High levels of phosphate in the cell favor glycogen breakdown and prevent the phos-phorylase reaction from synthesizing glycogen in vivo, despite the fact that G° for the phosphorylase r
Trang 1hibition by fructose-2,6-bisphosphate, whereas phosphofructokinase is allosterically
activated by fructose-2,6-bisphosphate The combination of these effects should
per-mit either phosphofructokinase or fructose-1,6-bisphosphatase (but not both) to
operate at any one time and should thus prevent futile cycling For instance, in
the fasting state, when food (that is, glucose) intake is zero, phosphofructokinase
(and therefore glycolysis) is inactive due to the low concentration of
fructose-2,6-bisphosphate In the liver, gluconeogenesis operates to provide glucose for the
brain However, in the fed state, up to 30% of fructose-1,6-bisphosphate formed
from phosphofructokinase is recycled back to fructose-6-P (and then to glucose)
Because the dependence of bisphosphatase activity on
fructose-1,6-bisphosphate is sigmoidal in the presence of fructose-2,6-fructose-1,6-bisphosphate (see
Figure 22.9), substrate cycling occurs only at relatively high levels of
fructose-1,6-bisphosphate Substrate cycling in this case prevents the accumulation of excessively
high levels of fructose-1,6-bisphosphate
Dietary Starch Breakdown Provides Metabolic Energy
As noted earlier, well-fed adult human beings normally metabolize about 160 grams
of carbohydrates each day A balanced diet easily provides this amount, mostly in the
form of starch If too little carbohydrate is supplied by the diet, glycogen reserves in
liver and muscle tissue can also be mobilized The reactions by which ingested starch
and glycogen are digested are shown in Figure 22.11 The enzyme known as
␣-amy-laseis an important component of saliva and pancreatic juice (-Amylase is found
in plants The - and -designations for these enzymes serve only to distinguish the
two and do not refer to glycosidic linkage nomenclature.) -Amylase is an
endogly-cosidase that hydrolyzes (1⎯→4) linkages of amylopectin and glycogen at random
positions, eventually producing a mixture of maltose, maltotriose [with three
(1⎯ →4)-linked glucose residues], and other small oligosaccharides -Amylase can
-Amylase
-Amylase
-(1 6)-glucosidase
FIGURE 22.11 (a) The sites of hydrolysis of starch by
- and -amylase are indicated (b) Glycogenin is a
glycosyltransferase that initiates eukaryotic glycogen synthesis from glucose Bound UDP-glucose (blue) and
Mn 2 ion (purple) are shown (pdb id 1LL2).
Trang 2cleave on either side of an amylopectin branch point, but activity is reduced in highly branched regions of the polysaccharide and stops four residues from any branch point
The highly branched polysaccharides that are left after extensive exposure to
-amylase are called limit dextrins These structures can be further degraded by the
action of a debranching enzyme, which carries out two distinct reactions The first of these, known as oligo(␣1,4→␣1,4) glucanotransferase activity, removes a
trisaccha-ride unit and transfers this group to the end of another, nearby branch (Figure 22.12) This leaves a single glucose residue in (1⎯→6) linkage to the main chain The
␣(1⎯→6) glucosidase activity of the debranching enzyme then cleaves this residue
from the chain, leaving a polysaccharide chain with one branch fewer Repetition of this sequence of events leads to complete degradation of the polysaccharide
-Amylase is an exoglycosidase that cleaves maltose units from the free,
nonre-ducing ends of amylopectin branches, as in Figure 22.11 Like -amylase, however,
-amylase does not cleave either the (1⎯→6) bonds at the branch points or the
(1⎯→4) linkages near the branch points
Metabolism of Tissue Glycogen Is Regulated
Digestion itself is a highly efficient process in which almost 100% of ingested food
is absorbed and metabolized Digestive breakdown of starch is an unregulated process On the other hand, tissue glycogen represents an important reservoir of potential energy, and it should be no surprise that the reactions involved in its degradation and synthesis are carefully controlled and regulated Glycogen re-serves in liver and muscle tissue are stored in the cytosol as granules exhibiting a molecular weight range from 6 106 to 1600 106 These granular aggregates contain the enzymes required to synthesize and catabolize the glycogen, as well as all the enzymes of glycolysis
The principal enzyme of glycogen catabolism is glycogen phosphorylase, a highly
regulated enzyme that was discussed extensively in Chapter 15 The glycogen phos-phorylase reaction (Figure 22.13) involves phosphorolysis at a nonreducing end of
a glycogen polymer The standard-state free energy change for this reaction is
O O
O
O O
O O
O
O O
O
O
O O
HO
O O
O O
O
O
O O
O O
O
O
O O
O O
O O
O
O
O
O
O O
O
O
O
O
HO
O O
HO
HO
Limit branch
Limit dextrin
Debranching enzyme
(1 6)-glucosidase activity
of debranching enzyme cleaves this residue
Further cleavage by -amylase
FIGURE 22.12 The reactions of debranching enzyme.
Transfer of a group of three (1⎯→4)-linked glucose
residues from a limit branch to another branch is
fol-lowed by cleavage of the (1⎯→6) bond of the residue
that remains at the branch point.
Trang 33.1 kJ/mol, but the intracellular ratio of [Pi] to [glucose-1-P] approaches 100, and
thus the actual G in vivo is approximately 6 kJ/mol There is an energetic
ad-vantage to the cell in this phosphorolysis reaction If glycogen breakdown were
hy-drolytic and yielded glucose as a product, it would be necessary to phosphorylate
the product glucose (with the expenditure of a molecule of ATP) to initiate its
gly-colytic degradation
The glycogen phosphorylase reaction degrades glycogen to produce limit
dex-trins, which are further degraded by debranching enzyme, as already described
Animals synthesize and store glycogen when glucose levels are high, but the
syn-thetic pathway is not merely a reversal of the glycogen phosphorylase reaction High
levels of phosphate in the cell favor glycogen breakdown and prevent the
phos-phorylase reaction from synthesizing glycogen in vivo, despite the fact that G° for
the phosphorylase reaction actually favors glycogen synthesis Hence, another
reac-tion pathway must be employed in the cell for the net synthesis of glycogen In
essence, this pathway must activate glucose units for transfer to glycogen chains
Glucose Units Are Activated for Transfer by Formation
of Sugar Nucleotides
We are familiar with several examples of chemical activation as a strategy for group
transfer reactions Acetyl-CoA is an activated form of acetate; biotin and
tetrahydro-folate activate one-carbon groups for transfer; and ATP is an activated form of
phos-phate Luis Leloir, a biochemist in Argentina, showed in the 1950s that glycogen
syn-thesis depended upon sugar nucleotides, which may be thought of as activated forms
of sugar units For example, formation of an ester linkage between the C-1 hydroxyl
group and the -phosphate of UDP activates the glucose moiety of UDP–glucose.
HOCH2
O
H
H
OH O
H
O
O–
O
O–
CH2 O
H
H
N
O
HN
O
Uridine diphosphate glucose
(UDPG)
CH2OH O
O
CH2OH O
O
CH2OH O
O
CH2OH O
O
+
CH2OH
O
CH2OH O
O
CH2OH O
O
CH2OH O
O OPO3–
P
OH HO
HO
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH HO
n
n – 1
Uridine diphosphate glucose (UDP–glucose).
Trang 4UDP–Glucose Synthesis Is Driven by Pyrophosphate Hydrolysis
Sugar nucleotides are formed from sugar-1-phosphates and nucleoside
triphos-phates by specific pyrophosphorylase enzymes (Figure 22.14) For example, UDP– glucose pyrophosphorylasecatalyzes the formation of UDP–glucose from glucose-1-phosphate and uridine 5-triphosphate:
Glucose-1-P UTP ⎯⎯→ UDP–glucose pyrophosphate The reaction proceeds via attack by a phosphate oxygen of glucose-1-phosphate on the-phosphorus of UTP, with departure of the pyrophosphate anion The reaction
is a reversible one, but—as is the case for many biosynthetic reactions—it is driven forward by subsequent hydrolysis of pyrophosphate:
Pyrophosphate H2O⎯⎯→ 2 Pi
The net reaction for sugar nucleotide formation (combining the preceding two equations) is thus
Glucose-1-P UTP H2O⎯⎯→ UDP–glucose 2 Pi
Sugar nucleotides of this type act as donors of sugar units in the biosynthesis of oligosaccharides and polysaccharides In animals, UDP–glucose is the donor of glu-cose units for glycogen synthesis, but ADP–gluglu-cose is the gluglu-cose source for starch synthesis in plants
Glycogen Synthase Catalyzes Formation of ␣(1⎯ →4) Glycosidic Bonds in Glycogen
The very large glycogen polymer is built around a tiny protein core The first
glu-cose residue is covalently joined to the protein glycogenin (see Figure 22.11b) via
an acetal linkage to a tyrosine–OH group on the protein Sugar units can then be
added by the action of glycogen synthase The reaction involves transfer of a
glu-P glu-P
CH2OH O
OH HO
HO
O
O–
O
–O
O
–O
O
–O
O
H
H
N
HN
O O
P
2
CH2OH O
OH HO
HO
O
–O
O
–O
O
H
H
N
HN
O O
UTP
Glucose-1-P
UDP–glucose pyrophosphorylase
UDP–glucose
ANIMATED FIGURE 22.14 The UDP–
glucose pyrophosphorylase reaction is a
phospho-anhydride exchange, with a phosphoryl oxygen of
glucose-1-P attacking the -phosphorus of UTP to form
UDP–glucose and pyrophosphate See this figure
ani-mated at www.cengage.com/login.
Glycogen synthase from Agrobacterium tumefaciens
consists of two Rossman folds (see Chapter 16)
sepa-rated by a deep cleft that includes the active site
(shown here with bound ADP, purple) (pdb id 1RZU).
Trang 5cosyl unit from UDP–glucose to the C-4 hydroxyl group at a nonreducing end of a
glycogen strand The mechanism proceeds by cleavage of the COO bond between
the glucose moiety and the -phosphate of UDP–glucose, leaving an oxonium ion
intermediate, which is rapidly attacked by the C-4 hydroxyl oxygen of a terminal
glu-cose unit on glycogen (Figure 22.15) The reaction is exergonic and has a G° of
13.3 kJ/mol
Glycogen Branching Occurs by Transfer of Terminal Chain Segments
Glycogen is a branched polymer of glucose units The branches arise from
(1⎯→6) linkages, which occur every 8 to 12 residues As noted in Chapter 7, the
branches provide multiple sites for rapid degradation or elongation of the
poly-mer and also increase its solubility Glycogen branches are formed by
amylo-HUMAN BIOCHEMISTRY
Advanced Glycation End Products—A Serious Complication of Diabetes
Covalent linkage of sugars to proteins to form glycoproteins
nor-mally occurs through the action of enzymes that use sugar
nucleo-tides as substrates However, sugars may also react
nonenzymati-cally with proteins The C-1 carbonyl group of glucose forms Schiff
base linkages with lysine side chains of proteins These Schiff base
adducts undergo Amadori rearrangements and subsequent
oxida-tions to form irreversible “glycation” products, including
carboxy-methyllysine and pentosidine derivatives (see accompanying
fig-ure) These advanced glycation end products (AGEs) can alter
the function of the protein Such AGE-dependent changes are thought to contribute to circulation, joint, and vision problems in people with diabetes
Nonenzymatic glycation of hemoglobin is a better diagnostic yardstick for type-2 diabetes than serum glucose levels Red blood cells have an average life expectancy of about 4 months By mea-suring the concentration of “glycated hemoglobin” in a patient, it
is possible to determine the average glucose concentration in the blood over the past several months
CH2OH
(CH2)4 (CH2)3
CH
H
CHO
OH C
N
O
NH2
CH
H
CH2OH
H
Protein
+
+
+
Protein
N
CH2OH
CH2
O C H
H
Protein
H N
N
H
O C HN C N
(CH2)4
NH
N
H C C
CH2
COO–
Rearrangement leads to irreversibly glycated proteins
Schiff base
Pentosidine Carboxymethyllysine
Other advanced glycation end products
Trang 6(1,4⎯→1,6)-transglycosylase, also known as branching enzyme The reaction involves
the transfer of a 6- or 7-residue segment from the nonreducing end of a linear chain at least 11 residues in length to the C-6 hydroxyl of a glucose residue of the same chain or another chain (Figure 22.16) For each branching reaction, the resulting polymer has gained a new terminus at which growth can occur
Glycogen Metabolism Is Highly Regulated
Synthesis and degradation of glycogen must be carefully controlled so that this im-portant energy reservoir can properly serve the metabolic needs of the organism Glu-cose is the principal metabolic fuel for the brain, and the concentration of gluGlu-cose in
circulating blood must be maintained at about 5 mM for this purpose Glucose derived
from glycogen breakdown is also a primary energy source for muscle contraction Con-trol of glycogen metabolism is effected via reciprocal regulation of glycogen phospho-rylase and glycogen synthase Thus, activation of glycogen phosphophospho-rylase is tightly linked to inhibition of glycogen synthase, and vice versa Regulation involves both al-losteric control and covalent modification, with the latter being under hormonal con-trol The regulation of glycogen phosphorylase is discussed in detail in Chapter 15
Glycogen Synthase Is Regulated by Covalent Modification
Glycogen synthase also exists in two distinct forms that can be interconverted by the
action of specific enzymes: active, dephosphorylated glycogen synthase I P–independent) and less active, phosphorylated glycogen synthase D
(glucose-6-H+
O
OH HO
CH2OH
HO
O–
O
O–
O
O N O
O
HN
OH OH
H H
O
OH O
CH2OH
HO
O
O
OH O
CH2OH
HO
O
OH O
CH2OH
HO
O
OH HO
CH2OH
HO
O
OH O
CH2OH
HO
O
O
OH O
CH2OH
HO
O
OH HO
CH2OH
HO
O
OH HO
CH2OH
HO
+
UDP–glucose
UDP
Glycogen (n residues)
Oxonium ion intermediate
Glycogen (n+ 1 residues)
ANIMATED FIGURE 22.15 The glycogen synthase reaction Cleavage of the C OO bond of UDP–glucose yields an oxonium intermediate Attack by the hydroxyl oxygen of the terminal residue of a
glycogen molecule completes the reaction See this figure animated at www.cengage.com/login.
(1 4)-terminal
chains of glycogen
Branching enzyme cuts here
and transfers
a seven-residue
terminal segment
to a C(6)–OH
group
FIGURE 22.16 Formation of glycogen branches by the
branching enzyme Six- or seven-residue segments of
a growing glycogen chain are transferred to the C-6
hydroxyl group of a glucose residue on the same or a
nearby chain.
Trang 7P–dependent) The phosphorylated form can be allosterically activated by
glucose-6-phosphate, but the unphosphorylated enzyme is insensitive to this allosteric effector
(Figure 22.17) The nature of phosphorylation is complex (Figure 22.17a) At least
nine serine residues on the enzyme appear to be subject to phosphorylation, each
site’s phosphorylation having some effect on enzyme activity Four protein kinases
are involved in phosphorylation of glycogen synthase: casein kinase, AMP-dependent
protein kinase, protein kinase A, and glycogen synthase kinase 3 (GSK3)
Dephosphorylation of both glycogen phosphorylase and glycogen synthase is
car-ried out by phosphoprotein phosphatase-1 (PP1) The action of PP1 inactivates
glycogen phosphorylase and activates glycogen synthase
Insulin receptor
Insulin
(a)
Glucose
Glucose
Glucose-6-P Allosteric
activation
ATP
ADP
P P
P
P P
Plasma membrane
GLUT4 vesicle
Protein kinase cascade
Protein kinase cascade
GSK3
(inactive)
GSK3 (active)
Glycogen
synthase I
(active)
Glycogen synthase D (inactive)
PP-1
+
+
+ +
+
(b)
Protein phosphorylation and second messenger modulation
Gluconeogenesis Active transport
Glycogen
synthesis
Lipid synthesis
Lipid breakdown
Insulin receptor
Insulin
FIGURE 22.17 (a) Binding of insulin to plasma
mem-brane receptors in the liver and muscles triggers protein kinase cascades that stimulate glycogen synthesis Insulin’s effects include inactivation of GSK3 and stimu-lation of PP1, both actions activating glycogen synthase,
as well as recruitment of GLUT4 to the plasma mem-brane Glucose uptake provides substrate for glycogen synthesis and glucose-6-phosphate, which allosterically activates the otherwise inactive form of glycogen
synthase (b) The metabolic effects of insulin are
medi-ated through protein phosphorylation and second mes-senger modulation.
Trang 8Hormones Regulate Glycogen Synthesis and Degradation
Storage and utilization of tissue glycogen, maintenance of blood glucose concentra-tion, and other aspects of carbohydrate metabolism are meticulously regulated by
hor-mones, including insulin, glucagon, epinephrine, and the glucocorticoids.
Insulin Is a Response to Increased Blood Glucose The primary hormone
responsi-ble for conversion of glucose to glycogen is insulin (see Figure 5.8) Insulin is secreted
by the -cells in the pancreas within the islets of Langerhans Secretion of insulin is a
re-sponse to increased glucose in the blood When blood glucose levels rise (after a meal, for
example), insulin is secreted from the pancreas into the pancreatic vein, which
emp-ties into the portal vein system (Figure 22.18), so insulin traverses the liver before it
enters the systemic blood supply Insulin acts to rapidly lower blood glucose concen-tration in several ways Insulin stimulates glycogen synthesis and inhibits glycogen breakdown in liver and muscle
Insulin Triggers Glycogen Synthesis When Blood Glucose Rises The action of insulin when blood glucose rises is immediate and powerful During periods be-tween meals, typical human blood glucose levels are 70 to 90 mg/dL Glucose lev-els normally rise to about 150 mg/dL within the first hour following a carbohydrate-rich meal (Figure 22.19) and then return to normal within 2 to 3 hours (For diabetic subjects, whose insulin response is impaired, glucose levels rise after a meal
to 250 mg/dL or even higher and remain high for much longer times.)
A DEEPER LOOK
Carbohydrate Utilization in Exercise
Animals have a remarkable ability to “shift gears” metabolically
dur-ing periods of strenuous exercise or activity Metabolic adaptations
allow the body to draw on different sources of energy (all of which
produce ATP) for different types of activity During periods of
short-term, high-intensity exercise (such as a 100-m dash), most of
the required energy is supplied directly by existing stores of
ATP and creatine phosphate (see figure, part a) Long-term,
low-intensity exercise (such as a 10-km run or a 42.2-km marathon) is
fueled almost entirely by aerobic metabolism Between these
ex-tremes is a variety of activities (an 800-m run, for example) that rely
on anaerobic glycolysis—conversion of glucose to lactate in the
muscles and utilization of the Cori cycle
For all these activities, breakdown of muscle glycogen provides
much of the needed glucose The rate of glycogen consumption
depends on the intensity of the exercise (see figure, part b) By contrast, glucose derived from gluconeogenesis makes only small contributions to total glucose consumed during exercise During prolonged mild exercise, gluconeogenesis accounts for only about 8% of the total glucose consumed During heavy exercise, this percentage becomes even lower
Choice of diet has a dramatic effect on glycogen recovery fol-lowing exhaustive exercise A diet consisting mainly of protein and fat results in very little recovery of muscle glycogen, even af-ter 5 days (see figure, part c) On the other hand, a high-carbo-hydrate diet provides faster restoration of muscle glycogen Even in this case, however, complete recovery of glycogen stores takes about 2 days
100
75
50
25
0
(a)
0
Duration of work (sec)
from phosphocreatine
Anaerobic metabolism
Aerobic metabolism from ATP
24
Muscle glycogen content (grams/kg of muscle)
20
16
12
0
(c)
0 Hours of recovery
8
4
2 hours of exercise
High-carbohydrate diet
No food Fat & protein diet
Light exercise 100
75
50
25
0
(b)
0 Exercise time (min)
Moderate exercise
Heavy exercise
䊱 (a) Contributions of the various energy sources to muscle activity during mild exercise (b)
Con-sumption of glycogen stores in fast-twitch muscles during light, moderate, and heavy exercise
(c)Rate of glycogen replenishment following exhaustive exercise (a and c adapted from Rhodes, R., and
Pflanzer, R G., 1992 Human Physiology Philadelphia: Saunders College Publishing; b adapted from Horton, E S., and
Terjung, R L., 1988 Exercise, Nutrition and Energy Metabolism New York: Macmillan.)
Liver
Spleen
Splenic vein
Pancreatic veins Pancreas
Portal vein
FIGURE 22.18 The portal vein system carries pancreatic
secretions such as insulin and glucagon to the liver and
then into the rest of the circulatory system.
Trang 9Insulin lowers blood glucose by triggering several cascades of reactions that
result in glucose uptake and glycogen synthesis (see Figure 22.17a) An
insulin-triggered protein kinase cascade increases glucose transport into muscle, liver, and
adipose tissues by stimulating exocytotic processes that translocate GLUT4, a
glu-cose transporter, from intracellular vesicles to the plasma membrane (see Figure
22.17a) Large amounts of glucose thus transported into the cell are converted to
6-P, which can be directed to glycogen synthesis (by conversion to
glucose-1-P) Also, glucose-6-P is the allosteric effector that activates the otherwise inactive,
phosphorylated form of glycogen synthase
Binding of insulin to the plasma membrane, in either liver or muscle cells,
trig-gers another protein kinase cascade (see Figure 15.17 and Chapter 32) that results
in phosphorylation and inactivation of glycogen synthase kinase 3 (GSK3) This
ki-nase normally phosphorylates and inactivates glycogen synthase Inhibition of GSK3
means that more of the cell’s glycogen synthase will remain in the
unphosphory-lated, active state (see Figure 22.17a) Insulin also stimulates PP1, which
dephos-phorylates (and activates) glycogen synthase
Several other physiological effects of insulin also serve to lower blood and tissue
glucose levels (see Figure 22.17b) Insulin increases cellular utilization of glucose by
inducing the synthesis of several important glycolytic enzymes, namely, glucokinase,
phosphofructokinase, and pyruvate kinase In addition, insulin acts to inhibit
sev-eral enzymes of gluconeogenesis These various actions enable the organism to
re-spond quickly to increases in blood glucose levels
Glucagon and Epinephrine Stimulate Glycogen Breakdown Catabolism of tissue
glycogen is triggered by the actions of the hormones epinephrine and glucagon
(Fig-ure 22.20) In response to decreased blood glucose, glucagon is released from the -cells
in pancreatic islets of Langerhans This peptide hormone travels through the blood
to specific receptors on liver cell membranes (Glucagon acts on liver and adipose
tissue but not other tissues.) Similarly, signals from the central nervous system cause
release of epinephrine—also known as adrenaline—from the adrenal glands into the
bloodstream Epinephrine acts on liver and muscles When either hormone binds to
its receptor on the outside surface of the cell membrane, a cascade is initiated that
activates glycogen phosphorylase and inhibits glycogen synthase (Figure 22.20) The
result of these actions is tightly coordinated stimulation of glycogen breakdown and
inhibi-tion of glycogen synthesis.
The Phosphorylase Cascade Amplifies the Hormonal Signal Stimulation of
glyco-gen breakdown involves consumption of molecules of ATP at three different steps in
the hormone-sensitive adenylyl cyclase cascade (see Figure 15.17) Note that the
cas-cade mechanism is a means of chemical amplification, because the binding of just a
300
Normal Diabetic
250
0
50 100 150 200
Time, minutes
FIGURE 22.19 A glucose tolerance test involves inges-tion of a glucose soluinges-tion followed by measurements
of blood glucose for about 3 hours Normal subjects exhibit a rise in blood glucose to about 150 mg/dL, followed by a decline to normal values over a 3-hour period In diabetic subjects, blood glucose rises to higher values and remains high for longer periods.
HUMAN BIOCHEMISTRY
von Gierke Disease—A Glycogen-Storage Disease
In 1929, the physician Edgar von Gierke treated a patient with a very
enlarged abdomen The patient’s liver and kidneys were severely
enlarged due to massive accumulations of glycogen, and von Gierke
appropriately called the condition “hepato-nephromegalia
glyco-genica.” Now termed von Gierke’s disease, or Type Ia glycogen
stor-age disease, this condition results from the absence of
glucose-6-phosphatase activity in the affected organs This simple genetic
defect causes a host of difficult complications, including a striking
el-evation of serum triglycerides, excess adipose tissue in the cheeks,
thin extremities, short stature, excessive curvature of the lumbar
spine, and delay of puberty
The absence of glucose-6-phosphatase activity in the liver
blocks the last steps of glycogenolysis and gluconeogenesis,
inter-rupting the recycling of glucose and causing affected individuals
to be hypoglycemic The accumulation of glucose-6-phosphate in the liver leads to greatly increased glycolytic activity, with conse-quent elevation of lactic acid, a condition known more commonly
as lactic acidosis Large amounts of uric acid and lipids are
pro-duced, and the high rates of glycolysis produce excess NADH The treatment of von Gierke’s disease consists of trying to maintain normal levels of glucose in the patient’s serum This of-ten requires oral administration of large amounts of glucose, in its various forms, including, for example, uncooked cornstarch, which acts as a slow-release form of glucose
Trang 10few molecules of epinephrine or glucagon results in the synthesis of many molecules
of cyclic AMP, which, through the action of cAMP-dependent protein kinase, can ac-tivate many more molecules of phosphorylase kinase and even more molecules of phosphorylase For example, an extracellular level of 1010to 108M epinephrine
prompts the formation of 106M cyclic AMP, and for each protein kinase activated by
cyclic AMP, approximately 30 phosphorylase kinase molecules are activated; these in
OH OH
HO
CH2
NH2+
CH3
muscle
Skeletal muscle
Epinephrine
+ Adenylyl cyclase cAMP ↑
+ cAMP-dependent protein kinase
(PKA)
PFK-2 F-2,6-BPase
+
PFK-1 F-1,6-BPase
+
Gluconeogenesis
+
Blood glucose
+
F-2,6-BP ↓
+ Phosphorylase kinase
+ Glycogen breakdown
Glycogen synthesis Glycolysis
PFK-1
+
PFK-2
Heart
Skeletal muscle
F-2,6-BPase
+
PFK-1
+
Glycolysis
F-2,6-BP ↑
+ Glycogen phosphorylase
association with actin Glucagon
FIGURE 22.20 Glucagon and epinephrine each activate a cascade of reactions that stimulate glycogen break-down and inhibit glycogen synthesis in liver and muscles, respectively The effects of these hormones on other metabolic pathways depend on the tissue In liver, glucagon inhibits glycolysis and stimulates gluconeogenesis, facilitating export of glucose into the bloodstream In muscles, epinephrine stimulates glycolysis to provide energy for contraction These effects all depend on protein phosphorylations by cAMP-dependent protein kinase Note that the liver and heart isoforms of PFK-2/F-2,6-BPase respond oppositely to phosphorylation by PKA Glucagon is a 29-residue peptide with the sequence H3 N-HSEGTFTSDYSKYLDSRRAQDFVQWLMNT-COO