Ebook The big picture: Medical biochemistry: Par 1

(BQ) Part 1 book The big picture: Medical biochemistry presents the following contents: Amino acids and proteins, carbohydrates, lipids, nucleosides, nucleotides, DNA, and RNA; integrated usmle style questions and answer, enzymes and amino acid protein metabolism, carbohydrate metabolism, lipid metabolism, membranes, DNA/RNA function and protein synthesis.

Medi ci ne i s a n ever-cha ngi ng s ci ence As new res ea rch a nd cl i ni ca l experi ence broa den our knowl edge, cha nges i n trea tment a nd drugthera py a re requi red The a uthors a nd the publ i s her of thi s work ha ve checked wi th s ources bel i eved to be rel i a bl e i n thei r efforts toprovi de i nforma ti on tha t i s compl ete a nd genera l l y i n a ccord wi th the s ta nda rds a ccepted a t the ti me of publ i ca ti on However, i n vi ew ofthe pos s i bi l i ty of huma n error or cha nges i n medi ca l s ci ences , nei ther the a uthors nor the publ i s her nor a ny other pa rty who ha s been

i nvol ved i n the prepa ra ti on or publ i ca ti on of thi s work wa rra nts tha t the i nforma ti on conta i ned herei n i s i n every res pect a ccura te orcompl ete, a nd they di s cl a i m a l l res pons i bi l i ty for a ny errors or omi s s i ons or for the res ul ts obta i ned from us e of the i nforma ti on conta i ned

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contra i ndi ca ti ons for a dmi ni s tra ti on Thi s recommenda ti on i s of pa rti cul a r i mporta nce i n connecti on wi th new or i nfrequentl y us ed drugs

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Dedications

Acknowledgements

About the Authors

SECTION I: THE BASIC MOLECULES OF LIFE

CHAPTER 1 Ami no Aci ds a nd Protei ns

Overvi ew

Ami no Aci ds —Structure a nd Functi ona l Groups

Es s enti a l a nd Non-Es s enti a l

Tra ns port/Cha nnel Protei ns

Revi ew Ques ti ons

CHAPTER 2 Ca rbohydra tes

Overvi ew

Ba s i c Ca rbohydra te Structure a nd Functi on

Monos a ccha ri des a nd Di s a ccha ri des

Gl ycogen a nd Sta rches

Gl ycoprotei ns

Gl ycos a mi nogl yca ns

Revi ew Ques ti ons

Li pi d-Deri ved Hormones /Vi ta mi n D

Corti cos teroi ds (Adrena l Gl a nd)

Androgens (Tes tes ) a nd Es trogens (Ova ri es )

Vi ta mi n D

Revi ew Ques ti ons

CHAPTER 4 Nucl eos i des , Nucl eoti des , DNA, a nd RNA

Overvi ew

Nucl eos i des a nd Nucl eoti des

Components of Nucl eos i des a nd Nucl eoti des

Synthes i s of Puri ne Nucl eos i des a nd Nucl eoti des

Synthes i s of Pyri mi di ne Nucl eos i des a nd Nucl eoti des

Forma ti on of Deoxy Nucl eos i des a nd Nucl eoti des

Brea kdown of Puri nes a nd Pyri mi di nes

RNA a nd DNA—Ba s i c Structure a nd Functi on

RNA

DNA

Revi ew Ques ti ons

SECTION I: Integra ted USMLE-Styl e Ques ti ons a nd Ans wers

Ques ti ons

Ans wers

SECTION II: FUNCTIONAL BIOCHEMISTRY

CHAPTER 5 Enzymes a nd Ami no Aci d/Protei n Meta bol i s m

Ami no Aci d Meta bol i s m

Ami no Aci d Synthes i s

Ami no Aci d Degra da ti on

The Urea Cycl e

Revi ew Ques ti ons

CHAPTER 6 Ca rbohydra te Meta bol i s m

Overvi ew

Gl ycol ys i s

Ci tri c Aci d Cycl e

Oxi da ti ve Phos phoryl a ti on

Gl uconeogenes i s

The Pentos e Phos pha te Pa thwa y

Gl ycogen Synthes i s

Gl ycogen Brea kdown

Modi fi ed Ca rbohydra tes (Gl ycoprotei ns , GAGs )Revi ew Ques ti ons

CHAPTER 7 Li pi d Meta bol i s m

Overvi ew

Fa tty Aci d Meta bol i s m

Fa tty Aci d Synthes i s

Fa tty Aci d Degra da ti on

Meta bol i s m of Compl ex Li pi ds

Tri a cyl gl ycerol Synthes i s

Phos phogl yceri de Synthes i s

Ketone Body Synthes i s

Cera mi de/Sphi ngol i pi ds Synthes i s

Chol es terol Synthes i s

Revi ew Ques ti ons

CHAPTER 8 Membra nes

Overvi ew

Membra ne Structure

Li pi ds

Protei ns

Membra ne Functi ons

Membra ne Cha nnel s

Membra ne Si gna l i ng

Revi ew Ques ti ons

CHAPTER 9 DNA/RNA Functi on a nd Protei n Synthes i s

Overvi ew

Structure of the Nucl eus

Hi s tones

Nucl ea r Ma tri x/Sca ffol d

Nucl eol us a nd Ri bos ome Synthes i s

DNA Repl i ca ti on a nd Tra ns cri pti on

Muta ti ons a nd Repa i r Mecha ni s ms

Regul a ti on of Cel l Growth a nd Di fferenti a ti onRevi ew Ques ti ons

SECTION II: Integra ted USMLE-Styl e Ques ti ons a nd Ans wers

Ques ti ons

Ans wers

SECTION III: APPLIED BIOCHEMISTRY

CHAPTER 10 Meta bol i s m a nd Vi ta mi ns /Mi nera l s

Co-authors/Editors: Maria L Valencik and Cynthia C Mastick

Revi ew Ques ti ons

CHAPTER 11 The Di ges ti ve Sys tem

Editor: Kshama Jaiswal

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

La rge Intes ti ne/Anus

Revi ew Ques ti ons

CHAPTER 12 Mus cl es a nd Moti l i ty

Co-author/Editor: Darren Campbell

Acti n-Bi ndi ng Protei ns

Exci ta ti on–Contra cti on Coupl i ng

Skel eta l Mus cl e

Structure a nd Genera l Overvi ew

Skel eta l Mus cl e Types

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

CHAPTER 13 Connecti ve Ti s s ue a nd Bone

Editor: Jacques Kerr, BSc, MB, BS, FRCS, FCEM

Ma rkers of Bone Forma ti on a nd Res orpti on

Revi ew Ques ti ons

CHAPTER 14 Bl ood

Co-authors/Editors: Matthew Porteus, MD, PhD and Tina Mantanona

Overvi ew

Ba s i c Components of Bl ood

Red Bl ood Cel l (RBC) Functi ons

Di s ea s es As s oci a ted wi th Ina dequa te Synthes i s of Hemogl obi n Components

The Fi bri n Mes hwork

Di fference between Pl a tel et Pl ug Forma ti on a nd Cl ot Forma ti on

Regul a ti on of Cl ot Forma ti on

Pl a s mi n a nd Cl ot Di s s ol uti on

Revi ew Ques ti ons

CHAPTER 15 The Immune Sys tem

Editor: Eric L Greidinger, MD

Compl ement s ys tem

Hypers ens i ti vi ty Rea cti ons

Revi ew Ques ti ons

CHAPTER 16 The Ca rdi ova s cul a r Sys tem

Editor: Ralph V Shohet, MD

Overvi ew

Ca rdi a c Mus cl e Structure a nd Functi on

Si noa tri a l a nd Atri oventri cul a r Nodes

The Ca rdi a c Cycl e

Bi ochemi ca l Mecha ni s ms As s oci a ted wi th Hea rt Atta ck

Revi ew Ques ti ons

CHAPTER 17 The Res pi ra tory Sys tem

Editor: Howard J Huang, MD

Overvi ew

Ba s i c Ana tomy a nd Devel opment

Pul mona ry Surfa cta nt a nd the Devel opi ng Lung

O2–CO2 Excha nge i n the Lung a nd Aci d–Ba s e Ba l a nce

Noni nfecti ve Di s ea s es of the Res pi ra tory Sys tem

Obs tructi ve Di s ea s es —Emphys ema

Obs tructi ve Di s ea s es —Bronchi ti s

Obs tructi ve Di s ea s es —As thma

Bi ochemi ca l Ba s i s of As thma Medi ca ti ons

Res tri cti ve Di s ea s es —Acute Res pi ra tory Di s ea s e SyndromeRes tri cti ve Di s ea s es —Occupa ti ona l Expos ures

Res tri cti ve Di s ea s es —Inters ti ti a l Lung Di s ea s es

Infecti ve Di s ea s es of the Res pi ra tory Sys tem

Revi ew Ques ti ons

CHAPTER 18 The Uri na ry Sys tem

Editor: Armando J Lorenzo, MD, MSc, FRCSC, FAAP Overvi ew

Ba s i c Ana tomy a nd Phys i ol ogy

Rena l Fi l tra ti on

The Rena l Corpus cl e

Nephron

Inul i n/Crea ti ni ne Cl ea ra nce

Reni n–Angi otens i n–Al dos terone Sys tem (RAAS)

Reni n a nd Bl ood Pres s ure

Ma cul a Dens a a nd Bl ood Fl ow/Os mol a ri ty

Angi otens i nogen/Angi otens i n I a nd II

Al dos terone

Va s opres s i n

Atri a l Na tri ureti c Pepti de (ANP)

Aci d–Ba s e Ba l a nce

NH3 a nd Aci d–Ba s e Ba l a nce

Syntheti c Functi ons

Synthes i s of Erythropoi eti n

Rol e i n Vi ta mi n D Synthes i s

Revi ew Ques ti ons

CHAPTER 19 The Nervous Sys tem

Editor: Kathryn Beck-Yoo, MD

Overvi ew

Components of the Nervous Sys tem

Nerve Impul s e Conducti on

Neuron a t Res t

Nerve Impul s e

Repol a ri za ti on

Autonomi c Nervous Sys tem

Sympa theti c Nervous Sys tem

Pa ra s ympa theti c Nervous Sys tem

Neurotra ns mi tters

Dopa mi ne

NE/Epi nephri ne

Serotoni n

Acetyl chol i ne (Ach)

Regul a ti on of Ca techol a mi nes

Gl yci ne, Gl uta ma te, a nd GABA

Neuropepti des

Bi ochemi s try of Vi s i on

Anes thes i a

Revi ew Ques ti ons

CHAPTER 20 The Reproducti ve Sys tem

Editor: Catrina Bubier, MD

Overvi ew

Ba s i c Ana tomy a nd Devel opment

Fema l e Reproducti ve Sys tem

The Mens trua l Cycl e

Mens trua ti on (Da ys 1–4)

Fol l i cul a r/Prol i fera ti ve Pha s e (Da ys 5–13)

The Lutea l /Secretory Pha s e (Da ys 15–28)

Ferti l i za ti on

Brea s t Devel opment a nd La cta ti on

Oxytoci n

Prol a cti n

Ma l e Reproducti ve Sys tem

Tes tos terone

FSH a nd LH

Revi ew Ques ti ons

SECTION III: Integra ted USMLE-Styl e Ques ti ons a nd Ans wers

Ques ti ons

Ans wers

SECTION IV: APPENDICES

APPENDIX I: Bi ochemi ca l Ba s i s of Di s ea s es

Contributing Editor: Harold Cross, MD, PhD

Ami no Aci d Synthes i s /Degra da ti on

Ami no Aci d Tra ns port

Urea Cycl e Di s orders

Structura l Protei ns

Ca rbohydra tes

Gl ycogen Stora ge

Mi tochondri a l Enzymes (Excl udi ng Urea Cycl e a nd Fa tty Aci d Oxi da ti on)

Li pi ds a nd Fa tty Aci d Oxi da ti on Errors

Nucl eoti de Meta bol i s m

Defecti ve DNA

Bi l i rubi n Meta bol i s m

Bl ood Cl otti ng Fa ctor Defects

Steroi d Hormone Synthes i s

Vi ta mi ns /Mi nera l s a nd El ectrol ytes

APPENDIX II: Bi ochemi ca l Methods

Pol ya cryl a mi de Gel El ectrophores i s (PAGE) [Sodi um Dodecyl Sul fa te (SDS)/Non-SDS]Immunoa s s a ys

RIA

ELISA or EIA

Chroma togra phy

Thi n La yer (Pa per) Chroma togra phy (TLC)

Col umn Chroma togra phy

Gel Fi l tra ti on Chroma togra phy

Ion-Excha nge Chroma togra phy

Affi ni ty Chroma togra phy

Hi gh-Performa nce/Pres s ure Li qui d Chroma togra phy (HPLC)

Protei n a nd Deoxyri bonucl ei c Aci d (DNA)/Ri bonucl ei c Aci d (RNA) Preci pi ta ti onDNA a nd RNA Sequenci ng

Southern, Northern, a nd Wes tern Bl ots

Hydroxyl Group (—OH−)

Ca rboxyl Group (—COOH)

Ami ne Group (—NH2)

Phos pha te Group (PO3 a nd PO4)

Sul fur–Sul fur Bonds (—S—S—)

Al dehyde Group (—COH)

Summa ry

Index

To my fa mi l y: my dea r wi fe, Meryl , who ha s unfa i l i ngl y s upported my profes s i ona l endea vors a nd endured my countl es s eveni ng hours a t thecomputer on thi s project; my da ughters , Rebecca , La ura , a nd Mi ri a m, who bri ng me i ncredi bl e “na ches ”; my mother a nd fa ther (ma y they res t i npea ce) for thei r s upport i n my forma ti ve yea rs ; my brothers Howa rd a nd Ma tthew; my mother-i n-l a w Ma rtha for her ever-pres ent a ccol a des ; my

fa ther-i n-l a w Ed (ma y he res t i n pea ce); a nd my fa ther-i n-l a w Lou for the profes s i ona l res pect a l wa ys a ccorded me

Fi na l l y to the more tha n 3000 medi ca l s tudents I ha ve ta ught who i ns pi red my s ucces s a s a tea cher a nd educa tor a nd who preceded thos e

s tudents who I trus t wi l l benefi t from thi s textbook

— Ma rc E Ti s chl er

To my pa rents , fa mi l y, a nd fri ends who pers evered throughout the wri ti ng, proofi ng, a nd publ i ca ti on of thi s book a s wel l a s the ma ny

i ns tructors , from hi gh s chool to uni vers i ty to gra dua te s chool to medi ca l s chool a nd beyond, who i ns ti l l ed i n me not onl y a l ove for l ea rni ng

but a l s o for tea chi ng

Thi s book i s pers ona l l y dedi ca ted to one s uch pers on, Ca s s i e Murphy-Cul l en, PhD (ma y s he res t i n pea ce), who s erved a s a tea cher, couns el or

a nd, mos t-of-a l l , cons ta nt a nd dedi ca ted fri end to a l l of her s tudents , i ncl udi ng mys el f

— Lee W Ja ns on

Si ncere tha nks to the current a uthors of Ha rper’s Il l us tra ted Bi ochemi s try for thei r revi ews a nd comments wi th s peci a l tha nks to Dr RobertMurra y, edi tor of Ha rper’s , for hi s pa ti ence, ki ndnes s , a nd excepti ona l efforts i n revi ewi ng thi s book The a uthors a l s o wi s h to tha nk AndreaAgui rre, Chi neyne Ana ko, Ma rti n Benja mi n, Na ta s ha Bhuya n, Jos eph Ca rrol l , Ka tha ri ne Fl a nnery, Si l vi ja Gottes ma n, Mi cha el Ori , Cha rl es

Ra ppa port, Chri s topher Ri l ey, Al a n Schuma cher, a nd Ka ren Stern, medi ca l s tudents a t the Uni vers i ty of Ari zona , who s erved on a focus group toprovi de va l ua bl e i ns i ght for thi s text from a medi ca l s tudent pers pecti ve

ABOUT THE AUTHORS

Ma rc E Ti s chl er recei ved a n undergra dua te degree i n bi ol ogy from Bos ton Uni vers i ty, a ma s ter degree i n chemi s try from the Uni vers i ty of South

Ca rol i na , a nd hi s doctora te degree i n bi ochemi s try from the Uni vers i ty of Penns yl va ni a After s ervi ng i n a pos tdoctora l pos i ti on i n phys i ol ogy

a t Ha rva rd Medi ca l School , he joi ned the fa cul ty a t the Uni vers i ty of Ari zona i n 1979 where he i s currentl y a profes s or of bi ochemi s try a ndmol ecul a r bi ophys i cs hol di ng joi nt a ppoi ntments i n phys i ol ogy a nd i n i nterna l medi ci ne Ha vi ng s erved a s coordi na tor of the medi ca l

bi ochemi s try cours e for a deca de, he wa s recrui ted to pl a y a ma jor rol e i n the devel opment of the revi s ed medi ca l curri cul um a t the Uni vers i ty

of Ari zona , whi ch debuted i n 2006 a nd offers a n i ntegra ted, orga n-ba s ed a pproa ch a ki n to the s econd ha l f of thi s textbook In tha t newcurri cul um, he des i gned a nd s erves a s di rector of the medi ca l bl ock enti tl ed Di ges ti on, Meta bol i s m, a nd Hormones He ha s ta ught more tha n

3000 medi ca l s tudents duri ng hi s tenure i n Ari zona

Lee W Ja ns on recei ved a BS i n Bi ochemi s try/mi nor i n La ti n from the Uni vers i ty of Roches ter fol l owed by a PhD i n bi ol ogi ca l

s ci ences /bi ochemi s try from Ca rnegi e Mel l on Uni vers i ty After a pos tdoctora l fel l ows hi p a t NASA-Johns on Spa ce Center doi ng res ea rch on

i mmunol ogi ca l a cti va ti on i n mi crogra vi ty, he entered medi ca l s chool a t the Uni vers i ty of Texa s Southwes tern Medi ca l Center a t Da l l a s ,conti nui ng wi th a fa mi l y pra cti ce res i dency i n both Da l l a s a nd Sa n Antoni o He entered the a cti ve duty Ai r Force a nd s erved a s a fa mi l yphys i ci a n a nd a fl i ght s urgeon, i ncl udi ng tours of Korea , Ira q, a nd Afgha ni s ta n After mi l i ta ry s ervi ce, he perma nentl y moved to Edi nburgh,Scotl a nd i n 2007, where he pra cti ces i n the Na ti ona l Hea l th Servi ce a s a n emergency room doctor a nd a genera l phys i ci a n i n the Uni ted

Ki ngdom wi th occa s i ona l work i n Aus tra l i a a nd other pa rts of the worl d In hi s free ti me, he wri tes a nd does res ea rch Pa s t book publ i ca ti ons

i ncl ude Brew Chem 101: The Basics of Home-brewing Chemistry (Storey Publ i s hi ng).

SECTION I

THE BASIC MOLECULES OF LIFE

CHAPTER 1 AMINO ACIDS AND PROTEINS

Ami no Aci ds —Structure a nd Functi ona l Groups

Ba s i c Protei n Structure

Ca tegori es of Protei ns

Revi ew Ques ti ons

OVERVIEW

Ami no a ci ds a re the ba s i c bui l di ng bl ocks of protei ns a nd s erve a s bi ol ogi ca l mol ecul es i n thei r own ri ght wi th a va ri ety of functi ons Ami no

a ci ds a re often ca tegori zed a s es s enti a l or non-es s enti a l , dependi ng on the a bi l i ty of the body to ma nufa cture ea ch a mi no a ci d vers usrequi rement for i nges ti on i n the di et Al though s evera l hundred a mi no a ci ds exi s t, 20 pl a y the predomi na nt rol e i n the huma n body Ea ch

a mi no a ci d ha s a cha ra cteri s ti c R-group tha t determi nes i ts chemi ca l na ture a nd, therefore, how i t wi l l i ntera ct wi th other a mi no a ci ds , othermol ecul es , a nd wi th i ts envi ronment

Ami no a ci ds l i nk together vi a pepti de bonds to form pepti des a nd protei ns Thes e pepti des a nd protei ns fol d i nto thei r fi na l

three-di mens i ona l s ha pe a s the res ul t of hydrophobi c, hydrophi l i c, hydrogen bonthree-di ng, a nd i oni c bonthree-di ng forces (a mong others ) tha t res ul t from the

a mi no a ci ds i n the pepti de cha i n, i ncl udi ng the cha ra cteri s ti cs of thei r R-groups Protei ns ma y be ca tegori zed a s enzymes , s tructura l protei ns ,motor protei ns , a nd tra ns port/cha nnel protei ns The s peci fi c rol es of a mi no a ci ds a nd protei ns i n the s ynthes i s of other mol ecul es a nd i n thefuncti ons of orga n s ys tems a nd the huma n bodi es wi l l be expl ored i n deta i l i n s ubs equent cha pters

AMINO ACIDS—STRUCTURE AND FUNCTIONAL GROUPS

ESSENTIAL AND NON-ESSENTIAL Amino acids a re the ba s i c bui l di ng bl ocks of protei ns Twenty a mi no a ci ds ma ke up protei ns i n l i vi ng orga ni s ms ; s evera l hundred more a mi no

a ci ds perform s peci a l i zed functi ons i n huma n a nd non-huma n bi ol ogy Ami no a ci ds a re often des cri bed a s

Essential (mus t be obta i ned di rectl y from food)

Non-essential (the huma n body i s a bl e to produce them on i ts own).

There i s s ome deba te a bout the exa ct defi ni ti ons of thes e terms , but 8–10 a mi no a ci ds a re us ua l l y deemed es s enti a l a nd 10–12 a re

non-es s enti a l (s ee Ta bl e 1-1)

TABLE 1-1 Ami no Aci ds —R-Group Cl a s s i fi ca ti ons

Succota s h, a combi na ti on of corn a nd l i ma bea ns , wa s us ed by Na ti ve Ameri ca n hunters a nd wa rri ors Li ght i n wei ght, ea s y to ca rry, a nd

s i mpl e to prepa re, s uccota s h conta i ns a l l the es s enti a l requi red a mi no a ci ds needed by huma ns a nd kept thes e tra vel ers wel l nouri s hed

a nd hea l thy duri ng l ong tri ps a wa y from thei r s ettl ements

Figure 1-1 Basic Structure of an Amino Acid A central alpha (α) carbon is bonded to an amino group (NH 2 ), a carboxyl group (COOH), and an R group.

[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.]

CHARACTERISTICS OF R-GROUPS

As a mi no a ci ds a re i denti ca l except for thei r R-group, four R-group cha ra cteri s ti cs cl a s s i fy the a mi no a ci ds (s ee a l s o Ta bl e 1-1)

1 Hydrophobic (Water Hating) R-groups: Thes e a mi no a ci ds prefer to be i ns i de a fol ded protei n or covered by a nother pa rt of a protei n or a l i pi d

membra ne (Cha pter 8) where they a re hi dden from the externa l wa ter envi ronment

2 Hydrophilic (Water Loving) R-groups: Wi th pa rti a l cha rges from the hydroxyl (OH−) or a mi no (NH3) pa rts of thes e R-groups , thes e a mi no a ci dsprefer to be a t or nea r the s urfa ce of a protei n where they i ntera ct wi th s urroundi ng wa ter mol ecul es An excepti on woul d be the s urfa ceporti on of a membra ne protei n tha t i ntera cts wi th the hydrophobi c regi on of the phos phol i pi d bi l a yer (Cha pter 8) Hydrophi l i c R-groups a reoften i mporta nt a t the a cti ve s i te of a n enzyme (Cha pter 5)

3 Charged R-groups: Ei ther pos i ti vel y or nega ti vel y cha rged, thes e a mi no a ci ds prefer to be a t the s urfa ce of a fol ded protei n or i n conta ct wi th

other cha rged a toms /mol ecul es

4 Special R-groups: There a re four a mi no a ci ds wi th s peci a l qua l i ty R-groups

• Prol i ne ha s a gl uta ma te R-group tha t ha s bonded onto i ts el f (s ee Fi gure 1-2A) formi ng a n “i mi no” a ci d Prol i ne i s often found a t s ha rpturns of fol ded protei ns (Fi gure 1-2B)

Figure 1-2 A–B Proline A Prol i ne forms from the a mi no a ci d gl uta ma te when the a mi no group ni trogen (bl ue) crea tes a bond wi th ca rbon 2 on

the R-group (red), ma ki ng a n a mi no a ci d tha t i s “fol ded” onto i ts el f The ca rbon a toms a re i ndi vi dua l l y numbered to a l l ow the rea der to fol l ow

the proces s tha t ta kes three s teps (i ndi ca ted by a rrows ) B Prol i ne’s s peci a l s tructure a l l ows the forma ti on of a “ha i rpi n” β-turn vi a forma ti on

of a n i mi no bond The a mi no group from prol i ne i s s ha ded i n bl ue [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.]

• Cys tei ne ha s a s ul fhydryl group tha t ca n bond wi th a nother cys tei ne s ul fhydryl group to form a cys ti ne “di s ul fi de” bond (Fi gure 1-3) Thi sbond ca n be ei ther wi thi n one protei n or between two di fferent protei ns a nd i s i mporta nt i n ma ki ng s trong s tructures s uch a s the protei nkera ti n found i n fi ngerna i l s

Figure 1-3 Formation of Cystine Disulfide Bond The s ul fhydryl groups (SH) from two cys tei ne a mi no a ci d res i dues from di fferent pa rts of a s i ngl e

or two s epa ra te a mi no a ci d s equences ma y l os e one hydrogen a tom ea ch to become a cys ti ne res i due by the forma ti on of a di s ul fi de bond (S

—S) [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.]

• Methi oni ne ha s a s ul fur a tom conta i ned wi thi n i ts R-group Al though i t does not ma ke di s ul fi de bonds , thi s s ul fur i s s een a t the s i te of

s ome enzyme rea cti ons or a t s peci a l a rea s of protei n s tructure

• Hi s ti di ne ha s a uni que i mi da zol e ri ng conta i ni ng two ni trogen a toms , whi ch ca n be uncha rged or pos i ti vel y cha rged Thi s uni que

cha ra cteri s ti c ma kes the hi s ti di ne R-group i mporta nt i n enzyme rea cti ons tha t ma ke or brea k bonds

Hair and Cystine Double Bonding: Ha i r, whi ch i s compos ed of l i nea r protei n s equences , i s curl y or s tra i ght dependi ng on the number of cys ti ne

di s ul fi de bonds The number a nd l oca ti on of cys tei ne res i dues a nd a cces s ory protei ns s peci fi c for ea ch pers on a ffect the number of

di s ul fi de bonds res ul ti ng i n thi s very i ndi vi dua l i zed cha ra cteri s ti c Chemi ca l s tha t promote thes e di s ul fi de bonds a re us ed for “perms ” a nd,

a l terna ti vel y, chemi ca l s tha t brea k thes e bonds a re us ed i n ha i r s tra i ghteni ng trea tments

BASIC PROTEIN STRUCTURE

Severa l fa ctors a ffect ba s i c protei n s tructure, i ncl udi ng the fol l owi ng:

Amino Acid Composition: Whether the R-group of ea ch a mi no a ci d wa nts to be a wa y from, nea r, or i n conta ct wi th wa ter a t the s urfa ce of the

fol ded protei n

Special Amino Acids: Prol i ne, cys tei ne, a nd/or methi oni ne exert effects on protei n fol di ng due to res ul ti ng bends a nd di s ul fi de bonds

Functional Sites: Structura l protei ns or protei ns tha t ca ta l yze a rea cti on (i e., enzymes ; Cha pter 5) us ua l l y conta i n s peci fi c a mi no a ci ds tha t a re

i mporta nt for tha t protei n’s pa rti cul a r functi on The R-groups a t thes e s i tes wi l l a ffect the protei n’s fi na l fol ded s ha pe

Final Modifications: Mos t protei ns a re i ni ti a l l y ma de wi th extra a mi no a ci ds a t thei r begi nni ng a nd/or end Thes e extra a mi no a ci ds ma y be

modi fi ed or removed duri ng the ma tura ti on of the protei n, res ul ti ng i n cha nges to the fi na l s tructure

Final Destination: Whether the protei n wi l l end up i n a n a queous s ol uti on or i n a membra ne wi l l a l s o cha nge the fol di ng, a s protei ns tha t go

to membra nes wi l l ul ti ma tel y wa nt thei r hydro-phobi c, “wa ter ha ti ng” R-groups on the outs i de i n conta ct wi th the hydrophobi c membra ne(s ee bel ow, Cha pter 8)

LEVELS OF PROTEIN STRUCTURE

When des cri bi ng protei n s tructure, we us e the fol l owi ng terms : pri ma ry (1°), s econda ry (2°), terti a ry (3°), a nd/or qua terna ry (4°) s tructure

Primary (1°) Structure: The pa rti cul a r s equence of a mi no a ci ds i n a protei n (a l s o ca l l ed a polypeptide) i s termed a s primary structure The a mi no

a ci ds wi thi n a pol ypepti de a re termed residues a nd a re l i nked vi a peptide bonds (Fi gure 1-4A), formed when the ca rboxyl i c a ci d group of one

a mi no a ci d i ntera cts wi th the a mi no group of a s econd a mi no a ci d The combi na ti on produces the pepti de bond a nd one mol ecul e of wa ter.Repea ted pepti de bonds form a cha i n of pepti de bond l i nka ges wi th the ni trogen from the a mi no group, the centra l ca rbon from the a mi no

a ci d, a nd the ca rbon from the ca rboxyl i c a ci d formi ng the protei n “ba ckbone.” The pri ma ry s tructure i s often s hown a s “bea ds on a s tri ng”

wi th ea ch bea d repres enti ng a n a mi no a ci d res i due (Fi gure 1-4B)

Figure 1-4 A Formation of a Peptide Bond A pepti de bond i s formed between the ca rboxyl i c a ci d (COOH) group a nd the a mi no ni trogen (HHN)

group to form a new C—N bond The proces s rel ea s es one mol ecul e of wa ter (OH a nd H a s s hown i n pi nk ci rcl e) By conventi on a protei n i s

a l wa ys dra wn s ta rti ng wi th the N-termi nus on the l eft [Reproduced wi th permi s s i on from Ba rrett KE, et a l : Ga nong’s Revi ew of Medi ca lPhys i ol ogy, 23rd edi ti on, McGra w-Hi l l , 2010.] B Primary (1°) Structure The pri ma ry s tructure of a protei n i s the cha i n of a mi no a ci ds from the N-

termi na l (NH2 group of a mi no a ci d 1) to i ts C-termi na l end (COOH group of the fi na l a mi no a ci d) Indi vi dua l a mi no a ci ds a re denoted a s green

“bea ds ” a nd bonds a re red “s tri ngs ” i n thi s s tyl i zed repres enta ti on Protei ns va ry grea tl y i n l ength from a few a mi no a ci ds to s evera l hundred.[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.]

Secondary (2°) Structure: From the l i nea r cha i n of a mi no a ci ds , the C—N a nd C—C bonds rota te a round the centra l ca rbon a tom (s ee Fi gure 1-1) Thi s rota ti on forms secondary structures (Fi gure 1-5A–C) ca l l ed a n α-helix, β-strand, or β-turn (s ee a l s o Fi gure 1-2B a bove) dependi ng on the

hydrophi l i c a nd hydrophobi c cha rge a nd s i ze i nfl uences of the R-groups a s wel l a s hydrogen a nd i oni c bondi ng Pa rts of the pepti de tha t donot form conventi ona l s econda ry s tructures a re referred to a s “ra ndom coi l ”

Figure 1-5 A–C Secondary (2°) Structure A The α-hel i x s tructure i s s ta bi l i zed by hydrogen bonds (bl ue dotted l i ne) between the N—H of one

a mi no a ci d a nd the of a nother a mi no a ci d The hydrophobi c a nd hydrophi l i c na ture of the R-groups from ea ch a mi no a ci d i n the hel i x

a l s o pl a ys a pa rt i n forma ti on of the α-hel i x B The β-s tra nds form when the one s equence of s ucces s i ve a mi no a ci ds form hydrogen bonds

between the N—H a nd the C═O of a nother group of s ucces s i ve a mi no a ci ds R-groups of thes e a mi no a ci ds a l s o i nfl uence the forma ti on of

β-s tra ndβ-s by both cha rge a nd β-s teri c forceβ-s β-Stra ndβ-s ca n be ei ther pa ra l l el (l eft) or a nti pa ra l l el (ri ght) a β-s noted by the a rrowβ-s C A β-turn formβ-s

a t the juncture between two a nti pa ra l l el β-s tra nds a nd us ua l l y i nvol ves a mi no a ci ds wi th s ma l l R-groups , i ncl udi ng gl yci ne, a l a ni ne, a nd

va l i ne β-turns ca n a l s o form vi a prol i ne’s uni que s tructure (Fi gure 1-2B) [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.]

Tertiary (3°) Structure: Seconda ry s tructure a nd the rema i ni ng a mi no a ci d s equences conti nue to fol d a nd i ntera ct wi th other pa rts of the a mi no

a ci d s equence to form terti a ry (3°) s tructure Thes e proces s es a ga i n a re dri ven by hydrophobi c a nd hydrophi l i c forces of the i ndi vi dua l pa rts

of the s equence, a s wel l a s hydrogen bondi ng a nd i oni c bondi ng between cha rged a mi no a ci d R-groups In pa rti cul a r, R-groups a nd the

pa rti a l pos i ti ve cha rge of the ni trogen a nd nega ti ve cha rge of oxygen (OH− a nd C═O−) mol ecul es often form hydrophi l i c a nd hydrophobi c

“s i des ” of the α-hel i x or β-s tra nd As a res ul t, thes e s econda ry s tructures wi l l pos i ti on thems el ves wi th ea ch other a nd wi th other s i mi l a r

a rea s of the fol ded protei n to keep thei r hydrophobi c a rea s a wa y from a nd thei r hydrophi l i c a rea s expos ed to the externa l wa ter

envi ronment Exa mpl es a re s hown i n Fi gure 1-6 Addi ti ona l l y, terti a ry s tructure s ta rts to devel op a t a cti ve s i tes of protei ns where cri ti ca l

a cti ons a nd i ntera cti ons wi l l ta ke pl a ce Thes e a cti ve s i tes wi l l be di s cus s ed i n s ubs equent cha pters

Figure 1-6 Examples of Tertiary (3°) Structure Seconda ry s tructures , i ncl udi ng α-hel i ces , β-s heets , β-turns /bends , a nd l oop regi ons combi ne to

form terti a ry s tructure doma i ns Severa l common forms of terti a ry s tructure ha ve been cha ra cteri zed a nd a re i l l us tra ted i n the fi gure

[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.]

Globular vs Fibrous Proteins: Protei ns a re often grouped i nto the broa d ca tegori es of “gl obul a r”—ha vi ng a n a pproxi ma tel y s pheri ca l

three-di mens i ona l s ha pe—or “fi brous ”—bei ng l ong a nd fa i rl y s tra i ght overa l l A va s t ma jori ty of protei ns a re gl obul a r, wi th fi brous protei ns often

pl a yi ng s tructura l or very s peci a l i zed functi ona l rol es Exa mpl es of fi brous protei ns i ncl ude a cti n, col l a gen, a nd kera ti n, whi ch pl a y

s tructura l rol es i n mus cl e, connecti ve ti s s ue, a nd s ki n/na i l s

Quaternary (4°) Structure: Al though ma ny protei ns a re ma de of onl y one pepti de cha i n (ca l l ed “monomers ” or “s ubuni ts ”), two or more fol ded cha i ns ma y combi ne together to ma ke a fi na l a cti ve “ol i gomer” protei n The s ubuni ts i n a mul ti meri c protei n ma y ha ve i denti ca l (homo- oligomer) or di fferent (hetero-oligomer) a mi no a ci d s equences a nd i ntera ct to opti mi ze hydrophobi c a nd hydrophi l i c a rea s a nd hydrogen/ i oni c

bondi ng The combi na ti on of the mul ti pl e protei n s ubuni ts ma kes qua terna ry (4°) s tructure (Fi gure 1-7)

Figure 1-7 Quaternary (4°) Structure Protei n monomers ma y joi n, hel d together by hydrogen bondi ng (s hown) a nd/or hydrophobi c–hydrophi l i c

i ntera cti ons , to ma ke ol i gomers Identi ca l protei n s ubuni t monomers ma y joi n together to ma ke a homo-ol i gomer Noni denti ca l protei n

s ubuni t monomers ma y joi n together to ma ke a hetero-ol i gomer [Reproduced 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.]

The proces s of protei n fol di ng i s not a trul y l i nea r one; a protei n never exi s ts a s a l ong a mi no a ci d s tri ng Ins tea d, protei n fol di ng i s acompl ex i ntera cti on of thes e proces s es a nd s econda ry a nd terti a ry s tructures a ctua l l y form s omewha t i n pa ra l l el Ma ny more compl ex fa ctorsnot di s cus s ed here a l s o occur to hel p i n determi ni ng the fi na l protei n conforma ti on The proces s of ma ki ng a nd tra ffi cki ng a protei n wi l l beexpl ored more ful l y i n Cha pters 5 a nd 9

Dystrophin and Muscular Dystrophy: Mus cul a r dys trophi es (i ncl udi ng Duchenne a nd Becker mus cul a r dys trophi es ) a re di s ea s es i n whi ch

s kel eta l mus cl e ra pi dl y brea ks down, res ul ti ng i n mus cl e wea knes s a nd wa s ti ng, decrea s ed motor s ki l l s , a nd, eventua l l y, the i na bi l i ty to

wa l k (us ua l l y by the a ge of 12 yea rs ) Of a pproxi ma tel y, 30 di fferent types of mus cul a r dys trophi es , the Duchenne a nd Becker forms s how Xchromos ome-l i nked i nheri ta nce a nd, therefore, a l mos t a l wa ys a ffect ma l es a t a ra te of a pproxi ma tel y one i n 3500 boys worl dwi de Both a re

ca us ed by the a bs ence or muta ti on of the protei n dystrophin, whi ch provi des s trength for s kel eta l mus cl e cel l s by a nchori ng the i nterna l cel l

components to the extra cel l ul a r ma tri x

Reproduced wi th permi s s i on from Ka ndel l E, et a l : Pri nci pl es of Neuros ci ence, 4th edi ti on, McGra w-Hi l l , 2000.

The i ntera cti on of dys trophi n wi th s evera l other protei ns i nvol ved i n thi s s tructura l s upport network i s a pri me exa mpl e of protei n–protei n i ntera cti ons i nvol vi ng the forces of thei r hydrophobi c a nd hydrophi l i c regi ons More i mporta ntl y, the muta ti ons i n the dys trophi nprotei n a re bel i eved to s i gni fi ca ntl y a l ter one or more of thes e regi ons , res ul ti ng i n brea kdown of the a nchori ng compl ex a nd thus di s ea s e

CATEGORIES OF PROTEINSAMINO ACID AND PEPTIDE-DERIVED HORMONES AND NEUROTRANSMITTERS

Ami no a ci ds a nd the pepti des /protei ns tha t they form s erve s evera l cri ti ca l rol es i n huma n bi ochemi s try a nd l i fe The ma jor rol e of a mi no

a ci ds i s to provi de the bui l di ng bl ocks for protei ns a nd a va s t ma jori ty of the body’s a mi no a ci ds a re i nvol ved i n thi s functi on However, a mi no

a ci ds a re a l s o the ma jor precurs ors of s evera l bi ol ogi ca l l y i mporta nt mol ecul es , a s noted i n Ta bl e 1-2

TABLE 1-2 Ami no Aci ds —Components of Va ri ous Bi ol ogi ca l Mol ecul es

Quaternary (4°) Structure: Qua terna ry (4°) s tructure i s exempl i fi ed i n ma ny other wa ys tha n thos e gi ven a bove, where two s econda ry s tructura l

el ements a re s i mpl y i n cl os e proxi mi ty to ea ch other Ma ny fi brous protei ns expa nd on thi s concept, wi th two or more α-hel i ces wound

a round ea ch other for mos t of thei r a mi no a ci d s equence Exa mpl es i ncl ude F-a cti n a nd the ta i l s ecti on of myos i n, kera ti n i n ha i r, a nd

i ntermedi a te fi l a ments , whi ch pl a y a n i mporta nt s tructura l rol e i ns i de a l l cel l s

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

Collagen, a nother fi brous s tructura l protei n of s ki n a nd connecti ve ti s s ue, i s compos ed of three i ntertwi ned hel i ca l protei n s equences

(s ee the fi gure on ri ght), whi ch di ffer from the α-hel i ca l s tructure Unl i ke a n α-hel i x where hydrogen bondi ng wi thi n the s a me protei n

s equence predomi na tes , col l a gen uti l i zes hydrogen bondi ng between the three hel i ca l protei n cha i ns Col l a gen opti mi zes thi s very uni que

s tructure by ha vi ng the s ma l l a mi no a ci d gl yci ne a s every thi rd a mi no a ci d to a l l ow the three hel i ces to fi t very cl os e together (s ee the fi gurebel ow) In a ddi ti on, col l a gen ha s a n a bunda nce of prol i ne res i dues to promote the hel i ca l protei n s tructure a nd a s peci a l form of prol i ne(hydroxyprol i ne) wi th a n extra hydroxyl (OH–) to form the i nterprotei n hydrogen bonds wi th the gl yci ne NH groups Hydroxyl ys i ne res i dueshel p to s ta bi l i ze the s tructure a s wel l

Ada pted (l eft) a nd reproduced (ri ght) 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.

Osteogenesis imperfecta (OI) i s a geneti c di s ea s e tha t a ffects col l a gen-conta i ni ng ti s s ues s uch a s bone, s ki n, joi nts , eyes , ea rs , a nd teeth

beca us e of poi nt muta ti ons tha t des ta bi l i ze or a l ter col l a gen’s i mporta nt tri pl e hel i x s tructure Pa ti ents wi th OI often di s pl a y frequentfra ctures a nd ea s y brui s i ng (s ometi mes mi s ta ken for chi l d a bus e); wea k joi nts ; a bl ui s h col or to the norma l l y whi te pa rt of thei r eyes ;hea ri ng l os s due pa rtl y to a bnorma l i ti es of the i nner ea r bones ; a nd poorl y s ha ped, s ma l l , bl ue-yel l ow teeth

As a res ul t, ei ther the exces s or defi ci ency of a mi no a ci ds ca n l ea d di rectl y to di s ea s e tha t ma y res ul t i n centra l nervous s ys tem defects ,

di eta ry a nd meta bol i s m probl ems , l i ver a nd ki dney fa i l ure, s ki n a nd eye l es i ons , a nd even dea th

ENZYMES

Enzymes a re s peci a l i zed protei ns tha t a ccel era te a chemi ca l rea cti on by s ervi ng a s a bi ol ogi ca l ca ta l ys t By ca ta l yzi ng thes e rea cti ons ,

enzymes ca us e them to ta ke pl a ce one mi l l i on or more ti mes fa s ter tha n i n thei r a bs ence Enzymes a re us ua l l y i denti fi ed by the endi ng of

“a s e” to thei r na me (e.g., hexoki na s e, the fi rs t enzyme i n the brea kdown of gl ucos e) There a re excepti ons for enzymes tha t were di s coveredbefore thi s na mi ng s cheme wa s a dopted (e.g., tryps i n, peps i n, a nd thrombi n) Enzyme rea cti ons wi l l be di s cus s ed i n grea ter deta i l i n Cha pter5

STRUCTURAL PROTEINS

Protei ns a l s o s erve a n i mporta nt rol e a s s tructura l el ements of cel l s a nd ti s s ues The bes t exa mpl es of thes e protei ns a re a cti n a nd tubul i n,whi ch form a cti n fi l a ments a nd mi crotubul es , res pecti vel y (Fi gure 1-8A-B) In s kel eta l mus cl e, a cti n fi l a ments provi de the “s ca ffol di ng” a ga i ns twhi ch the motor protei n myos i n ca n genera te force to produce mus cl e contra cti on In s mooth mus cl e a nd non-mus cl e (e.g., s ki n a nd i mmune

s ys tem), a cti n fi l a ments crea te the mecha ni ca l s tructure of the cel l a nd a re di rectl y a s s oci a ted wi th l i nka ges to s urroundi ng cel l s a l l owi ng

i ntercel l ul a r s i gna l i ng The a cti n fi l a ments a l s o provi de tra cks on whi ch s peci a l i zed myos i n mol ecul es move ves i cl es a nd orga nel l es (s eeCha pter 12) Fi na l l y, a cti n fi l a ments a re i nti ma tel y i nvol ved i n cel l moti l i ty, a wi de a rra y of cel l ul a r movements s uch a s wound hea l i ng (themovement of s ki n cel l s i nto cuts ), the i mmune res pons e (the proces s of whi te bl ood cel l s conta cti ng a nd recogni zi ng ea ch other i n the hi ghl y

s el ecti ve proces s of i mmune rea cti ons ), a nd cytoki nes i s (the di vi s i on of one cel l i nto two duri ng mi tos i s )

Figure 1-8 A–B A Actin and B Tubulin in Monomer and Filamentous Forms [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.]

The s tructura l protei n tubul i n crea tes mi crotubul e tra cks for the movement by two mol ecul a r motor protei ns , dynei n a nd ki nes i n, of

ves i cl es , gra nul es , orga nel l es , a nd chromos omes Mi crotubul es a re a l s o the s tructura l component i n fl a gel l a a nd ci l i a i nvol ved i n functi ons

s uch a s s perm moti l i ty, the movement of the egg down the Fa l l opi a n tubes , a nd the expul s i on of di rt a nd mucus out of the l ungs a nd tra chea Nonmoti l e ci l i a a re a l s o i mporta nt i n rod cel l s i n the eye a nd neurons i nvol ved i n ol fa cti on (s mel l ) Mi crotubul es a l s o s erve a mecha ni ca l –

s tructura l rol e i n the cel l s i mi l a r to a cti n mi crofi l a ments a nd a re res pons i bl e for the movement a nd s epa ra ti on of chromos omes duri ng

mi tos i s (s ee Cha pter 12)

MOTOR PROTEINS

“Motor” protei ns tra ns port mol ecul es i ns i de a cel l , provi de movement of certa i n pa rts of i ndi vi dua l cel l s i nvol ved i n s peci a l i zed functi ons(e.g., i mmune res pons es a nd wound hea l i ng), genera te l a rger s ca l e movements of fl ui ds a nd s emi s ol i ds s uch a s the ci rcul a ti on of bl ood a ndmovement of food through the di ges ti ve tra ct, a nd fi na l l y provi de movement of the huma n body through thei r rol es i n s kel eta l mus cl es

Myos i n i s a protei n wi th a hydrophobi c ta i l ; a hea d group, whi ch ca n a tta ch a nd deta ch from a cti n fi l a ments ; a nd a “hi nge” s ecti on, whi chmoves the hea d group ba ck a nd forth res ul ti ng i n movement Two ma jor types of myos i n exi s t Myos i n I i s compos ed of one mol ecul e wi th a n

a ddi ti ona l a rea on i ts s hort ta i l tha t ca n bi nd to other protei ns a nd membra nes Myos i n II (s evera l s ubtypes exi s t) i s compos ed of a l ong ta i ltha t bi nds vi a hydrophobi c i ntera cti ons to other myos i n II mol ecul es , res ul ti ng i n a compos i te mol ecul e tha t ca n s horten s kel eta l mus cl es by

i ts i ntera cti on wi th a cti n fi l a ments i n thos e mus cl es Ki nes i n a nd dynei n a re very much l i ke myos i n I i n form a nd functi on (s ee Cha pter 12)

Microtubules, Cilia, and Flagella—Roles in Disease Processes: Al though us ua l l y ra re, defects i n ci l i a /fl a gel l a , known a s ci l i opa thi es , l ea d to

s evera l di s ea s es /s yndromes i ncl udi ng the fol l owi ng:

Kartagener Syndrome/Primary Ciliary Dyskinesia—defecti ve ci l i a i n the res pi ra tory tra ct, Eus ta chi a n tube, a nd Fa l l opi a n tubes l ea di ng to chroni c

l ung i nfecti ons , ea r i nfecti ons a nd hea ri ng l os s , a nd i nferti l i ty Pos s i bl e a s s oci a ti on wi th “s i tus i nvers us ,” a condi ti on i n whi ch ma jor

i nterna l orga ns a re “fl i pped” l eft to ri ght

Senior–Loken Syndrome/Nephronophthisis—eye di s ea s e a nd forma ti on of cys ts i n the ki dneys l ea di ng to rena l fa i l ure.

Bardet–Biedl Syndrome—dys functi on of ci l i a throughout the body l ea di ng to obes i ty due to i na bi l i ty to s ens e s a ti a ti on, l os s of eye

pi gment/vi s ua l l os s a nd/or bl i ndnes s , extra di gi ts a nd/or webbi ng of fi ngers a nd toes , menta l a nd growth reta rda ti on a nd beha vi ora l/s oci a l probl ems , s ma l l a nd/or mi s s ha ped geni ta l i a (ma l e a nd fema l e), enl a rged a nd da ma ged hea rt mus cl e, a nd ki dney fa i l ure

Alstrom Syndrome—chi l dhood obes i ty, brea kdown of the reti na l ea di ng to bl i ndnes s , hea ri ng l os s , a nd type 2 di a betes

Meckel–Gruber Syndrome—forma ti on of cys ts i n ki dneys a nd bra i n l ea di ng to rena l fa i l ure a nd neurol ogi ca l defi ci ts , extra di gi ts a nd

bowi ng/s horteni ng of the l i mbs

Increased Ectopic (Tubal) Pregnancies/Male Infertility—defi ci ent ci l i a i n Fa l l opi a n tubes or defi ci ent fl a gel l a / s perm ta i l moti l i ty.

Autosomal Recessive Polycystic Kidney Disease—much ra rer tha n the a utos oma l domi na nt form, dys functi on of ba s a l bodi es a nd ci l i a i n rena l

cel l s l ea ds to a l tera ti ons of the l ungs a nd ki dneys l ea di ng to a va ri ety of s econda ry medi ca l condi ti ons a nd often dea th

Parkinson’s and Alzheimer’s diseases—Al though work i s s ti l l ongoi ng, res ea rchers now feel tha t s ome forms of Pa rki ns on’s a nd Al zhei mer’s

di s ea s es ma y res ul t, i n pa rt, from da ma ge to mi crotubul es a nd a s s oci a ted protei ns Trea tments a i med a t s ta bi l i zi ng mi crotubul es ma yhel p ma ny s ufferers of thes e ma l a di es

TRANSPORT/CHANNEL PROTEINS

Another group of protei ns fol d i nto a terti a ry or qua terna ry s tructure tha t crea tes cha nnel s for the movement of mol ecul es i nto a nd out of thenucl eus , va ri ous cel l orga nel l es , a nd from cel l s to thei r outs i de envi ronment s uch a s the bl ood s trea m The hydrophobi c a nd hydrophi l i c

na ture of the a mi no a ci ds tha t ma ke up thes e cha nnel protei ns a l l ows a n exteri or of the protei n tha t ca n exi s t i ns i de the extremel y

hydrophobi c envi ronment of a membra ne bi l a yer a nd a hydrophi l i c i nteri or tha t ca n a l l ow cha rged mol ecul es to move through the membra ne(Cha pter 8) Cha nnel s a re es s enti a l for the tra ns porta ti on of nutri ents i nto a nd out of cel l s a s wel l a s for nerve s i gna l s a nd the s el ecti ve

fi l tra ti on of mol ecul es i n the ki dneys Thes e s peci a l i zed functi ons of cha nnel s wi l l be di s cus s ed i n deta i l i n Cha pter 8 a nd Secti on III

REVIEW QUESTIONS

1 Wha t i s the mea ni ng a nd s i gni fi ca nce of es s enti a l a nd non-es s enti a l a mi no a ci ds ?

2 Wha t i s the s i gni fi ca nce of ea ch a mi no a ci d R-group (hydrophobi c, hydrophi l i c, a nd cha rged)?

3 Wha t a re the four ma jor types of s tructura l el ements of protei ns a nd how a re they defi ned?

4 Wha t i s a n enzyme a nd how do the terms ca ta l ys t a nd a cti ve s i te rel a te to enzymes ?

5 Wha t i s the ba s i c s tructure of a mi no a ci ds ?

6 How do the el ements pepti de bond, pepti des , α-hel i x, β-s tra nd, β-turn, ha i rpi n turn, a nd di s ul fi de bond rel a te to the s tructure of protei ns ?

7 How does a n a mi no a ci d s equence fol d?

8 Wha t a re the rol es of R-groups a nd pri ma ry to qua terna ry s tructure i n the fi na l conforma ti on of protei ns ?

9 Wha t a re the di fferent ca tegori es of protei ns a nd how a re they defi ned?

CHAPTER 2 CARBOHYDRATES

Ba s i c Ca rbohydra te Structure a nd Functi on

Monos a ccha ri des a nd Di s a ccha ri des

Gl ycogen a nd Sta rches

Gl ycoprotei ns

Gl ycos a mi nogl yca ns

Revi ew Ques ti ons

cons ti tuents of gl ycoprotei ns a nd gl ycol i pi ds ) However, a number of a ddi ti ona l mol ecul es crea ted by l i nka ges of ca rbohydra tes to protei ns

pl a y va ri ous rol es i n cel l –cel l i ntera cti ons a nd bi ol ogi ca l s tructures

BASIC CARBOHYDRATE STRUCTURE AND FUNCTION

Carbohydrates, whos e na mes end i n “-ose,” ha ve a formul a of (CH2O)x where x i s a number from three to s even (gi vi ng the na mes of triose, tetros e, pentose, hexose, a nd heptose) Al l ca rbohydra tes conta i n a ketone or a n a l dehyde group, a s wel l a s one or more hydroxyl groups (Fi gure

2-1A–B; Appendi x III) The oxygen a toms of the ketone a nd a l dehyde groups ha ve s i mi l a r rea cti ve qua l i ti es to tha t of the ca rboxyl i c a ci d group

s een i n a mi no a ci ds a nd a re the s i tes of chemi ca l rea cti ons wi thi n the ca rbohydra te mol ecul e, a s wel l a s wi th other ca rbohydra te, protei n, or

l i pi d mol ecul es Often, the ketone or a l dehyde rea cts wi th a hydroxyl group from the s a me s uga r mol ecul e to form a ca rbohydra te ri ng

s tructure a s s hown

Figure 2-1 A–B Basic Carbohydrate Structures A The rea cti ve ketone group of ca rbon 2 (green ca rbon group) from the hexos e fructos e rea cts wi th

the hydroxyl group of ca rbon 5 to form a new bond a nd a fi ve-s i ded (pentos e) ri ng s tructure Al l ca rbon a toms a re numbered for cl a ri ty Thi srea cti on i s ful l y revers i bl e a s i ndi ca ted by the bi di recti ona l a rrows As a res ul t, the l i nea r a nd ri ng s tructures a re cons ta ntl y cha ngi ng i n

s ol uti on B The rea cti ve a l dehyde group of ca rbon 1 (green ca rbon group) from the hexos e gl ucos e rea cts wi th the hydroxyl group of ca rbon 5 to

form a new bond a nd a s i x-s i ded (hexos e) ri ng s tructure Al l ca rbon a toms a re numbered for cl a ri ty Thi s rea cti on i s ful l y revers i bl e a s

i ndi ca ted by the bi di recti ona l a rrows As a res ul t, the l i nea r a nd ri ng s tructures a re cons ta ntl y cha ngi ng i n s ol uti on [Ada pted wi th permi s s i onfrom 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.]

Ca rbohydra tes pl a y a ma jor rol e i n huma ns a s energy s ources a nd s tora ge, a nd thei r rol e i n di et a nd nutri ti on, a l though s ometi mes

controvers i a l , i s a l wa ys one of s upreme i mporta nce However, ca rbohydra tes pl a y other rol es a s noted i n Ta bl e 2-1

TABLE 2-1 Bi ochemi ca l Rol es of Ca rbohydra tes

MONOSACCHARIDES AND DISACCHARIDES

Al though there a re mul ti pl e tri os es , pentos es , hexos es a nd heptos es dependi ng on the va ri ous a rra ngements of hydroxyl groups a nd

hydrogens a round the centra l ca rbon ba ckbone, onl y a few of thes e s i ngl e res i due s uga rs a re commonl y s een i n huma n bi ol ogy Common

s i ngl e s uga r groups , ca l l ed monosaccharides, i ncl ude the tri os e glyceraldehyde; the pentos e ribose; a nd the hexos es fructose, glucose, a nd

galactose (s hown i n Fi gure 2-2).

Figure 2-2 Common Monosaccharides in Human Biology The common monos a ccha ri de ca rbohydra tes found i n huma ns a re s hown a bove, i ncl udi ng

the three-ca rbon tri os e gl ycera l dehyde; the fi ve-ca rbon pentos e ri bos e; a nd the s i x-ca rbon hexos es fructos e, gl ucos e, a nd ga l a ctos e Note theonl y s tructura l di fference between gl ucos e a nd ga l a ctos e i s the pl a cement of the hydrogen a tom a nd hydroxyl group a t ca rbon 4 Ca rbon a toms

a re numbered for cl a ri ty [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.]Hydroxyl groups (OH) a re often l oca ti ons of enzyme rea cti ons , es peci a l l y the forma ti on of a new bond between two ca rbohydra te mol ecul es

wi th the res ul ti ng rel ea s e of a wa ter mol ecul e When monos a ccha ri des form s uch bonds , the res ul ti ng mol ecul es a re a disaccharide,

trisaccharide, a nd s o on The va ri ous combi na ti ons of a l l the di fferent monos a ccha -ri des woul d produce a va s t mi xture of thes e new mol ecul es

but, i n fa ct, onl y a few a re common i n huma ns (Fi gure 2-3), na mel y lactose (the pri ma ry s uga r found i n mi l k), trehalose [found i n pl a nts (e.g.,

s unfl ower s eeds ), a ni ma l s (e.g., s hri mp), Ba ker’s yea s t, a nd s evera l types of mus hrooms )], maltose [(found i n ma ny foods ma de from gra i ns (e.g., ba rl ey)], a nd sucrose (found na tura l l y i n pl a nts ; us ua l l y a rti fi ci a l l y ma de for huma n cons umpti on a s common ta bl e s uga r) The ri ng

s tructure of monos a ccha ri des a l s o ha s rea cti ve hydroxyl groups a t ea ch of thei r ca rbon a toms , es peci a l l y a t the fi rs t a nd s i xth ca rbons , whi ch

ca n bond to other s uga r mol ecul es a nd a mi no groups a nd protei ns (di s cus s ed bel ow a nd i n the fol l owi ng cha pters )

Figure 2-3 Common Disaccharides in Human Biology The common di s a ccha ri de ca rbohydra tes found i n huma ns a re s hown a bove, i ncl udi ng

l a ctos e, treha l os e, ma l tos e, a nd s ucros e Component monos a ccha ri des a nd s peci fi c α- a nd β-bond confi gura ti ons a re i ndi ca ted i mmedi a tel yunder ea ch di s a ccha ri de Note tha t the s econd gl ucos e mol ecul e i n treha l os e a nd the fructos e mol ecul e i n s ucros e a re fl i pped hori zonta l l y i nthe fi na l di s a ccha ri de mol ecul e (s ee ca rbon numbers ) [Ada pted wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee BrothersMedi ca l Publ i s hers (P) Ltd., 2009.]

Carbohydrate Intolerance: The di ges ti on of ca rbohydra tes from food i nvol ves s evera l proces s es rel yi ng on protei ns , both enzymes a nd

tra ns port/cha nnel types Defects i n a ny of thes e protei ns l ea d to di s ea s e s ta tes i n whi ch a pa rti cul a r ca rbohydra te ca nnot be tol era ted i n

the pa ti ent’s di et One of the bes t known exa mpl es i s lactose intolerance, whi ch devel ops i n a dol es cence or a dul thood a nd i s ca us ed by the

i na bi l i ty to di ges t the s uga r l a ctos e, the pri ma ry ca rbohydra te i n cow’s mi l k Decrea s ed di ges ti on i ncrea s es ba cteri a l fermenta ti on of theexces s s uga r mol ecul es produci ng i ntes ti na l ga s , bl oa ti ng, na us ea , a nd pa i nful cra mpi ng The os moti c effect of the exces s monos a ccha ri de

a nd di s a ccha ri de mol ecul es l ea ds to i ncrea s ed wa ter retenti on a nd a bs orpti on i n the l a rge i ntes ti ne, ca us i ng wa tery di a rrhea

In fa ct, hi s tori ca l evi dence i ndi ca tes tha t huma ns onl y recentl y evol ved the a bi l i ty to di ges t l a ctos e when cow’s mi l k beca me a s ta pl e ofthei r di et In a ddi ti on, s ome ra ces of huma ns a re l es s a bl e to di ges t l a ctos e, l ea di ng to i ncrea s ed i nci dence of l a ctos e i ntol era nce i n tha t

ra ci a l group

Other types of ca rbohydra te i ntol era nce i ncl ude enzyme defi ci enci es i n the di ges ti on of s ucros e, ma l tos e, a nd treha l os e—the l a tter s eenpredomi na tel y i n Inui t a nd Greenl a nd popul a ti ons —a nd the a bs ence or decrea s ed a cti on of tra ns porter/cha nnel protei ns tha t ca n ca us eprofound effects on di ges ti on of gl ucos e, fructos e, a nd ga l a ctos e Some ca rbohydra te i ntol era nce ca n l ea d to s eri ous probl ems of fa i l ure tothri ve a nd ki dney a nd/or l i ver di s ea s e Trea tment of ca rbohydra te i ntol era nces i s norma l by a voi da nce of the offendi ng s uga r or by

s uppl ementa ti on of the a ffected enzyme

GLYCOGEN AND STARCHES

Li nka ges of monos a ccha ri des a nd di s a ccha ri des form l ong ca rbohydra te cha i ns ca l l ed pol ys a ccha ri des The common pol ys a ccha ri des found i n

na ture a re glycogen a nd starch In fa ct, over ha l f of a l l the ca rbohydra tes i n the huma n di et a re s ta rch mol ecul es Al though gl ycogen i s a l wa ys a bra nched pol ys a ccha ri de mol ecul e, s ta rch ca n be ei ther bra nched (ca l l ed amylopectin) or unbra nched (ca l l ed amylose) The gl ycogen mol ecul e

a nd s ta rch mol ecul es a re s hown i n Fi gure 2-4

Figure 2-4 A–B Glycogen and the Plant Starch Forms Amylopectin and Amylose A Gl ucos e mol ecul es , bondi ng both l i nea rl y between the ca rbons 1

a nd 4 (green bonds ) a nd a s bra nches between ca rbons 1 a nd 6 (red bond) of s ucces s i ve gl ucos e mol ecul es , crea te gl ycogen (bra nches

a pproxi ma tel y every 10 gl ucos e res i dues ) or the form of pl a nt s ta rch ca l l ed a myl opecti n (bra nches a pproxi ma tel y every 30 gl ucos e mol ecul es )

Gl ycogen a nd s ta rch a re us ua l l y thous a nds of gl ucos e mol ecul es l ong a nd a re extremel y i mporta nt forms of ca rbohydra te s tora ge i n the

huma n body a nd pl a nts , res pecti vel y B Gl ucos e mol ecul es , bondi ng onl y l i nea rl y between the ca rbons 1 a nd 4 (green bonds ) of s ucces s i ve

gl ucos e mol ecul es , crea te the form of pl a nt s ta rch ca l l ed a myl os e, whi ch ha s no bra nchi ng Amyl os e i s a n i mporta nt form of ca rbohydra te

s tora ge i n pl a nts [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.]

Glycogen Storage Diseases: Gl ycogen s tora ge di s ea s es i ncl ude 11 cl a s s es of i nborn errors i n the producti on a nd brea kdown of thes e l ong

ca rbohydra te cha i ns The geneti c errors , a l though ra re, res ul t i n a n i na bi l i ty of the body to res pond to the i ncrea s ed need for gl ucos e

mol ecul es As a res ul t, pa ti ents s ufferi ng from gl ycogen s tora ge di s ea s es a re l i mi ted i n thei r a bi l i ty to exerci s e or devel op l ow bl ood s uga r

a fter a rel a ti vel y s hort peri od of food depri va ti on Thes e gl ycogen s tora ge di s ea s es wi l l be expl ored i n ful l er deta i l i n l a ter cha pters

Cellulose, the a nother ma jor pl a nt pol ys a ccha ri de bes i des s ta rch, di ffers from amylose onl y i n the bonds between ca rbons 1 a nd 4 Cha nges

i n the wa y the a l dehyde a nd hydroxyl groups of the two gl ucos e mol ecul es form the bond res ul ts i n ei ther a n a myl os e α-bond [i ndi ca ted by adownwa rd bond (Fi gure 2-4A)] or a cel l ul os e β-bond [i ndi ca ted by a n upwa rd bond (Fi gure 2-5)] Al though the di fference ma y s eem

i ns i gni fi ca nt, thi s β-bond res ul ts i n a ma rkedl y di fferent overa l l s tructure of the pol ys a ccha ri de Al though α-l i nka ges crea te a n overa l l hel i ca l

s tructure of the cha i n, β-l i nka ges crea te a s tra i ght cha i n The α-l i nked hel i ca l s tructure i s i mporta nt for a cces s i ng the ca rbohydra te mol ecul esfor meta bol i s m, wherea s the β-l i nked l i nea r cha i n i s s tronger a nd, therefore, wel l s ui ted for cel l ul os e-conta i ni ng s tructures s uch a s pl a nt

wa l l s (e.g., wood) In a ddi ti on, the β-l i nka ges ca nnot be di ges ted by huma ns but ca n be di ges ted by a ni ma l s s uch a s cows a nd termi tes , a nd i t

i s the rea s on huma ns ca nnot l i ve on gra s s or wood, both of whi ch a re compos ed of β-bonded gl ucos e mol ecul es

Figure 2-5 Cellulose Note the β-l i nka ges (upwa rd-goi ng green bond) between ca rbons 1 a nd 4 of the two gl ucos e mol ecul es tha t di ffer from the

α-l i nka ges s een i n gl ycogen a nd s ta rches Cel l ul os e i s compos ed of mul ti pl e repea ts of thi s ba s i c uni t a s i ndi ca ted by the s ubs cri pt “n.”

[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.]

GLYCOPROTEINS

Ca rbohydra tes ma y a l s o form bonds wi th protei ns vi a a ny of the ca rbohydra te hydroxyl groups combi ni ng wi th the a mi no a ci d hydroxyl groups

of s eri ne or threoni ne or the a mi ne ni trogen of a s pa ra gi ne The res ul ti ng ca rbohydra te–protei n mol ecul es a re referred to a s glycoproteins, a nd

a pproxi ma tel y ha l f of the protei ns i n the huma n body a re es ti ma ted to be gl ycoprotei ns The di vers i ty of gl ycoprotei ns s een i n na ture a ndhuma ns i s i mmens e wi th compl ex mi xtures of protei ns , a mi no a ci ds , a nd s uga rs (monos a ccha ri des , di s a ccha ri des , a nd tri s a ccha -ri des ) l i nked

together i n a va s t number of l i nea r a nd bra nched forma ti ons generi ca l l y ca l l ed oligosaccharides Thes e ol i gos a ccha ri des pl a y a di vers e number

of functi ona l rol es i n bi ndi ng, s i gna l i ng, a nd regul a ti on tha t wi l l be more ful l y expl ored i n Secti on III

GLYCOSAMINOGLYCANSEven more compl ex tha n s i mpl e ol i gos a ccha ri des a re the glycosaminoglycans (often referred to a s “GAGs”), whi ch conta i n repea ti ng

di s a ccha ri de cha i ns of a modi fi ed gl ucos e a nd/or ga l a ctos e Pri or to thei r l i nka ge to the GAG mol ecul e, thes e ca rbohydra te mol ecul es ha ve a n

a mi ne group a dded wi th a n a ddi ti ona l a cetyl (e.g., NHCOCH3) or nega ti vel y cha rged s ul fa te (e.g., NHSO3) group, produci ng glucosamine a nd galactosamine mol ecul es In a ddi ti on, nega ti vel y cha rged s ul fa te (SO3), vi a the rea cti ve hydroxyl groups , a nd/or ca rboxyl a te (COO−) groups a re

l i nked to a t l ea s t one of the s uga rs of the repea ti ng cha i n (Fi gure 2-6) A very wel l known GAG i s heparin, a potent i nhi bi tor of bl ood cl ot

forma ti on, us ed i n pa ti ents wi th hea rt a tta cks , s trokes , a nd cl otti ng di s ea s es Other GAGs i ncl ude chondroitin a nd hyaluronic acid (the l onges t of

the GAGs ), whi ch bond wi th a centra l l i nea r core protei n to crea te proteoglycans Thes e mol ecul es a re i mporta nt a s s trong s tructura l el ements

i n connecti ve ti s s ue a nd ca rti l a ge (Fi gure 2-6C a nd Ta bl e 2-2)

Figure 2-6 A–C Examples of Glycosaminoglycans (GAGs) and of Proteoglycan Associated with Collagen A Hepa ri n, a GAG a nd a n i mporta nt mol ecul e

i n bl ood cl ot regul a ti on, i s compos ed of two ca rbohydra te mol ecul es l i nked vi a a β-l i nka ge between ca rbons 1 a nd 4 a nd the a ddi ti on of aCOO− group, a s wel l a s s ul fa te a nd ni trogen a nd s ul fa te groups a t va ri ous other ca rbon a toms Al though mul ti pl e forms of hepa ri n exi s t,

dependi ng on the pa rti cul a r ca rbon tha t i s modi fi ed, one of the mos t common i s s hown a bove B Chondroi ti n, a GAG i mporta nt i n ca rti l a ge,

tendon, a nd bone s tructure, i s compos ed of a l terna ti ng ca rbohydra te mol ecul es (gl ucuroni c a ci d N-a cetyl -ga l a ctos a mi ne; note COO− a nd

ni trogen groups ) l i nked vi a a n αl i nka ge between ca rbons 1 a nd 3 Ea ch ca rbohydra te mol ecul e ma y be s ul fa ted (once or twi ce) or l eft uns ul

-fa ted The more common s ul -fa ted forms a re referred to a s chondroi ti n s ul -fa te a nd a re fel t to be ma i nl y res pons i bl e for the mol ecul e’s

bi ol ogi ca l a cti vi ty Chondroi ti n ha s recentl y become popul a r to i nges t i n pi l l form by s ome pa ti ents wi th knee a nd other joi nt pa i n i n hopes of

“repl a ci ng” ca rti l a ge tha t ha s been depl eted by ti me a nd wea r a nd tea r C Col l a gen, the ma i n protei n i n connecti ve ti s s ue, i s s trongl y

a s s oci a ted wi th proteogl yca ns compos ed of s evera l GAGs Common components i ncl ude hya l uroni c a ci d, a nd l ong, l i nea r cha i ns of repeti ti veuni ts of uroni c a ci ds (l eft) a nd chondroi ti n s ul fa te or kera ta n s ul fa te bound together by l i nk a nd core protei ns The res ul ti ng protei n a nd

ca rbohydra te mol ecul es a s wel l a s i ntera cti ons between the cha rged GAG groups a nd s urroundi ng wa ter mol ecul es crea te a n overa l l s tructure(ri ght) tha t i s both s trong a nd ri gi d but a l s o fl exi bl e a nd conforma bl e Thes e qua l i ti es hel p to ma ke col l a gen the perfect s ubs ta nce to provi de

s tructure but a l s o a l l ow movement i n joi nts [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.]

TABLE 2-2 Bi ochemi ca l Rol es of Gl ycos a mi nogl yca ns

Gl ycos a mi nogl yca ns a re res pons i bl e for a va s t number of functi ons i n huma n bi ol ogy, mos tl y i nvol vi ng s tructure outs i de the cel l a nd/or

a tta chment of cel l s to externa l s tructures An exa mpl e of thi s s tructura l moti f i s s hown i n Fi gure 2-7

Figure 2-7 Example of Extracellular Matrix Structure The rol e of col l a gen, chondroi ti n, proteogl yca ns , a nd l i nk protei ns i n the forma ti on of the

extra cel l ul a r ma tri x i s i l l us tra ted [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.]

Carbohydrates and Fertilization: The ferti l i za ti on of a huma n egg rel i es on ca rbohydra te bi ndi ng a nd s i gna l i ng Bi ndi ng of a receptor on the

s perm’s s urfa ce to a galactose mol ecul e wi thi n a n ol i gos a ccha ri de on the egg’s s urfa ce s i gna l s the s perm to rel ea s e mol ecul es tha t a l l ow

s perm entry i nto the egg, res ul ti ng i n ferti l i za ti 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 l i s t bel ow i l l us tra tes jus t a few of thes e mol ecul es a nd thei r functi ons , whi ch wi l l be expl ored further i n l a ter cha pters

REVIEW QUESTIONS

1 Wha t a re tri os e, pentos e, a nd hexos e ca rbohydra tes a nd thei r key fea tures ?

2 Wha t a re ketone a nd a l dehyde groups a nd thei r key fea tures ?

3 Wha t a re monos a ccha ri des a nd di s a ccha ri des a nd thei r key fea tures ?

4 Wha t a re the ba s i c s tructures of gl ycera l dehyde, ri bos e, gl ucos e, ga l a ctos e, fructos e, ma l tos e, l a ctos e, s ucros e, gl ycogen, s ta rch,

a myl opecti n, a myl a s e, gl ycoprotei ns , a nd gl ycos a mi nogl yca ns ?

5 Wha t a re the ba s i c rol es a nd functi ons of ca rbohydra te mol ecul es , i ncl udi ng the va ri ous other types of mol ecul es to whi ch they ma y bond

a nd the res ul ti ng s tructura l cha ra cteri s ti cs ?

CHAPTER 3 LIPIDS

Ba s i c Li pi d Functi ons

Ba s i c Membra ne Li pi d Structure

Compl ex Li pi ds

Li pi d-deri ved Hormones /Vi ta mi n D

Revi ew Ques ti ons

OVERVIEW

Li pi ds a re the thi rd ma jor type of bi ochemi ca l mol ecul e found i n huma ns Al though one of thei r ma jor functi ons rel a tes to the forma ti on of

bi ol ogi ca l membra nes (phos phol i pi ds a nd chol es terol ), l i pi d mol ecul es a re a l s o es s enti a l for energy s tora ge a nd tra ns port (tri a cyl gl ycerol s ),cel l ul a r bi ndi ng a nd recogni ti on a nd other bi ol ogi ca l proces s es (gl ycol i pi ds ), s i gna l i ng (s teroi d hormones ), di ges ti on (bi l e s a l ts ), a nd

meta bol i s m (fa tty a ci ds , ketone bodi es , a nd vi ta mi n D) Li pi d mol ecul es a re ma i nl y hydrophobi c a nd a re, therefore, found i n a rea s a wa y from

wa ter mol ecul es or a re i nvol ved i n mecha ni s ms s uch a s l i poprotei n compl exes tha t a l l ow thei r movement i n a nd through wa ter envi ronments The s ma l l er hydrophi l i c pa rts of l i pi ds a re, thems el ves , i mporta nt i n forma ti on of bi ol ogi ca l membra nes a nd i n the s evera l s peci fi c functi ons

of l i pi ds a nd l i pi d-deri ved mol ecul es

BASIC LIPID FUNCTIONS

A ma jor rol e of l i pi d mol ecul es i s to provi de the bui l di ng bl ocks for bi ol ogi ca l membra nes , i ncl udi ng phospholipids, glycolipids, a nd cholesterol However, other l i pi ds known a s triacylglycerols (a l s o referred to a s tri gl yceri des or fa ts ) functi on i n the s tora ge of bi ol ogi ca l energy a nd bile salts, deri ved i n the l i ver from chol es terol a nd s erve i n the di ges ti on of di eta ry fa t Fi na l l y, s evera l l i pi d-deri ved mol ecul es s erve a s i mporta nt

hormones a nd i ntra cel l ul a r mes s engers

It i s i mporta nt to note tha t the ma jor pa rt of every l i pi d mol ecul e i s hydrophobi c i n na ture a nd, l i ke the hydrophobi c pa rts of protei ns

di s cus s ed ea rl i er (Cha pter 1), prefers to be a wa y from a nd protected a ga i ns t i ntera cti on wi th wa ter mol ecul es Thi s hydrophobi c cha ra cter i sfunda menta l i n membra ne forma ti on, l i pi d tra ns port, a nd i n ma ny of the functi ons tha t the va ri ous types of l i pi d mol ecul es perform

BASIC MEMBRANE LIPID STRUCTURE

A membra ne l i pi d i s compos ed of three ba s i c components tha t a re a s fol l ows :

1 Fatty acids a re compos ed of l ong cha i ns of ca rbon mol ecul es wi th a ca rboxyl i c a ci d (COOH) a t ca rbon 1 a nd a CH3 (methyl ) group a t the end ofthe cha i n (Fi gure 3-1A) The ca rboxyl i c a ci d group i s i nvol ved i n bondi ng of the fa tty a ci d to the other components of a l i pi d mol ecul e Inhuma ns , fa tty a ci ds a re us ua l l y 12–24 ca rbons l ong a nd mos t often the number of ca rbons i n the fa tty a ci d ba ckbone i s even Fa tty a ci ds ca nconta i n s i ngl e (C—C), doubl e (C═C), or tri pl e ca rbon–ca rbon bonds

Figure 3-1 A Common Saturated and Unsaturated Fatty Acids Pa l mi ta te (16-ca rbon), s tea ra te (18-ca rbon), a nd a ra chi da te (20-ca rbon), fa tty a ci ds ,

s hown by the ca rbon ba ckbone a nd i n “s ti ck di a gra m” form for a ra chi da te often us ed for s i mpl i ci ty The ca rbon a toms of fa tty a ci ds a re

numbered from the ca rboxyl i c a ci d (COOH) to the termi na l methyl (CH3) group Hydrogen a toms a re not s hown for cl a ri ty B Fatty Acid Chain

Double Bonding Deta i l of uns a tura ted fa tty a ci d ca rbon cha i n, i l l us tra ti ng trans doubl e bond (l eft: hydrogen a toms on oppos i te s i des of the

bond a nd res ul ti ng l i nea r ca rbon cha i n) a nd uns a tura ted cis doubl e bond (ri ght: hydrogen a toms on the s a me s i de of the bond a nd res ul ti ng

“ki nked” ca rbon cha i n) C Common Unsaturated Fatty Acids (Top a nd mi ddl e) Two 18-ca rbon uns a tura ted a ci ds s howi ng a cis doubl e bond (ol ei c

a ci d) a nd a trans doubl e bond (el a i di c a ci d) both a t ca rbon 9 Arrows i l l us tra te di fferent conforma ti ons of fa tty a ci d cha i n tha t res ul t from the two types of s a tura ted bonds (Bottom) An 18-ca rbon uns a tura ted fa tty a ci ds wi th two cis doubl e bonds (l i nol ei c a ci d) a t ca rbons 9 a nd 12 (s ee

a rrows ) Note how the a ddi ti on of a s econd cis doubl e bond crea tes a n even more nonl i nea r fa tty a ci d cha i n, whi ch ca us es i ncrea s ed di s order

of pa cki ng a nd, therefore, i ncrea s ed fl ui di ty of bi ol ogi ca l membra nes [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.]

• Saturated fa tty a ci ds conta i n onl y s i ngl e ca rbon–ca rbon bonds , a nd a l l of the ca rbon mol ecul es a re bonded to the ma xi mum number of

hydrogen mol ecul es

• Unsaturated fa tty a ci ds ha ve a t l ea s t one doubl e ca rbon–ca rbon bond wi th the potenti a l for a ddi ti ona l hydrogen a tom bondi ng s ti l l

exi s ti ng for s ome of the ca rbon a toms i n the ba ckbone cha i n If more tha n one doubl e bond i s pres ent, the term pol yuns a tura ted i s us ed

Thes e doubl e bonds ca n exi s t i n ei ther a “ki nked” cis doubl e bond or a more l i nea r trans doubl e bond (Fi gure 3-1B-C).

2 Glycerol i s a s i mpl e three-ca rbon mol ecul e wi th hydroxyl groups a t ea ch ca rbon (Fi gure 3-2A) Thes e hydroxyl groups a re the rea cti ve l oca ti on

where fa tty a ci ds a nd other components of a l i pi d mol ecul e bond to form di a cyl gl ycerol (Fi gure 3-2A) a nd tri a cyl gl ycerol (Fi gure 3-2B)

mol ecul es

Figure 3-2 A–B A Glycerol, Diacylglycerol, and Triacylglycerol Gl ycerol i s a s i mpl e, three-ca rbon cha i n mol ecul e (green) wi th a hydroxyl group (OH)

bonded to ea ch of the ca rbon a toms The hydroxyl groups a t ca rbons 1 a nd 2 of gl ycerol bond rea ct wi th the ca rboxyl i c a ci d groups (COO–) of the

fa tty a ci d cha i ns , res ul ti ng i n two new bonds a nd two wa ter (H2O) mol ecul es In genera l , uns a tura ted fa tty a ci ds bond to ca rbon 1, wherea s

s a tura ted fa tty a ci ds bond to ca rbon 2 The res ul ti ng mol ecul e i s ca l l ed “di a cyl gl ycerol ” a nd i s i nvol ved i n i mporta nt s i gna l i ng pa thwa ys(Cha pter 8) B Tri a cyl gl ycerol i s formed when a thi rd fa tty a ci d bonds to the thi rd gl ycerol hydroxyl group Thi s res ul ta nt mol ecul e i s a n

i mporta nt s tora ge form of energy (Cha pter 8) [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 lPubl i s hers (P) Ltd., 2009.]

Double Bonds and Melting Temperatures: The number a nd type of doubl e bonds i n a pa rti cul a r l i pi d mol ecul e’s fa tty a ci d a ffects how tha t fa tty

a ci d “pa cks ” wi th other fa tty a ci ds a nd, therefore, the tempera ture a t whi ch the pa rti cul a r l i pi d mol ecul e mel ts For exa mpl e, the s a tura ted

fa tty a ci ds l i s ted i n Ta bl e 3-1 ha ve mel ti ng poi nts between 44°C a nd 77°C The uns a tura ted fa tty a ci ds ha ve fa r l ower mel ti ng poi nts , ra ngi ng

from 13°C to –50°C, decrea s i ng a s the number of doubl e bonds (pol yuns a tura ti on) i ncrea s es “Ki nked” cis doubl e bonds ma ke the pa cki ng of

fa tty a ci ds even more di s orga ni zed a nd l ower the mel ti ng tempera ture even further The effects of s a tura ted/uns a tura ted/pol yun-s a tura ted

a nd cis/trans fa tty a ci ds a re rea di l y s een i n the di fferent mel ti ng tempera tures of butter, compos ed of a hi ghl y s a tura ted l i pi ds , a nd

ma rga ri ne, compos ed of uns a tura ted l i pi ds The l i nea r na ture of trans fa tty a ci ds ma kes them s i mi l a r to the s tructure of s a tura ted fa tty

a ci ds Thi s s tructura l fea ture, rel a ti ve to the cis confi gura ti on, s eems to ma ke meta bol i s m of trans fa ts di ffi cul t Cons equentl y, trans fa ts

rema i n l onger i n the ci rcul a ti on, thereby contri buti ng to a rteri a l depos i ti on a nd s ubs equent devel opment of corona ry hea rt di s ea s e In

genera l , uns a tura ted fa ts a re hea l thi er for the huma n body a nd, therefore, di eta ry fa ts compos ed mos tl y of cis doubl e bonded,

pol yuns a tura ted fa ts a re recommended by di eti ci a ns a nd cl i ni ci a ns to hel p a voi d hea rt di s ea s e a nd other medi ca l probl ems

TABLE 3-1 Common Fa tty Aci ds Found i n Huma ns

Essential Fatty Acids: Much l i ke there a re essential a mi no a ci ds tha t the body ca n onl y get from di eta ry s ources , certa i n fa tty a ci ds a re a l s o

deemed es s enti a l Two pa rti cul a r es s enti a l fa tty a ci ds , l i nol ea te a nd l i nol ena te, ha ve doubl e bonds a t the s i xth a nd thi rd ca rbon a tomscounti ng from the methyl end of thei r cha i ns , res pecti vel y, a nd a re needed to produce certa i n 20-ca rbon l ong fa tty a ci ds conta i ni ng doubl e

bonds Thes e two fa tty a ci ds a re known a s omega-6 (ω-6) a nd omega-3 (ω-3) fa tty a ci ds Huma ns do not ha ve the a bi l i ty to produce doubl e

bonds a t thes e l oca ti ons a nd, therefore, mus t obta i n thes e two requi red fa tty a ci d bui l di ng bl ocks from vegeta bl e oi l s Ara chi dona te wi th a

20-ca rbon cha i n a nd four cis doubl e bonds i s a l s o a n es s enti a l fa tty a ci d i nvol ved i n s evera l i mporta nt bi ol ogi ca l functi ons Recentl y, l onger

ca rbon cha i n ω-3 fa tty a ci ds ha ve been propos ed to decrea s e hea rt a tta cks a nd s trokes ; s uppl ements a nd s ome food products a re now

a va i l a bl e, whi ch conta i n thes e fa tty a ci ds Interes ti ngl y, exces s i ve di eta ry i nta ke of ω-6 fa tty a ci ds ha s been i mpl i ca ted i n a n i ncrea s ed ri s k

of hea rt a tta cks , s trokes , s ome ca ncers , a nd even depres s i on

3 Head Group The fi na l component of a l i pi d mol ecul e va ri es wi th ea ch type of l i pi d a nd, a l ong wi th the two s peci fi c fa tty a ci ds , defi nes ea ch

pa rti cul a r l i pi d Thi s thi rd pa rt of the l i pi d mol ecul e i s often ca l l ed the “hea d group,” a ptl y na med i f one envi s i ons the end methyl group ofthe fa tty a ci d cha i ns to be the ta i l of the l i pi d mol ecul e (Fi gure 3-3A) Mos t l i pi ds i n a bi ol ogi ca l membra ne ha ve a phos pha te group (PO4–3)

a tta ched to the thi rd gl ycerol ca rbon a nd a re, therefore, ca l l ed phospholipids Us ua l l y, a n a ddi ti ona l mol ecul e (s evera l common exa mpl es

found i n huma ns a nd the res ul ti ng phos phol i pi d mol ecul es a re s hown i n Fi gure 3-3B) i s a tta ched to the phos pha te mol ecul e, res ul ti ng i nthe fi na l hea d group of the l i pi d mol ecul e Thi s hea d group i s us ua l l y cha rged, crea ti ng a pa rt of the l i pi d tha t i s hydrophi l i c, a nd wa nts to

be nea r wa ter, a qua l i ty tha t i s es s enti a l for the forma ti on of bi ol ogi ca l membra nes (Cha pter 8) a nd ma ny l i pi d functi ons

Figure 3-3 A Phospholipid Components and Formation Bondi ng between hydroxyl (OH) of a phos pha te group wi th the hydroxyl (OH) of gl ycerol

ca rbon 3 (green) res ul ts i n a phos phol i pi d mol ecul e a nd one wa ter mol ecul e The ba s i c phos phol i pi d i l l us tra ted a bove i s termed

phos pha ti di c a ci d a nd i s the bui l di ng bl ock of common phos phol i pi ds found i n the cel l membra ne (s ee bel ow) Fa tty a ci d cha i ns a re depi cted

i n bl a ck B Common Phospholipids Found in Humans Common hea d groups , whi ch form phos phol i pi ds (top a nd mi ddl e) a nd a re s hown i n bl ue,

bonded to the hydroxyl (OH) of a phos pha te group (purpl e), whi ch i ts el f i s bonded to the hydroxyl (OH) of gl ycerol ca rbon 3 (green) Thi s

s tructure res ul ts i n a phos phol i pi d mol ecul e tha t i s genera l l y found i n membra nes Li pi d mol ecul es a re often repres ented i n “s ti ck di a gra m”form (bottom) wi th the cha rged phos pha te group a nd hydrophi l i c hea d group s hown a s a ci rcl e a nd ova l a nd wi th the fa tty a ci d “ta i l s ,”depi cted a s ei ther s tra i ght or ja gged l i nes , formi ng the hydrophobi c regi on [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 common fa tty a ci ds found i n huma ns a re l i s ted i n Ta bl e 3-1

COMPLEX LIPIDSGLYCOLIPIDS/SPHINGOLIPIDS

Jus t a s ca rbohydra te a nd protei n mol ecul es ca n bi nd together (di s cus s ed i n Cha pter 2), ca rbohydra tes ca n a l s o bi nd to l i pi ds to form a

glycolipid However, i n a huma n gl ycol i pi d, the gl ycerol ba ckbone i s genera l l y repl a ced by a ba ckbone of sphingosine [ma de from the a mi no a ci d

s eri ne a nd the 16-ca rbon fa tty a ci d pa l mi ta te (Fi gure 3-4A)] a nd i s , therefore, referred to a s a sphingolipid Sphi ngos i ne ca n bi nd two othermol ecul es wi th the rema i ni ng hydroxyl (OH) a nd a mi no (NH3) groups from the s eri ne a mi no a ci d In huma n s phi ngol i pi ds , the a mi no group i s

a l wa ys bound to a nother fa tty a ci d to ma ke the mol ecul e ceramide From cera mi de, the pa rti cul a r mol ecul e(s ) a tta ched to the rema i ni ng hydroxyl group defi nes both the na me a nd the cha ra cteri s ti cs of the res ul ti ng s phi ngol i pi d For exa mpl e, the mol ecul e sphingomyelin, whi ch

ca n ma ke up to 20% of the tota l phos phol i pi d i n ma ny bi ol ogi ca l membra nes , i s ma de of cera mi de a nd a phos phoryl chol i ne hea d group(Fi gure 3-4B)

Figure 3-4 A-B Ceramide and Sphingolipids A Cera mi de i s produced from the combi na ti on of the a mi no a ci d s eri ne a nd the 16-ca rbon, fa tty a ci d

pa l mi ta te (green) wi th the s ubs equent a ddi ti on of a s econd fa tty a ci d (bl a ck) to the a mi no (NH3) group (referred to a s N-a cetyl a ti on) Other

mol ecul es ca n then bi nd to the cera mi de hydroxyl (OH) to produce a wi de ra nge of s phi ngol i pi ds i mporta nt to huma ns , a n exa mpl e of whi ch i s

s phi ngomyel i n (B) s hown i n the ri ght pa nel a nd di s cus s ed i n the text C Common Cerebrosides Cerebros i des a re compos ed of s phi ngos i ne a nd

a s i ngl e gl ucos e or ga l a ctos e mol ecul e a tta ched vi a the hydroxyl group a t ca rbon 4 D A Sulfatide Sul fa ti des a re s i mpl y cerebros i des wi th the

a ddi ti on of a ca rbohydra te-l i nked s ul fa te mol ecul e Compa re wi th ga l a ctocerebros i de i n Fi gure 3-4B E A Globoside and GalNAc Carbohydrate

Gl obos i des a re compos ed of cera mi de bonded to a fa tty a ci d vi a the NH group (green) a nd s evera l ca rbohydra te mol ecul es , i ncl udi ng Ga l NAc

(l i ght bl ue s qua re), bonded vi a the s eri ne OH (upper pa nel ) The s tructure of N-a cetyl -ga l a ctos a mi ne or Ga l NAc i s s hown i n the l ower pa nel

wi th the NH a tta chment hi ghl i ghted i n green F A Ganglioside and NANA The s tructure of N-a cetyl neura mi ni c (NANA), a type of s i a l i c a ci d, i s

s hown i n the l ower pa nel (N-a cetyl group i ndi ca ted i n bl ue) [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.]

From the ba s e mol ecul e of a s phi ngol i pi d (e.g., cera mi de), ca rbohydra te mol ecul es ma y a l s o be a tta ched to form a glycosphingolipid In

genera l , huma n gl ycos phi ngol i pi ds a re grouped i nto four ca tegori es

1 Cerebrosides—Cera mi de (s ee a bove) a tta ched to onl y a single gl ucos e or ga l a ctos e res i due, produci ng gl ucos yl cera mi de or

ga l a ctos yl cera mi de, res pecti vel y (Fi gure 3-4C) Cerebros i des a re i mporta nt i n the membra nes of mus cl e a nd nerve cel l s a nd a re l oca ted i nmyel i n, whi ch covers nerve a xons a nd ena bl es fa s t a nd effi ci ent conducti on of nerve i mpul s es Cerebros i des ma y a l s o be i nvol ved i n the

bi ndi ng of morphi ne a nd other opi a tes

2 Sulfatides—Ga l a ctos e-ba s ed gl ycos phi ngol i pi d mol ecul es , whi ch conta i n a s ul fur a tom-conta i ni ng s ul fa te group i n pl a ce of thephos phorous a tom (Fi gure 3-4D) Sul fa ti des a re found ma i nl y i n the bra i n a nd centra l a nd peri phera l nervous s ys tems but a re s een i n tra ce

a mounts i n other ti s s ues Sul fa ti des a re bel i eved to be i nvol ved i n the regul a ti on of cel l growth a nd s i gna l i ng a nd ma y s erve to both hel pform a nd, a l terna ti vel y, brea k down bl ood cl ots pos s i bl y by a ffecti ng the tra ns porta ti on of s odi um a nd pota s s i um i n a nd out of cel l s s uch a s

pl a tel ets Sul fa ti des a l s o ma y pl a y rol es a s a n a dhes i on mol ecul e, i ncl udi ng the recrui tment of i mmune cel l s to i nfl a med ti s s ue a nd the

bi ndi ng a nd repl i ca ti on of i nfl uenza vi rus es Cha nges i n the producti on of s ul fa ti des ha ve been noted a s one of the ea rl i es t i ndi ca tors of

Al zhei mer’s di s ea s e

3 Globosides—Gl ycos phi ngol i pi d mol ecul es wi th the ca rbohydra te mol ecul e N-acetyl-galactosamine (a k.a Ga l NAc) a l ong wi th two or more other

ca rbohydra te mol ecul es (Fi gure 3-4E) Gl obos i des a re found i n s evera l orga ns i ncl udi ng red bl ood cel l s , s erum, l i ver, a nd s pl een Al thoughthe functi ons of gl obos i des a re not wel l unders tood, they a re bel i eved to pl a y a n i mporta nt rol e i n cel l receptors Interes ti ngl y, the bi ndi ng

of Escherichia coli, a ba cteri um common i n uri na ry tra ct i nfecti ons , to cel l s i n the uri na ry tra ct i s bel i eved to occur through gl obos i des

4 Gangliosides—Gl ycos phi ngol i pi d mol ecul es wi th one or more a tta ched sialic acid mol ecul es , mos t often N-acetylneuraminic acid (a.k.a “NANA”),

a compl ex, ni ne-ca rbon ca rbohydra te mol ecul e (Fi gure 3-4F) There a re a l a rge number of di fferent ga ngl i os i des , whi ch di ffer i n thei r

s tructure dependi ng on the number a nd l oca ti on of the ca rbohydra te a nd NANA mol ecul es Ga ngl i os i des a re i nvol ved i n bi ndi ng,

recogni ti on, a nd s i gna l i ng between cel l s Al though ga ngl i os i des a re a bunda nt i n the nervous s ys tem, they a re a l s o bel i eved to pl a y a n

i mporta nt rol e i n bi ndi ng i mmune cel l s Ga ngl i os i des a re a l s o found i n l es s a bunda nce i n other cel l types Ga ngl i os i des a re a l s o bel i eved

to pl a y a rol e i n the bi ndi ng a nd entra nce i nto cel l s of the i nfl uenza vi rus a nd the toxi n tha t ca us es chol era

EICOSANOIDS Eicosanoid i s the genera l term for mol ecul es tha t a re a l l compos ed of 20-ca rbon fa tty a ci ds a nd i nvol ved i n s i gna l i ng The four ma jor groups of

ei cos a noi ds i ncl ude the prostaglandins (PGs), the prostacyclins (PGIs), the thromboxanes (TXs), a nd the leukotrienes (LTs) Functi ons of ei cos a noi ds

i ncl ude promoti on of i nfl a mma ti on (us ua l l y ω-6 deri ved), i mmune res pons e, neurol ogi ca l s i gna l i ng, regul a ti on of bl ood pres s ure, control of

pl a tel et a ggrega ti on/ di s a ggrega ti on, a nd modul a ti on of l evel s of tri a cyl gl ycerol s They a l s o ha ve di rect/i ndi rect effects on a va ri ety of

di s ea s es , i ncl udi ng ca rdi ova s cul a r a nd rheuma toi d pa thol ogi es , a mong other rol es The s i gna l i ng a cti ons of ei cos a noi ds a re ma i nl y

tra ns mi tted vi a G-protei n receptors (Cha pter 8)

Al l ei cos a noi ds a re produced from ei ther ω-6 acids (dihomo-gamma-linolenic acid (DGLA), arachidonic acid (AA), or a n ω-3 acid [eicosapentaenoic acid (EPA)] The predomi na nt s yntheti c pa thwa y for ei cos a noi ds i s vi a the ω-6, AA pa thwa y whos e products a re denoted by the s ubs cri pt “2”

(Fi gure 3-5) LTs a re produced from AA vi a a di fferent pa thwa y i l l us tra ted i n the fi gure Importa ntl y, ei cos a noi ds deri ved from ω-6/DGLA a nd theω-3/EPA precurs ors a re much l es s i nfl a mma tory/a nti -i nfl a mma tory i n na ture Increa s ed i nta ke of DGLA (di eta ry s uppl ements ), es peci a l l y EPA(“ω-3” fi s h oi l s ), res ul ts i n l owered a s s oci a ted di s ea s es vi a di rect competi ti on wi th the AA pa thwa y Medi ca ti ons s uch a s a s pi ri n,

nons teroi da l a nti -i nfl a mma tory drugs , a nd cycl ooxygena s e (COX)-2 i nhi bi tors a l s o decrea s e the i nfl a mma tory effects of PG, PGI, a nd TX

(col l ecti vel y known a s prostanoids) by di rect i nhi bi ti on of COX-1 or -2, whi ch a re key enzymes i n pros ta noi d s ynthes i s (Fi gure 3-5).

Corti cos teroi ds (e.g., predni s ol one) i nhi bi t phos phol i pa s e A2 (Fi gure 3-5)

Figure 3-5 Overview of Eicosanoid Synthetic Pathway Phos phol i pi ds genera ted a s noted a bove (s ee a l s o Fi gure 3-3A) provi de the ba s i c bui l di ng

bl ocks for the forma ti on of a ra chi doni c a ci d (AA), the s ource of a l l ei cos a noi ds The va ryi ng s yntheti c pa thwa ys comi ng from AA a re s hown See

a l s o Ta bl e 3-2 for a revi ew of the ma jor known ei cos a noi ds a nd thei r functi ons [Ada pted wi th permi s s i on from Na i k P: Bi ochemi s try, 3rdedi ti on, Ja ypee Brothers Medi ca l Publ i s hers (P) Ltd., 2009.]

TABLE 3-2 Overvi ew of Ei cos a noi ds

More s peci fi ca l l y, PGs a re ei cos a noi ds whos e ma jor functi ons i ncl ude regul a ti on of i nfl a mma ti on, s mooth mus cl e contra cti on (bl oodves s el s , ga s troi ntes ti na l , bronchi a l , a nd uterus ), neurol ogi ca l pa i n, pl a tel et functi on, hormone a cti vi ty, a nd cel l growth PGIs a re deri ved

di rectl y from a pros ta gl a ndi n precurs or (PGH2) a nd a re i mporta nt i n decrea s i ng pl a tel et functi on a nd, therefore, bl ood cl ot forma ti on a s wel l

a s di l a ti on of bl ood ves s el s TXs a re a l s o deri ved from PGH2 a nd, oppos i te of PGIs , a ct a s va s ocons tri ctors to promote pl a tel et a ggrega ti on a nd

bl ood cl ot forma ti on LTs , the fourth cl a s s of ei cos a noi ds , a re produced vi a a pa thwa y tha t devi a tes from the other ei cos a noi ds ’ producti on a t

AA (Fi gure 3-5) LTs a re ma i nl y s een i n i nfl a mma tory proces s es of the l ung, i ncl udi ng a s thma ti c rea cti ons a nd the i nfl a mma ti on a s s oci a ted

wi th bronchi ti s Speci fi c functi ons of the ma jor ei cos a noi ds a nd thei r rol e i n di s ea s e a nd trea tments a re revi ewed i n Ta bl e 3-2 a nd wi l l becovered further i n Secti on III

ABO Blood Groups: The huma n bl ood groups O, A, B, a nd AB a re determi ned by s peci fi c gl ycos phi ngol i pi ds found i n the red cel l membra ne The ba s i c gl ycos phi ngol i pi d, ca l l ed “H-substance,” i s compos ed of a s phi ngol i pi d connected to three ca rbohydra te mol ecul es a nd a

membra ne-bound protei n The a ddi ti on of s peci fi c, extra ca rbohydra te mol ecul e to a ga l a ctos e res i due on H-s ubs ta nce produces the fourcommon bl ood types a s fol l ows :

Eicosanoids and Inflammation: Infl a mma ti on i s often cha ra cteri zed by the four s i gns of ca l or, dol or, tumor, a nd rubor Ea ch of thes e fea tures

res ul ts , a t l ea s t i n pa rt, from the a cti on of one or more ei cos a noi ds Calor (wa rmth) i s ca us ed by the pros ta gl a ndi n PGE2 Dolor (pa i n) i s

hei ghtened vi a the a cti on of PGE2, whi ch a l s o i ncrea s es the s ens i ti vi ty of neurons Tumor (s wel l i ng) res ul ts from the l ea ka ge of pl a s ma from

bl ood ves s el s whos e permea bi l i ty i s i ncrea s ed by the l eukotri ene LTB4 Infl a mma tory rubor (rednes s ) res ul ts from the a cti on of

thromboxa ne TXA2, i ni ti a l l y rel ea s ed a fter i njury, whi ch s ubs equentl y i ncrea s es the concentra ti on a nd, therefore, the bl ood ves s el di l a ti on

a cti vi ty of PGE2 a nd LTB4, res ul ti ng i n engorged ves s el s a nd reddeni ng

CHOLESTEROL Cholesterol i s a n extremel y i mporta nt mol ecul e found onl y i n euka ryoti c orga ni s ms wi th a va ri ety of functi ons i n the huma n body Al though

huma ns ca n ma ke chol es terol , they ha ve to rel y on a compl ex mecha ni s m of bi ndi ng a nd modi fi ca ti ons by other mol ecul es s o tha t chol es terol

ma y be el i mi na ted from the body (s ee bel ow) As a res ul t, properl y control l i ng the da y-toda y a mount of chol es terol i n the body—a ba l a ncebetween producti on, el i mi na ti on, a nd the externa l i nfl uence of di eta ry i nta ke—ca n pl a y a key rol e i n hea l th a nd i l l nes s The functi ons ofchol es terol a re l i s ted bel ow

1 Chol es terol i s one of the es s enti a l l i pi d components of bi ol ogi ca l membra nes where i t i s a modul a tor of the fl ui di ty of membra nes The

a bi l i ty of membra nes to modi fy thei r s tructure a nd/or the a bi l i ty for other mol ecul es to be a bl e to move wi thi n the membra ne i s cri ti ca l forcel l s i gna l i ng, bi ndi ng, wound hea l i ng, i mmune res pons e, a nd s o on

2 Chol es terol s erves a s the pri ma ry s ource for the producti on of s teroi d hormones (s ee next s ecti on bel ow), bi l e s a l ts , a nd even vi ta mi n D.

3 Chol es terol meta bol i s m i s a l s o i mporta nt i n the regul a ti on of the tra ns porta ti on of l i pi ds throughout the body, a nd di s turba nce of thi s

s ys tem l ea ds to the depos i ti on of chol es terol i n the a rtery wa l l ca us i ng a theros cl eros i s , whi ch ul ti ma tel y l ea ds to hea rt a tta cks a nd s trokes

An unders ta ndi ng of thi s regul a ti on ha s l ed to i mporta nt trea tments for decrea s i ng the ri s k of thes e di s ea s es

The chol es terol mol ecul e ha s four ri ngs ma de of ca rbon a toms —three ri ngs ha ve s i x s i des a nd one ha s fi ve s i des —wi th a s i x-ca rbon ri ng

ta i l (Fi gure 3-6A) Mos t of the ca rbons a re s i ngl e bonded a nd, therefore, ha ve thei r ful l compl ement of hydrogen a toms The three-di mens i ona l

s tructure of chol es terol i s a pproxi ma tel y a fl a t pl a ne, expos i ng a l l of the hydrophobi c pa rts of the chol es terol mol ecul e to the envi ronment.Onl y one hydroxyl group wi th i ts hydrophi l i c na ture crea tes a ny cha rged qua l i ty to the chol es terol mol ecul e As a res ul t, chol es terol does not

l i ke to be expos ed to wa ter envi ronments , preferri ng to be s hi el ded by other hydrophobi c mol ecul es s uch a s l i pi ds or hydrophobi c pa rts ofprotei ns The i mpa ct of chol es terol ’s uni que s tructure a nd i ts rol e i n pl a s ma membra ne s tructure a nd fl ui di ty wi l l be exa mi ned further i nCha pter 8

Figure 3-6 Cholesterol Molecule (A) Unesterified and (B) Esterified A Unes teri fi ed chol es terol mol ecul e wi th free end hydroxyl group crea ti ng a hydrophi l i c cha rge i mporta nt i n bi ol ogi ca l membra ne pa cki ng B Es teri fi ed chol es terol mol ecul e wi th R group bonded by es ter bond to oxygen

from end hydroxyl group The R group i s us ua l l y a fa tty a ci d bonded to chol es terol by the enzyme l eci thi n chol es terol a cyl tra ns fera s e (LCAT).[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.]

However, s ome chol es terol i s a l s o found outs i de of bi ol ogi ca l membra nes i n a drena l gl a nds , bl ood, a nd other ti s s ues where i t i s oftenbonded vi a the hydroxyl group to a l ong fa tty a ci d a s a chol es terol es ter (Fi gure 3-6B) Thes e chol es terol es ters a re hi ghl y hydrophobi c a nd

i ns ol ubl e a nd ca n form fa tty l es i ons or “pl a ques ” i n the a rtery wa l l tha t ca n l ea d to hea rt a tta cks or s trokes Fortuna tel y, the huma n body ha sdevel oped a uni que wa y of a ddres s i ng thi s probl em, na mel y by formi ng l i poprotei ns (s ee bel ow a nd Fi gure 3-7)

Figure 3-7 Basic Lipoprotein Structure Li poprotei n compl exes a re compos ed of a centra l l i pi d core (chol es terol es ter a nd tri a cyl gl ycerol

mol ecul es ), a cha rged l i pi d outer s hel l (phos phol i pi d a nd chol es terol mol ecul es ), a nd s urroundi ng a poprotei ns tha t hel p to tra ns port

hydrophobi c l i pi d mol ecul es throughout the body [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, 28thedi ti on, McGra w-Hi l l , 2009.]

Cholesterol, Phospholipids, Gangliosides, and Cancer: Emergi ng res ea rch ha s s hown tha t s ome ca ncer cel l s (e.g., meni ngos a rcoma a nd certa i n

l eukemi a s ) ha ve s i gni fi ca nt cha nges i n thei r cel l membra ne chol es terol , phos phol i pi d, a nd ga ngl i os i de content tha t a l ters the membra ne

fl ui di ty a s wel l a s l i pi d s i gna l i ng tha t produces unregul a ted growth or ca rci nogenes i s Thes e cha nges ca n a l s o ca us e res i s ta nce to a gents

us ed to trea t ca ncer Unders ta ndi ng how cha ngi ng membra ne compos i ti on l ea ds to thes e fi ndi ngs ma y hel p to devel op new a nd di fferent

ca ncer-fi ghti ng a gents wi th a uni que mecha ni s m of l i pi d a tta ck

LIPOPROTEINS Lipoproteins, a s the na me i mpl i es , a re formed from the compl exes of l i pi d a nd protei n mol ecul es Unl i ke gl ycol i pi ds , i n whi ch s i mpl e bonds

connect the pri nci pa l component mol ecul es , l i poprotei ns a re fa r more compl ex a nd form l a rge pa rti cl es conta i ni ng s evera l l i pi d cl a s s es a ndprotei n Thei r compl exi ty emerges from the pri ma ry functi on of l i poprotei ns , na mel y the tra ns porta ti on a nd del i very of fa tty a ci ds ,

tri a cyl gl ycerol , a nd chol es terol to a nd from ta rget cel l s i n a va ri ety of orga ns (s ee a l s o Cha pter 7 for further di s cus s i on) Thus , a l though

gl ycol i pi ds once produced a nd i n thei r fi na l l oca ti on rema i n there for rel a ti vel y l ong peri ods of ti me, l i po-protei ns a re more tra ns i ent Thebondi ng a nd s tructure of l i poprotei ns refl ect thi s cha ra cteri s ti c

A s i mpl i fi ed model of a l i poprotei n i ncl udes a center core compos ed of chol es terol es ter a nd tri a cyl gl ycerol mol ecul es s urrounded by a nouter s hel l of phos phol i pi ds a nd chol es terol mol ecul es wi th thei r hydrophobi c a rea s i nwa rd towa rd the l i pi d core a nd thei r cha rged,

hydrophi l i c a rea s fa ci ng outwa rd towa rd the a queous envi ronment (Fi gure 3-7) Speci a l i zed protei ns , known a s apoproteins, wra p a round theouter s hel l of the l i po-protei n pa rti cl e a l s o i nvol ved i n i ntera cti ons wi th externa l wa ter The compos i ti on of l i poprotei n pa rti cl es va ri es butthey ca n be broa dl y ca tegori zed dependi ng on thei r dens i ty a s s hown i n Ta bl e 3-3 Li poprotei ns , thei r components , functi on, meta bol i s m, a ndmedi ca l i mpl i ca ti ons wi l l be di s cus s ed i n much more deta i l i n Cha pters 11 a nd 16

TABLE 3-3 Ba s i c Li poprotei n Cha ra cteri s ti cs

BILE SALTS Bile salts, compos ed of bi l e a ci ds conjuga ted wi th gl yci ne or ta uri ne (Fi gure 3-8A), a re produced i n the l i ver di rectl y from chol es terol a nd a re

i mporta nt i n s ol ubi l i zi ng di eta ry fa ts i n the ma i nl y wa tery envi ronment of the s ma l l i ntes ti ne After producti on i n the l i ver a nd pri or to

s ecreti on i nto the ga l l bl a dder a nd/or di ges ti ve s ys tem, they a re often bonded to the a mi no a ci d gl yci ne (Cha pter 1) or ta uri ne, a deri va ti ve ofthe common a mi no a ci d cys ti ne (Cha pter 1), to i ncrea s e thei r wa ter s ol ubi l i ty (Fi gure 3-8B) Gl yco- a nd ta uro-bi l e a ci ds a re a l s o ca l l ed a sconjuga ted bi l e a ci ds

Figure 3-8 A-B Major Bile Acids and Bile Salts Found in Humans A Bi l e s a l ts , i ncl udi ng the pri ma ry forms chol i c a ci d a nd chenodeoxychol i c a ci d,

a re produced by the l i ver a nd commonl y found i n huma ns Remova l of hydroxyl groups (OH) by i ntes ti na l ba cteri a produces the s econda ry bi l e

a ci ds deoxychol i c a ci d a nd l i thochol i c a ci d [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.] B The a ddi ti on of the a mi no a ci d gl yci ne (l eft) or the cys ti ne-rel a ted ta uri ne (bottom ri ght) i ncrea s es the

s ol ubi l i ty of the bi l e s a l ts [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.]

Bile Salt Sequestrants: Medi ci nes tha t bi nd wi th or “s eques ter” a nd hel p excrete bi l e s a l ts a re s ometi mes us ed i n pa ti ents wi th hi gh

chol es terol l evel s i n thei r bl ood The remova l of thes e bi l e s a l ts ca us es further producti on of repl a cement bi l e a ci ds from the body’s

chol es terol s tore to a l l ow fa t di ges ti on, thereby l oweri ng the tota l chol es terol i n thes e pa ti ents However, s uch trea tments ca n i nterfere

wi th norma l l i pi d a bs orpti on a ffecti ng di eta ry requi rements a s wel l a s res ul ti ng i n the unpl ea s a nt s i de effect of fa tty, foul -s mel l i ng bowelmovements

LIPID-DERIVED HORMONES/VITAMIN DSteroid hormones , whi ch a re a l l produced from chol es terol (Fi gure 3-9), perform a va ri ety of di fferent functi ons i n the huma n body a s l i s ted

bel ow