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Carbohydrate Storage and
Synthesis in Liver and Muscle:Glycogen
Copyright 1999-2004 by Gene C. Lavers
No part of this presentation may be reproduced by any mechanical, photographic, or electronic process, or inthe form of a phonographic recording, nor may it be stored in a retrieval system, transmitted, or otherwise
copied for public or private use, without written permission from the publisher.
Lecture 21 and 22
Baynes & Dominiczak, Chapter 12Gene C. Lavers, Ph.D. [email protected]/~glc1
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Glycogen 12 topics Carbohydrate Metabolism Investing for the future Outline of Topics
IntroductionStructure of Glycogen highly branced a 1,4)-glucose polymerGlycogenesis Glc incorporated into glycogen (liver & muscle, kidney)Glycogenolysis Glucose mobilized from glycogen in liver and muscle
Hormonal regulation of hepatic glycogenesis vs. glycogenolysis insulin vs. glucagonMechanisms of glucagon action Signals phosphorylations, pathways flip Glycogenolysis in liver plasma glycemia maintenance: acute vs. postabsorbtive Glycogenolysis in muscle Mobilizing glucose for ATP contraction activityRegulation of glycogenesis replenish glycogen stores vs. immediate needsGluconeogenesis de novo ( new) glucose from non carbohydrate carbon skeletonsRegulation of gluconeogenesis De novo glucose synthesis fueled by fat oxidation Interconversions of fructose/galactose/mannose/glucose glycoproteins, etc., Inborn errors of metabolism glycogen storage diseases
Glucose Fuel Storage and mobilization for oxidaton
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Metabolic Fate of Glucose Glycogen Metabolism Introduction
Red cells and the brain Have an absolute requirement for bloodglucose for their energy metabolism.
These cells consume about 80% of the glucose (200 g , 1.1 mol, ca.1500 kcal ) consumed per day by a 70 kg human , in good health.
Blood and extracellular fluid volume contains about 10 g glucose must be replenished constantly .
Assumes a blood volume = 7 L, hematocrit = 45%, and no other
distribution system operates.Normally, blood [glucose] range is between 4 6.5 mM = glycemia
(about 80 120 mg/dL)
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Hypoglycemia hyperglycemia - glycemia Glycogen Metabolism[glucose], in blood plasma Introduction
hypoglycemia ( 4 2.5 mM, 45 mg/dL);
extreme hypoglycemia, 6.5 mM) lasts 2- 3 hrs, glycemia
homeostasis glycemia maintained: ~ 4-5 mM (80-100
mg %), resting [glucose]. Such control due to: in part, glycogen synthesis (alltissues). Up to max of 1 2 % of muscle tissue wt(work) and 4 6 % liver wt for later release ofglucose from liver to supply glucose to body.
Before meal
After meal
Post meal
Prandial (meal): preprandial, postprandial, postabsorptive
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Glycogenesis vs. glycogenolysis Glycogen MetabolismLiver maintains blood [glucose] Cyclic responses
Fig. 12.1 Sources of Blood Glucose.
Glucose stored as glycogen:highly branched dendrite-likepolymer, a polysaccharide.Glycogenesis glycogensynthesized during and aftera meal.
Glycogenolysis releasesglucose into blood (Like acontrolled time-release)
Total heptic glycogen stores barely able to maintain blood[glucose] beyond 12 hour(fasting).
Gluconeogenesis makes new glucose during post absorptive state,before meals, and during sleep. Glycogenolysis declines to neardepletion of glycogen after 12-24 hrs Liver uses gluconeogenesis tomaintain blood [glucose].
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Glycogen Storage Carbohydrate Metabolism Various Tissues Structure
Blood glucose = 10 g, tissues needs easilydeplete.Glycogen degraded to glucose-1P G6P
for oxidative metabolism in tissues tosynthesize ATP.Liver: G6P G + P, by G6P phosphatase .Muscle lacks G6P phosphatase .
Fig. 12.2 Tissue distribution ofcarbohydrate energy reserves(70 kg adult).
Fig. 12.3 Close-up ofglycogen structure.
Highly branched dendritic polymer
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Structure of Glycogen Carbohydrate Metabolism Properties
KEY FEATURES
non reducingend
a -1,6 acetallinkage
a -1,4 acetallinkage
a
O
O
Oa 16
14
C O
OH
H
C O
O C
H
reducing end hemiacetal
acetal
enedicts
solut on
C C
OH
H
alcohol
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Glycogen metabolism Carbohydrate Metabolism Anabolism vs. Catabolism Comparison
Glycogenesis
Glucose glycogen 5 steps
1. Glucokinase2. Phosphogluco-
mutase3. UDP-Glc PPase4. Glycogen
synthase
5. Branching GlycogenolysisGlycogen glucose
4 steps1. Glycogen
phosphorylase
2. transglycosylase3. transglycosylase4. G6Pase
____________Regulatory enzymeRate-limiting enzyme
Fig. 12.4 Glycogenesis (L)Glycogenolysis (R)
Different enzymes
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Glycogenesis Carbohydrate Metabolismvs. glycolysis, PMP In: Liver, Muscle, Adipose tissues
Portal blood: delivers glucose-rich blood to liver during/shortly after a meal . Liver rich in GLUT-2: high capacity, low affinity (k m >10 mM), high glucose flux .
Glucokinase (GK): gene induced by continuous glc-rich diet.GK K m ~ 5-7 mM: activity when portal blood [Glc] above 5 mM.GK not G6P inhibited : thus G6P pushed into all pathways glycolysis, PMP, and
glycogenesis (muscle uses lipid oxidative metabolism for ATP).Fate of excess glucoseIn Liver: goes to
glycogenesis reserve : for maintaining post absorptive blood [glc].glycolysis: after glycogen reserve is full.
energy/ATP synthesis and triglycerides: FAS and TGs exported toadipose tissue for storage.In muscle: glucose stored in glycogen; glycolytic pyruvate formed.In adipose: glucose DHAP glycerol TGsIn RBC: glucose pyruvate lactate; NADPH (protect from ROS)
Priority: favor synthesis of glycogen first: save first!
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Fate of diet fuels Carbohydrate Metabolism Glucose is central metabolite Overview of Topics
DIETDigestion and Absorption
Glucose
carbohydrate fatprotein
amino acids TGs
liver
Transport via portal vein
intestines
amino acids
GLYCOGEN musclesmovement
gluconeogenesis
brain
glycogenolysis
GLUCOSE
GLUCOSE
GLYCOGEN
organs
glycogenesis glycogenolysis
glycogenesis
Transport via blood vessels
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Hormonal control Carbohydrate MetabolismGlycogenolysis In Liver Comparison
Glycogenolysis: response to lowblood [glc] from:Post absorptive utilization.Response to stress.
3 hormones activation mode:Glucagon 3.5 kd peptide, from a -cells of endocrine pancreas; mainfunction: activate hepaticglycogenolysis to maintainnormoglycemia.
Epinephrine tyrosine derivative, acatecholamine from adrenal
medulla activates glycogenolysis inresponse to acute stress .
Cortisol adrenocortical steroidvaries diurnally in plasma, but maybe chronically elevated undercontinuously stressful conditions.
Glucagon, Epinephrine, Cortisol, Insulin
Fig. 12.5 Hormones involved in control ofglycogenolysis.
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Glucagon Carbohydrate MetabolismIn Liver Hormonal Regulation of Glycogenolysis
Glucagon 3500 MW protein (29-aa): secreted by a -cellsof endocrine pancreas, activates glycogenolysis tomaintain normal glycemia, when blood [glucose] becomes
hypoglycemic.Glucagon t/2 ~ 5 minutes. (removal from blood by receptorbinding, renal filtration, proteolytic inactivation in liver.)
Elevated blood [glucagon]: between meals; chronically
elevated during fasting or low-carbohydrate diet.Decreased blood [glucagon]: decreases during and soonafter a meal ([glucose] is very high).
Glucagon, epinephrine (adrenalin), cortisol, insulin
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Acute & Chronic Stress Carbohydrate MetabolismGlycogenolysis Activation
Physiologic -- in response to increased blood glucoseutilization during prolonged exercise.
Pathologic -- as a result of blood loss .
Psychological -- in response to acute or chronic threats .
Acute stress (regardless of source): activates glycogenolysisthrough the action of catecholamine hormone, epinephrine
(released by the adrenal medula) .During prolonged exercise: both glucagon and epinephrinecontribute to stimulation of glycogenolysis.
Glycogenolysis is activated in response to stress
l
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Insulin Carbohydrate MetabolismHormonal regulation Inhibition of Glycogenolysis
Insulin secreted by pancreas b-cells when blood [glucose] is high.
Synthesized as single peptide chain zymogen: proinsulin.
In secretory granules, selective proteolysis releases an internalpeptide and a 2-chained (via 2 -S S- ) insulin hormone.
Insulin elicits uptake and intracellular use or storage of glucose,an anabolic hormone.
Hyperglycemia results in elevated blood [insulin] associated withfed state.
Hyperinsulinism associated with insulin resistance and ifchronic can lead to diabetes type-2 and related pathologies.
Antagonist of glucagon, epinephrine (adrenalin) , cortisol
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Glycogen Carbohydrate Metabolism Signal Transduction Regulation Mechanism
Fig 12.6 Mobilization of liverglycogen by glucagon.
1. Glucagon binds hepatic membrane receptor :activates cascade reactions .
2. G-protein-GDP in resting state: releasesGDP, a -subunit binds GTP.
3. G-protein-GTP: conformation change, releases a -subunit:GTP complex.
4. a -GTP binds to adenylate cyclase (AC) .5. AC converts ATP cAMP (+PP; 2 P).
6. cAMP binds regulatory subunit of proteinkinase A : active catalytic subunit released= PKA.
7. PKA phosphorylates 3-enzymes: uses ATP Inhibitor 1 inhibitor-1 (+P) ACT.
phosphorylase kinase b PKa (+P) ACT. glycogen synthase a b (+P) INACT.
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Glycogen Carbohydrate Metabolism Signal Transduction Regulation Mechanism
Fig 12.6 Mobilization of liverglycogen by glucagon.
PKA phosphorylates 3-enzymes: uses ATP Inhibitor 1 inhibitor-1 (+ P) ACT. Phosphorylase Kinase b PK a (+ P) ACT. Glycogen Synthase a GS b (+ P) INACT.
Phosphorylase kinase a : uses ATPGlycogen Phosphorylase b GP a (+P)
7. Glycogen Phosphorylase a : glycogenolysisreleases G1P
8. Inhibitor 1-P keeps phospho-protein
phosphatase ( PPP ) inactive: glycogendegradation continues.
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Glycogen Carbohydrate Metabolism Reciprocal Synthesis and Degradation Regulation Mechanism
Glu 1P
Phospho rylase a
Glycogen synthase I
Glycogen synthase D
Phosphorylase b b
PhK
ATP
ADPa
PPP
p
IPhK
ADP
ATP
D PPP
p
inactive
active
inactive
active
glycogen
Phosphorylation-Dephosphorylation PPP = Protein Phosphatase
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Balancing Pathway Activities Carbohydrate MetabolismAvoiding futile cycles Inhibiting glucose
Prandial glucose used up, glycemia falls into hypoglycemia.
Glucagons enzyme cascade amplification turns on liverglycogenolysis balanced inhibition of glycogenesis. Also producesinhibition of
Protein synthesis uses considerable ATP and GTPCholesterol synthesis uses ATP Fatty acid (FA) synthesis uses ATP to activate acetyl CoA (malonyl CoA)Triglyceride (TGs) synthesis from glycolytic DHAP derived from glucoseGlucose synthesis (gluconeogenesis) uses GTP
Glucose utilization (glycolysis) uses ATPKey enzymes phosphorylated in opposing pathways, avoids futile cycles.
Glucagon shifts liver metabolism to keep blood [glc] glycemic tomaintain vital body functions (see Ch 20) .
Glycogenolysis floods system with G1P, G6P, and glucose
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Termination of glucagon response Carbohydrate MetabolismMust be rapid Hepatic mechanisms
Rapid, redundant shutdownmechanisms: accompany blood[glucagon] . Enzyme cascade foramplifying glycogenolysis activation isvia dephosphorylaton.
1. Ga -GTP Ga -G DP: by phosphodiesterase2. Phosphodiesterase : cAMP AMP
3. [cAMP] , R-cAMP dissociates4. 2R + 2C R 2C2 : adenylate cyclaseinactive again .
5. PhosphoProtein Phosphatase (PPP):removes- P ;
all enz-P enz + P;glycogenolysis stops. Inhibitor 1, increases PPP activity .
Glycogenolysis stops. Decreased blood [glucagon] accompaniesrise in blood [glucose] .
Fig. 12.7 Mechanisms of terminationof hormonal response to glucagon.
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Glycogen-storage Diseases Carbohydrate MetabolismInherited Metabolic Diseases Inborn errors of Metabolism
Six rare genetic diseases affect glycogen synthesis at differentenzyme deficiency steps in the pathway.
Fig. 12.8 Major classes of glycogen-storage diseases.
E i h i C b h d M b li
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Epinephrine Carbohydrate Metabolism Hormonal Regulation Activation of Glycogenolysis
Epinephrine ( Adrenaline ) and precursor (norepinephrine alsohormonally active), derived from tyrosine. Adrenal gland cells releasewhen neural signals trigger the fight-or-flight response; many diversephysiological effects follow.
Epinephrine stimulates release of G1P from glycogen; produceselevated intracellular [G6P]. Glycolysis increases in muscle; liverreleases glucose into the bloodstream.
Glucagon, Epinephrine, Cortisol, Insulin
HONH 3 +
COO-
HO NH 2 +
CH3
HO
HOtyrosine
L-dopa
HO NH 3 +
HO
HO
epinephrinenorepinephrine
E i h i
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Epinephrine Carbohydrate MetabolismMobilizing hepatic glycogen Second Messengers
Epinephrine binds to a - and b-adrenergic receptors.Two pathways stimulated.b-receptor: similar to glucagonmechanism. G-proteins, cAMP .
Epinephrine response: augmentsglucagons during severehypoglycemia : rapid heartbeat,sweating, tremors and anxiety.
a -receptor: G-proteins , active membraneisozyme of phospholipase C (PLC):specific for cleavage of membranephospholipid (PL), and PIP 2. PIP 2 DAG +IP 3 , 2nd messengers.DAG activates PKC (like PKA).
IP 3 promotes Ca 2+ into cytosol.Ca 2+ binds calmodulin: activates
phosphorylase kinase , leads to activationof glycogen phosphorylase : glucosereleased to blood.
Fig. 12.9 Glycogenolysis viaa -adrenergic receptor
P i ki A i M l
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Protein kinase A in Muscle Carbohydrate MetabolismDuring Exercise Activating Glycogenolysis
Muscle reacts to epinephrinenot glucagon.b-adrenergic receptor (cAMP)activates glycogenolysis for:
Fight or flightProlonged exercise
2 hormone independent modes:Influx of Ca 2+ activates
phosphorylase kinase via Ca 2+ calmodulin complex.
AMP activates phosphorylasedirectly2 ADP ATP + AMP; [AMP]
AMP activates phosphorylase .
Muscle lacks glucagon receptorand G6Phosphatase enzyme.
Fig 12.10 Regulation of PKA
in muscle.
l ff b l
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Regulatory effects by Insulin Carbohydrate MetabolismReceptor dimerization Glycogenesis
Insulins 2 main functions: lowers blood glucose byreversing the effect ofglucagons phosphorylationof enzymes and proteins.
Stimulates gene expression
of carbohydrate metabolismenzymes.
Fig 12.1 1 Regulatory effects of insulin onhepatic and muscle carbo metab.
Gl i (GNG) C b h d M b li
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Gluconeogenesis (GNG) Carbohydrate MetabolismGlucose from non carbohydrates Cytosol-Mitochondrion
Gluconeogenesis: essential during fasting andstarvation, when hepatic glycogen depleted, tomaintain blood glucose . Energy and carbon source required:oxidation of FA released from adipose tissueprovides ATP; carbons from 3-sources.Lactate from RBC and active muscle.
Large muscle mass: major source ofglucogenic amino acids; transamination.Glycerol from TGs: DHAP via glycerol-3P.3 glycolytic irreversible reactions: PK, PFK-1, GK bypassed by phosphatases: FBPase, andG6Pase after PEPCKase1,3BPG 3PG is reversible, DG similar.Lactate cycle: Cori cycle (ch 20). Muscle lactate and pyr liver-GNG glc, to muscle-glycolysis lactateGlucose-alanine cycle: [muscle: glc pyr
ala ] [liver: GNG glc] [muscle: glc pyr ala ]
3-Sources: Lactate, amino acids, glycerol
Fig 12.12 Pathways of gluconeogenesis.
R g l ti g gl g i C b h d M b li
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Regulating gluconeogenesis Carbohydrate MetabolismHormonal mechanisms Glycolysis vs. Gluconeogenesis
Gluconeogenesis vs. glycolysis: avoid a futilecycle; active GNG inhibit glycolysis Enz- P or inactive GNG active glycolysis. EnzF26BP: allosteric (+) regulator of F16BP . Made by:PFK2 : F6P F26BP ; enhances glycolysis.F26BPase : F6P F26BP ; enhances GNG .
PFK2 / F26BPase : a bifunctional, with P switch: PFK2 /F26BPase PFK2 /F26BPase -PPFK1 : F6P F16BP; F26BP Rx rate ! F16BPase : F6P F16BP; F26BP inhibits GNG ![acetyl CoA ]: slows TCA; act. PC [OAA ] Glc
Glucagon: promotes phosphorylation (PK , inact.) Insulin: promotes de -phosphorylation ( PK act.)
During fasting: glucagon , PK -P inact , GNG , EM Eat Carbo meal: insulin , PK act, GNG , EM
Control: liver PFK1 and F1,6BPase
Fig. 12.13 Gluconeogenesisregulated by heptic[F26BP] and[acetyl CoA]
F t d g l t C b h d t M t b li
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Fructose and galactose Carbohydrate MetabolismSugar Interconversions Other sugars
a -D-Glucose
Triose-P
OO O
a -D-Galactose-D-Fructose
Exclusively in liver
pyruvate
glycolysis
(P ) (P)(P) (P )
(P )a a a
b
pyruvate
glycolysisgluconeogenesis
OAA
PC
Acetyl CoA
PDH
epimers
+
PEP
PEPCK
aldose aldoseketose
l f
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Hormonal features Carbohydrate MetabolismRegulation Gluconeogenesis
Fig. 12.14 Features of hormone action. Multihormonalregulation of gluconeogenesis illustrates fundamentalprinciples of hormone action
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Carbohydrate Storage and Synthesisin Liver and Muscle
END
M t b li F t f Gl Gl M t b li
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Metabolic Fate of Glucose Glycogen Metabolism Introduction
Red cells and the brain Have an absolute requirement forblood glucose for their energy metabolism .
These cells consume about 80% of the glucose (200 g, 1.1 mol,ca. 1500 kcal) consumed per day by a 70 kg human, in good health.
Blood and extra cellular fluid volume contains about 10 gglucose, which must be replenished constantly.
Assumes a blood volume = 7 L, hematocrit = 45%, and noother distribution system operates.
Normally, blood [glucose] range is between 4 6.5 mM(about 80 120 mg/dL)
Gl i Gl M b li
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Gluconeogenesis Glycogen Metabolism
A backup system makes new glucose Introduction
Liver can synthesize glucose from non carbohydrate precursors.
Amino acids supply carbon skeletons, as does glycerol.
During starvation*, liver uses degraded muscle protein asthe primary precursor of glucose; also lactate (fromglycolysis) and glycerol (from fat) .
Fatty acids from triacylglycerides (TAGs) mobilzed (fromadipose tissue**) provide the energy for gluconeogenesis.
__________________________* Metabolically may begin about 12 hours after the last meal.** During well-fed states, excess glucose is converted to triacylglycerides
(TGs) in adipose cells.
GLUT 2 T t C b h d t M t b li
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GLUT-2 Transporter Carbohydrate Metabolism In liver Crossing the plasma membrane
A high capacity GLUT-2 transporter (low-affinity, km>10 mM) allows glucose free entry into and exit fromliver cells across the plasma membrane.
Liver cells have a large number of GLUT-2, so high[glucose] coming from the portal blood can easily enterthe cytoplasm.
GLUT-2 transporter getting GLUCOSE in and out of cell
Gl ki C b h d M b li
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Glucokinase Carbohydrate Metabolism In liver Preparing G-6-P
Glucokinase (GK) specifically phosphorylates glucose toglucose-6-phosphate (G6P) trapping glucose inside cell.Liver has copious amounts of GK.
GK gene is inducible (more GK made) when a highcarbohydrate diet is continued .
Km GK ~ 5 7 mM, GK becomes more active when portal
blood [glucose] exceeds 5 mM (100 mg %).G6P is not a product inhibitor of GK! (G6P inhibits hexokinase)
Keeping glucose in the cell investing for metabolism
P th ti f G6P C b h d t M t b li
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Pathway options for G6P Carbohydrate Metabolism In liver Pathways in the cytosol
After a carbohydrate meal, G6P floods the cell via GKG6P forced into several major pathways:
Glycogenesis yields highly branched, dense glucose
polymer. After glycogen is replenished, then
Glycolysis oxidizes excess G6P to pyruvate (andlactate) for energy production and triglyceride (TAG)synthesis for export to adipose cellsand
Pentose phosphate pathway yields NADPH (andribose and other sugars) for fatty acid synthesis (theregoes the waistline!)
What fates await G6P?
Activated UDP -Glucose Carbohydrate Metabolism
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Activated UDP Glucose Carbohydrate MetabolismPolymerization step Glycogenesis pathway
UDP-Glucose adds glucose to glycogen via Glycogen Synthase
Glucose 6PGlucose 1PUDP-GlucoseGlycogenn+1
UDP-glucose pyrophosphorylase
123
12
3 Glycogen Synthase
Phosphoglucomutase
Three-step Pathway
UTPpp
HOO
O pOHHOOH
H
pU pp pU
pp
2
2
Glucose 1P
Regulatedstep
activated
p + p
Gl i C b h d t M t b li
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Glycogenin Carbohydrate MetabolismGlycogenesis
{Octamer of Glucose glycogenin protein} primer
Glycogen Synthase requires glycogen primereight a -1,4-linked glucose residues (at least) .
Primer = Glucose 8 Tyr C1 Glycogenin (Mr 37,000 protein) .
Glycosyltransferase adds C 1 of Glu 1 -ppU to a tyrosyl residue ofGlycogenin ; 7 UDP-Glu yield 8-mer Glucose 8 -Glycogenin protein primer .
Glycogen Synthase adds glu of UDP-glu to non reducing C 4 -OH ofGlucose- Glycogenin synthesizing a glycogen 50,000 polymer. amylo-(1,4 to 1,6)-transglycolase creates the branches; transfers6-mer to the C
6-OH so 4-residues separate branches formed by a -1,6-
acetal linkage.
All the enzymes required are associated with the glycogen for rapidsynthesis of glycogen
Branching Glycogen Carbohydrate Metabolism
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Branching Glycogen Carbohydrate Metabolisma -1,6 acetal linkage Glycogenesis pathway
UDP-glucose
GlycogeninHO
1. Glucosyl-
transferase
2. Amylo-1,4 1,6-transglycosylase
3. Glycogen Synthase
O
1
7 + 1
O
6
4
O
O6
O
3
Glycogen synthase Carbohydrate Metabolism
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Glycogen synthase Carbohydrate MetabolismA principle? Regulation
Step 3, Glycogen synthase is regulated, not 1 or 2
Regulate a pathway after a branch branch*
UDP-glucose
Glycoproteins
Glycolipids
Other sugarsGlycogen
Glucose-1P
Regulate here?
Regulate here.
___________________________________________* Recall: Does the regulated, committed step of glycolysis (F1,6BP) follow this principle?
Polysaccharide Phosphorylases Carbohydrate Metabolism
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Polysaccharide Phosphorylases Carbohydrate Metabolism
In Liver Glycogenolysis
Using phosphate to cleave C O bonds: phosphorolysis
* Glucose stored asglycogen or starch animals plants
Glycogen
Muscle
Liver
P OO
O
O
HOO
OP OHHO
OHH HO O
OR-1OH
HO
OHH
+
Glucose 1P Glycogen n-1
P+
4-residues
from branch
~ribosome
Non-reducing end
P
P
Branch point
Glycogen Phosphorylase Carbohydrate Metabolism
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BrainRBC
Fat cellsPeripheral tissues
Glycogen Phosphorylase Carbohydrate MetabolismLiver vs. Muscle Glycogenolysis Pathway
Glycogen Glucose 1P
[ATP]
Muscle
Liver
Glucose 6P Glycolysis
TCAGlucose 1P
Glucose 6P
Glucose
Glucose
Fate of glycogen glucose
+
CO2 + H 2 O
[AMP]
3 ATP
GlucoseHex Kinase
2 ATP
P Glc mutase
G6Pase
ATP
ADP