl es ) a nd β- a nd γ-a cti ns (found i n nonmus cl e cel l s ) Thes e F-a cti n fi l a ments

provi de s tructure a s pa rt of the cel l ’s cytoskeleton The cytos kel eton i s a l s o di rectl y l i nked to the pl a s ma membra ne vi a i ntegra l membra ne

protei ns a nd i ntra cel l ul a r juncti ons (Cha pter 8) a nd, a s s uch, i s i mporta nt i n ma ny s i gna l i ng functi ons

Acti n thi n fi l a ments i ntera ct wi th myos i n thi ck fi l a ments (Fi gure 12-2C a nd s ee bel ow) a nd a re i ntegra l i n a mul ti tude of cel l moti l i tyfuncti ons , i ncl udi ng mus cl e contra cti on, the movement of i ntra cel l ul a r ves i cl es , cel l di vi s i on a nd cytoki nes i s , i mmune res pons e, pha gocytos i s ,wound hea l i ng, a nd others Acti n i s a l s o requi red i n the nucl eus for RNA pol ymera s e I, II, a nd III compl ex forma ti on a nd functi on, export ofRNA a nd protei ns from the nucl eus , a nd s ome a s pects of chroma ti n remodel i ng

Figure 12-2 A–C Molecules Composing Thin and Thick Filaments The contra cti l e protei ns a re the thi n a nd thi ck myofi l a ments wi thi n myofi bri l s A.

Ea ch thi n fi l a ment i s compos ed of F-a cti n, tropomyos i n, a nd troponi n compl exes B Ea ch thi ck fi l a ment cons i s ts of ma ny myos i n hea vy cha i n mol ecul es bundl ed together a l ong thei r rod-l i ke ta i l s , wi th thei r hea ds expos ed a nd di rected towa rd nei ghbori ng thi n fi l a ments C Bes i des

i ntera cti ng wi th the nei ghbori ng thi n fi l a ments , thi ck myofi l a ment bundl es a re hel d i n pl a ce by l es s wel l -cha ra cteri zed, myos i n-bi ndi ngprotei ns wi thi n the M-l i ne [Reproduced wi th permi s s i on from Mes cher AL: Junquei ra ’s Ba s i c Hi s tol ogy Text a nd Atl a s , 12th edi ti on, McGra w-

Hi l l , 2010.]

TROPOMYOSIN–TROPONINS Tropomyosin i s a regul a tory protei n tha t bi nds to F-a cti n thi n fi l a ments a nd revers i bl y bl ocks myos i n hea d bi ndi ng s i tes (Fi gure 12-2A–C) In

noncontra cti ng mus cl e, troponin T and troponin I mol ecul es (pa rt of a troponin compl ex, Fi gure 12-2A) hol d tropomyos i n over the myos i n-bi ndi ng

s i te Upon expos ure to Ca2+ rel ea s ed from the SR, troponin C, the thi rd protei n of the troponi n compl ex, crea tes a conforma ti ona l cha nge of the

tropomyos i n–troponi n compl ex expos i ng the s i te When ca l ci um concentra ti ons fa l l , the cha nge revers es a nd the bl ock i s a ga i n pres ent.Smooth mus cl e a nd nonmus cl e cel l s do not conta i n troponi n a nd rel y on other regul a tory proces s es to control a cti n–myos i n contra cti on/forcegenera ti on Troponi n C conta i ns a s peci fi c a mi no a ci d s equence na med a n EF ha nd In thi s terti a ry s tructure moti f (Cha pter 1), a n α-hel i x(termed E for i ts s equence i n a s eri es of α-hel i ces ) i s joi ned to a n F α-hel i x by a l oop of a pproxi ma tel y 12 a mi no a ci ds The hel i x–l oop–hel i xforms a s tructure remi ni s cent of a n extended forefi nger (E hel i x) a nd thumb (F hel i x) wi th the curve between repres enti ng the l oop Among the

12 a mi no a ci ds of the l oop a re pos i ti ons , 1, 3, 5, 7, 9, a nd 12, whi ch bi nd the Ca2+ Ami no a ci d 12 i s a l wa ys gl uta ma te or a s pa rta te whos e group provi des two pa rti a l l y nega ti vel y cha rged oxygen mol ecul es (Cha pter 1) for bi ndi ng the pos i ti vel y cha rged ca l ci um The s ma l l s i ze of a

R-hi ghl y cons erved gl yci ne a mi no a ci d a t res i due 6 provi des s pa ce for tR-hi s s tructure to form The other a mi no a ci ds a re ma i nl y hydrophobi c tha t

s ta bi l i ze the E a nd F hel i ces a nd, therefore, the hel i x– l oop–hel i x s tructure

MYOSIN The huma n genome hol ds more tha n 40 di fferent types of myosin genes Thes e di fferent genes produce va ri a ti ons of myos i n s ha pes , whi ch i n

turn a ffect the s peed a t whi ch the fi l a ments move To da te, there a re 12 cl a s s es of myos i n defi ned i n the huma n genome Al l myos i n

mol ecul es ha ve three doma i ns , i ncl udi ng a head, neck, a nd tail porti on of the a mi no a ci d s equence (Fi gure 12-3A) The myos i n hea d bi nds a cti nthi n fi l a ments a nd us es hydrol ys i s of ATP to a denos i ne di phos pha te (ADP) to genera te force The ta i l doma i n va ri es dependi ng on the type ofmyos i n but, i n genera l , ca n bi nd to tra ns port ves i cl es or combi ne wi th other myos i n mol ecul es Some myos i n ta i l doma i ns ca n a l s o regul a tethe protei ns ’ a cti vi ty by fol di ng over a nd effecti vel y bl ocki ng the myos i n hea d doma i n The neck doma i n s erves a s a l i nk or l ever a rm for thetra ns fer of thi s force between the hea d a nd ta i l The va ryi ng types of myos i n protei ns produce di fferent s peeds of movement, dependi ng on

the l ength of the neck regi on Four myosin light chains: two essential light chains, a nd two regulatory light chains a re a l s o bound to the neck regi ons

(Fi gure 12-3A) The functi on of thes e l i ght cha i ns i s di s cus s ed bel ow

Figure 12-3 A–C Myosin I and II A Basic Myosin Molecule The hea vy a nd l i ght cha i ns (es s enti a l –red, regul a tory–da rk bl ue) form the ba s i c

s tructure of a l l myos i n mol ecul es , i ncl udi ng the l ong ta i l compos ed of two coi l ed α-hel i ces a nd the gl obul a r hea d regi on B Myosin I Ves i cl es

for tra ns port a re a tta ched by the myos i n I ta i l s ecti on The s i ngl e hea d of myos i n I moves down the a cti n fi l a ment i n a s i mi l a r ma nner to othermyos i n hea ds Myos i n I mol ecul es ca n a l s o l i nk between F-a cti n fi l a ments , res ul ti ng i n l i mi ted moti l i ty s i mi l a r to myos i n II mol ecul es

[Ada pted wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l Publ i s hers (P) Ltd., 2009.] C Myosin II The ta i l s ecti on

of the two hea vy cha i ns of myos i n II forms a coi l ed-coi l a rra ngement Thi s s tructure ca n i ntera ct wi th s evera l other myos i n II ta i l s to form thi ck

fi l a ments The two hea d regi ons of ea ch myos i n mol ecul e conta i n a n a cti n-bi ndi ng s i te (red ci rcl e) a nd a n ATP-bi ndi ng s i te (bl ue l i ne).Coordi na ted movement of the myos i n hea ds produces force a nd, therefore, movement when i ntera cti ng wi th a cti n fi l a ments See text forfurther deta i l s [Ada pted wi th permi s s i on from Mes cher AL: Junquei ra ’s Ba s i c Hi s tol ogy Text a nd Atl a s , 12th edi ti on, McGra w-Hi l l , 2010.]

Myosin I i s the s i mpl es t form cons i s ti ng of a ba s i c myos i n hea d, neck, a nd a ta i l of va ryi ng l engths (Fi gure 12-3A–B) The ba s i c functi on of

myos i n I i s mos t often des cri bed a s ves i cl e tra ns port, a l though other functi ons a re emergi ng Myosin II i s compos ed of two i denti ca l a mi no

a ci d cha i ns , termed the “hea vy cha i ns ” (Fi gure 12-3A) The ta i l s ecti on of ea ch cha i n coi l s a round the other, ma ki ng a di mer myos i n fi l a ment

wi th two hea ds Mul ti pl e myos i n II di mers bi nd a t the ta i l doma i n, formi ng a s tructure ca l l ed a thick filament (Fi gures 12-2B–C a nd 12-3C).Addi ti ona l myos i n s ubtypes ha ve s tructures s i mi l a r to ei ther myos i n I or myos i n II a nd a re res pons i bl e for di vers e types of cel l moti l i ty Thes efuncti ons i ncl ude i ntra cel l ul a r tra ns port (both to a nd from the nucl eus to the cel l peri phery), ma i ntena nce a nd movement of ves i cl es a ndorga nel l es i n s ubregi ons of the cytopl a s m, a nd, pos s i bl y, the percepti on of l i ght i n the reti na a nd s ound wa ves i n the i nner ea r

MYOSIN LIGHT CHAINS

Ea ch myos i n hea d conta i ns two essential myosin light chains a nd two regulatory myosin light chains bound to the neck regi on (Fi gure 12-3A)

Di fferent forms of myos i n l i ght cha i n a re found on di fferent myos i n types a nd i nfl uence thei r a cti vi ty a nd regul a ti on Myos i n l i ght cha i ns s erve

a n i mporta nt regul a tory rol e for myos i n a cti vi ty i n s mooth a nd nonmus cl e cel l contra cti on where the tropomyos i n–troponi n mecha ni s m i s

a bs ent In s kel eta l mus cl e, the myos i n l i ght cha i ns i nfl uence the s peed of contra cti on but a re not es s enti a l for myos i n a cti vi ty In ca rdi a cmus cl e, myos i n l i ght cha i ns a ffect myos i n hea d ATPa s e a nd a re bel i eved to ha ve s ome rol e i n the devel opment of hea rt fa i l ure Acti vi ty of

myos i n i n s mooth/nonmus cl e cel l s rel i es on phos phoryl a ti on of s eri ne 19 on the regul a tory cha i ns by myosin light chain kinase (MLCK) MLCK

a cti vi ty i s regul a ted by Ca2+ tha t bi nds to the regul a tory protei n ca l modul i n, a l s o by a n EF ha nd-bi ndi ng moti f (s ee a bove) Ca l modul i n

s ubs equentl y a cti va tes MLCK When ca l ci um concentra ti ons fa l l , myosin light chain phosphatase (MLCP) removes the phos pha te group a nd

i na cti va tes the regul a tory l i ght cha i ns a nd, therefore, myos i n Ca l ci um a l s o i nhi bi ts MLCP by the a cti ons of a nother s eri ne/ threoni ne enzyme

ca l l ed Rho kinase; other s i gna l i ng pa thwa ys a nd enzymes ha ve a l s o been i mpl i ca ted i n myos i n l i ght cha i n phos phoryl a ti on a nd

dephos phoryl a ti on One enzyme, s phi ngos i ne-1-phos pha ta s e, ma y pl a y a n i mporta nt rol e i n modul a ti ng contra cti on a nd rel a xa ti on of bl oodves s el s a nd, therefore, ma i ntena nce of bl ood fl ow i n res pons e to cha nges i n bl ood pres s ure

ACTIN-BINDING PROTEINS Actin-binding proteins (ABPs) a re a va ri ed group of protei ns tha t regul a te a cti n fi l a ment forma ti on a nd l ength a s wel l a s a cti n–myos i n

i ntera cti ons Al though more promi nent i n non-mus cl e cel l a nd s mooth mus cl e contra cti on, s ome, i ncl udi ng tropomyos i n a nd the troponi ns

(s ee a bove), a re found i n s kel eta l a nd ca rdi a c mus cl es One s uch ABP, α-actinin bi nds a cti n thi n fi l a ments to s kel eta l mus cl e Z-l i nes a nd

s mooth mus cl e dens e bodi es (Fi gures 12-4 a nd 12-8A) α-Acti ni n i s a l s o bel i eved to bi nd to a cti n fi l a ment bundl es a nd s epa ra tes ea ch thi n

fi l a ment by a pproxi ma tel y 35 nm Thi s s epa ra ti on a l l ows myos i n thi ck fi l a ments the proper s pa ci ng for opti ma l contra cti on Addi ti ona l ABPs

cros s -l i nk thi n fi l a ments (filamin), s ever thi n fi l a ments (gelsolin, tropomodulin, a nd villin) a nd ca p them to res tri ct thei r l ength (capZ), regul a te

a cti n–tropomyos i n a cti vi ty i n s mooth mus cl e cel l s where troponi ns a re a bs ent (caldesmon), regul a te myos i n ATPa s e a cti vi ty (calponin), a nd connect mi crofi l a ments to the cel l membra ne (dystrophin, vinculin, a nd integrins) Ma ny other ABPs a l s o exi s t a nd perform other functi ons i n a

va ri ety of cel l types

Figure 12-4 Excitation–Contraction Coupling Acti n a nd myos i n form s a rcomere s tructures i n s kel eta l mus cl e a s s hown The i nfl ux of ca l ci um i ons

(Ca2+) a l l ows myos i n hea ds from thi ck fi l a ments to bi nd to the a cti n fi l a ments Ca2+ a l s o a cti va tes myos i n hea d cros s -bri dge cycl i ng, l ea di ng toforce genera ti on a nd, ul ti ma tel y, s horteni ng of the s a rcomere Shorteni ng of mul ti pl e s a rcomeres l ea ds to mus cl e contra cti on The proces s i s

s i mi l a r i n ca rdi a c a nd s mooth mus cl e contra cti on, a l though s tructura l orga ni za ti on a nd regul a ti on di ffer ADP, a denos i ne di phos pha te; ATP,

a denos i ne tri phos pha te [Reproduced wi th permi s s i on from Ki bbl e JD a nd Ha l s ey CR: The Bi g Pi cture: Medi ca l Phys i ol ogy, 1s t edi ti on, McGra

w-Hi l l , 2009.]

EXCITATION–CONTRACTION COUPLING

Mus cl e a chi eves i ts ma jor functi on of genera ti ng movement by contra cti on through a s eri es of bi ndi ng events a nd enzyma ti c rea cti ons Thi s

proces s i s ca l l ed excitation–contraction coupling (Fi gure 12-4) Certa i n pa rts of thi s mecha ni s m a re cons erved i n a l l types of a cti n–myos i n

contra cti on/moti l i ty, wherea s a l terna ti ve forms of i ni ti a ti on a nd/or regul a ti on a re found i n pa rti cul a r mus cl e types Ma ny of the components

a re s i mi l a r i n nonmus cl e cel l s , but ma ny di fferences exi s t beca us e of the va ri a ti ons i n orga ni za ti on a nd a ddi ti ona l protei ns a nd thei r

functi ons Nonmus cl e cel l contra cti on wi l l be di s cus s ed s epa ra tel y bel ow

Two ba s i c proces s es mus t ha ppen i n a l l mus cl e types for contra cti on to occur: (1) bi ndi ng of myos i n hea ds to the a cti n thi n fi l a ment a nd (2)

s ti mul a ti on of myos i n to genera te force Both of thes e proces s es rel y, a t l ea s t i n pa rt, on Ca2+ In a l l mus cl e types , a s i gna l from a nerve or

pa cema ker cel l s ca us es a n i ni ti a l i ncrea s e i n Ca2+ concentra ti ons Thi s rel a ti vel y s ma l l i nfl ux of Ca2+ l ea ds to a l a rger rel ea s e from the SR

Thi s concept of a s ma l l ca l ci um s i gna l l ea di ng to hi gher ca l ci um concentra ti ons a nd contra cti on i s termed calcium-induced calcium release (CICR).

The rel ea s e from the SR va ri es dependi ng on the type of mus cl e a nd i s di s cus s ed bel ow T-tubul es a l l ow del i very of thi s ca l ci um to a l l a rea s

of a mus cl e uni t to permi t s ynchronous contra cti on The rel ea s ed ca l ci um i ntera cts wi th a n ABP—troponi n/tropomyos i n i n s kel eta l a nd ca rdi a cmus cl e a nd ca l des mon i n s mooth mus cl e—to a l l ow myos i n hea d bi ndi ng to a cti n thi n fi l a ments

Myos i n force genera ti on i s the s econd ba s i c functi on requi red for contra cti on In a l l mus cl e types , ATP bi nds to the myos i n mol ecul e hea d

An ATPa s e on the myos i n hea d cl ea ves ATP i nto ADP a nd a phos pha te mol ecul e (PO43–), produci ng a cha rged form of the myos i n protei n tha t

bi nds to the now open F-a cti n fi l a ments a t a n a ngl e Rel ea s e of the phos pha te mol ecul e from the myos i n hea d ca us es i t to s wi vel to a more

a cute a ngl e, res ul ti ng i n a ra tcheti ng movement between i t a nd a cti n Thi s ra tcheti ng movement s l i des the thi ck a nd thi n fi l a ments pa s t ea chother, converti ng the chemi ca l energy of the ATP i nto the mecha ni ca l energy movi ng the fi l a ments Rel ea s e of the ADP mol ecul e a nd bi ndi ng of

a new ATP mol ecul e brea ks the bond between myos i n hea d a nd F-a cti n thi n fi l a ment As thi s proces s repea ts ma ny ti mes , the overa l l l ength

of the s a rcomere s hortens Ca l ci um a l s o pl a ys a promi nent rol e i n s mooth mus cl e myos i n a cti vi ty vi a a cti va ti on of regul a tory myos i n l i ghtcha i ns (s ee a bove)

The cycl e conti nues a s l ong a s the concentra ti on of ca l ci um i n the s a rcopl a s m of the cel l rema i ns el eva ted At the end of thi s proces s , the

ca l ci um entry i nto the cel l s s l ows a nd begi ns to be col l ected a ga i n by the SR by a sarco/endoplasmic reticulum Ca 2+ -ATPase pump, a l s o powered

by ATP The pump ca n produce a n a pproxi ma tel y 10,000-fol d hi gher concentra ti on i ns i de the SR vers us the s a rcopl a s m An a ddi ti ona l protei n

calsequestrin a l s o bi nds Ca2+ i ns i de the SR to reduce the effecti ve, free Ca2+ concentra ti on tha t the pump mus t work a ga i ns t Ca l s eques tri n ca n

bi nd over 40 Ca2+ per protei n mol ecul e not by a n EF ha nd s tructure but, i ns tea d, by us i ng cha rged a mi no a ci ds res i dues a nd cha nges of

s econda ry s tructure to α-hel i ces Once the ca l ci um concentra ti on l owers , ca l ci um i s rel ea s ed from troponi n C, the previ ous conforma ti ona lcha nge i s revers ed a nd troponi n T a nd I a ga i n bl ock the bi ndi ng of myos i n to the a cti n bi ndi ng s i te As the cycl e ends , a new mol ecul e of ATPthen bi nds to the myos i n hea d, whi ch di s pl a ces the ADP a nd the i ni ti a l s a rcomere l ength i s res tored

SKELETAL MUSCLESTRUCTURE AND GENERAL OVERVIEW

Skel eta l mus cl e compri s es the bul k of the mus cl e ma s s found i n our bodi es (Fi gure 12-5) The a vera ge a dul t ma l e i s ma de up of a pproxi ma tel y42% s kel eta l mus cl e a nd a n a vera ge a dul t fema l e cons i s ts of 36% s kel eta l mus cl e Ea ch mus cl e ha s a n ori gi n a nd i ns erti on on the s kel eton,

wi th the i ndi vi dua l mus cl e fi bers runni ng pa ra l l el or obl i que to the l ong a xi s of the mus cl e Skel eta l mus cl es a re ca pa bl e of produci ng aforceful contra cti on a nd movi ng the el ements of the mus cl e over a rel a ti vel y l a rge di s ta nce Wi th the s horteni ng of l ength duri ng the

contra cti on, thi s mus cl e wi l l often cha nge i n di a meter, l i ke the s wel l produced when contra cti ng the bi ceps mus cl e In s kel eta l mus cl e, the

F-a cti n thi n fi l F-a ments F-a re bound end to end F-a t F-a s tructure cF-a l l ed the Z-l i ne (Fi gure 12-4) The repea ted Z-l i nes a nd a l terna ti ng thi n a nd thi ck

fi l a ments gi ve the mus cl e the s tri a ted a ppea ra nce s een on l i ght mi cros copy