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GLYCOGEN GLYCOGEN METABOLISMMETABOLISM

GLUCONEOGENESISGLUCONEOGENESIS

GLUCONEOGENESISGLUCONEOGENESIS synthesis of glucose from noncarbohydrate synthesis of glucose from noncarbohydrate

precursors during longer periods of precursors during longer periods of starvationstarvation a very important pathway since the brain a very important pathway since the brain depends on glucose as its primary fuel depends on glucose as its primary fuel ((120g 120g of of the 160g daily need for glucosethe 160g daily need for glucose)) and RBCs and RBCs use only use only glucose as fuelglucose as fuel amount of glucose in body fluids is 20g and amount of glucose in body fluids is 20g and

the the amount that can be derived from amount that can be derived from glycogen is glycogen is 190g190g major noncarbohydrate sources are major noncarbohydrate sources are lactatelactate, ,

amino acidsamino acids, and , and glycerolglycerol

noncarbohydrate sources need to be first noncarbohydrate sources need to be first converted to either converted to either

pyruvatepyruvate,,oxaloacetate oxaloacetate or or dihydroxyacetone phosphate (DHAP)dihydroxyacetone phosphate (DHAP)

to be converted to glucoseto be converted to glucose major site is the major site is the liverliver with small amount with small amount taking taking

place in the place in the kidneyskidneys gluconeogenesis in the liver and kidneys gluconeogenesis in the liver and kidneys

helps helps maintain the glucose demands of maintain the glucose demands of the the brain and brain and muscles by increasing muscles by increasing blood glucose blood glucose levelslevels

little occurs in the brain, skeletal muscle little occurs in the brain, skeletal muscle or or heart muscleheart muscle

not a reversal of glycolysisnot a reversal of glycolysis

NONCARBOHYDRATE SOURCESNONCARBOHYDRATE SOURCES PyruvatePyruvate is converted to glucose in the is converted to glucose in the

gluconeogenetic pathwaygluconeogenetic pathway

LactateLactate is formed by is formed by active skeletal muscleactive skeletal muscle when when glycolytic rate exceeds oxidative rate; becomes glycolytic rate exceeds oxidative rate; becomes glucose by first converting it to glucose by first converting it to pyruvatepyruvate

Amino acidsAmino acids are derived from are derived from dietary proteinsdietary proteins and and internal protein breakdowninternal protein breakdown during starvationduring starvation; ; becomes glucose by converting them first to either becomes glucose by converting them first to either pyruvate or oxaloacetatepyruvate or oxaloacetate

Glycerol Glycerol is derived from the is derived from the hydrolysis of hydrolysis of triacylglycerols (TAG) or triglyceridestriacylglycerols (TAG) or triglycerides; becomes ; becomes glucose by conversion first to glucose by conversion first to dihydroxyacetone dihydroxyacetone phosphate (DHAP)phosphate (DHAP)

IRREVERSIBLE STEPS of GLYCOLYSISIRREVERSIBLE STEPS of GLYCOLYSISCauses of most of the decrease in free energy Causes of most of the decrease in free energy

in glycolysisin glycolysis

Bypassed steps during gluconeogenesisBypassed steps during gluconeogenesis

Steps catalyzed by the enzymesSteps catalyzed by the enzymesHexokinase Hexokinase

((glucose + ATP glucose + ATP G-6-P + ADP G-6-P + ADP))Phosphofructokinase Phosphofructokinase

((F-6-P + ATP F-6-P + ATP F-1,6-BP + ADP F-1,6-BP + ADP))Pyruvate kinasePyruvate kinase

((PEP + ADP PEP + ADP Pyruvate + ATP Pyruvate + ATP))

NEW STEPS in GLUCOSE FORMATION from PYRUVATE via NEW STEPS in GLUCOSE FORMATION from PYRUVATE via GLUCONEOGENESISGLUCONEOGENESIS

PEP is formed from pyruvate by way of PEP is formed from pyruvate by way of oxaloacetateoxaloacetate

PyruvatePyruvate + CO + CO22 + ATP + HOH ------------ + ATP + HOH ------------ oxaloacetateoxaloacetate + ADP + Pi + 2H + ADP + Pi + 2H++

OxaloacetateOxaloacetate + GTP ------------- + GTP ------------- PEPPEP + GDP + CO + GDP + CO22

F-6-P is formed from F-1,6-BP by hydrolysis of F-6-P is formed from F-1,6-BP by hydrolysis of the phosphate ester at carbon 1, an the phosphate ester at carbon 1, an exergonic exergonic hydrolysishydrolysis

Fructose-1,6-bisphosphateFructose-1,6-bisphosphate + HOH -------------- + HOH -------------- fructose-6-phosphatefructose-6-phosphate + Pi + Pi

Glucose is formed by hydrolysis of G-6-PGlucose is formed by hydrolysis of G-6-P

Glucose-6-phosphate + HOH -------------Glucose-6-phosphate + HOH ------------- glucose + Pi glucose + Pi

Pyruvate carboxylase

PEP carboxykinase

Fructose-1,6-bisphosphatase

Glucose-6-phosphatase

RECIPROCAL REGULATION OF GLYCOLYSIS & RECIPROCAL REGULATION OF GLYCOLYSIS & GLUCONEOGENESISGLUCONEOGENESIS

Glucose

Fructose-6-phosphate

Fructose-1,6-bisphosphate

PEP

Pyruvate

Oxaloacetate

PFK F-1,6-BPase

Several steps

PK

PEP carboxykinase

Pyruvate carboxylase

GLUCONEOGENESIS

F-2,6-BP +

AMP +

ATP -

Citrate -

H+ -

F-2,6-BP -

AMP -

Citrate +

F-1,6-BP +

ATP -

Alanine -AcetylCoA +

ADP -

ADP -

GLYCOGEN GLYCOGEN Readily mobilized storage form of glucoseReadily mobilized storage form of glucose very large, branched polymer of glucose very large, branched polymer of glucose

residues linked via residues linked via αα-1,4 (straight) and -1,4 (straight) and αα--1,6 glycosidic bonds1,6 glycosidic bonds

branching occurs for every 10branching occurs for every 10thth glucose glucose residue of the open helical polymerresidue of the open helical polymer

not as reduced as fatty acids are and not as reduced as fatty acids are and consequently not as energy-richconsequently not as energy-rich

serves as buffer to maintain blood sugar serves as buffer to maintain blood sugar levelslevels

Released glucose from glycogen can provide Released glucose from glycogen can provide energy anaerobically unlike fatty acidsenergy anaerobically unlike fatty acids

Two major sites of glycogen storage are the Two major sites of glycogen storage are the liver (10% by weight) and skeletal muscles (2% liver (10% by weight) and skeletal muscles (2% by weight)by weight)

In the liver, its synthesis and degradation are In the liver, its synthesis and degradation are regulated to maintain normal blood glucoseregulated to maintain normal blood glucose

in the muscles, its synthesis and degradation is in the muscles, its synthesis and degradation is intended to meet the energy needs of the intended to meet the energy needs of the muscle itselfmuscle itself

present in the cytosol as granules (10-40nm)present in the cytosol as granules (10-40nm)

GLYCOGENOLYSISGLYCOGENOLYSIS Consists of three stepsConsists of three steps

1. 1. release of glucose-1-phosphate from release of glucose-1-phosphate from from the nonreducing ends of from the nonreducing ends of glycogen glycogen (phosphorolysis) (phosphorolysis)

2. 2. remodeling of glycogen substrate to remodeling of glycogen substrate to permit further degradation with a permit further degradation with a

transferase transferase and and αα-1,6 -1,6 glucosidaseglucosidase

3. 3. conversion of glucose-1-phosphate conversion of glucose-1-phosphate to glucose-6-phosphate for further to glucose-6-phosphate for further

metabolismmetabolism

Fates of Glucose-6-PhosphateFates of Glucose-6-Phosphate Initial substrate for Initial substrate for glycolysisglycolysis

Can be processed by the Can be processed by the pentose pentose phosphate pathwayphosphate pathway to NADPH and to NADPH and ribose derivativesribose derivatives

Can be Can be converted to free glucoseconverted to free glucose in the in the liver, intestine and kidneys for release into liver, intestine and kidneys for release into the blood streamthe blood stream

GlycogenGlycogen

Glycogen Glycogen n-1n-1

Glucose-1-phosphateGlucose-1-phosphate

Glucose-6-phosphateGlucose-6-phosphate

GlycolysisGlycolysis PPPPPP

PyruvatePyruvate GlucoseGlucose Ribose + Ribose + NADPHNADPH

Lactate Lactate COCO22 + HOH + HOH

Blood for use byBlood for use by other tissuesother tissues

Muscle,Brain

Liver

Glycogen phosphorylase

Glucose-6-phosphatase

Phosphoglucomutase

GLYCOGENESISGLYCOGENESIS Regulated by a complex system and requires a Regulated by a complex system and requires a

primer, primer, glycogeninglycogenin

Requires an Requires an activated form of glucoseactivated form of glucose, the, theUridine diphosphate glucose (UDP-Uridine diphosphate glucose (UDP-

glucose) formed from UTP and glucose) formed from UTP and glucose-1-glucose-1-phosphatephosphate

UDP-glucose is added to the nonreducing UDP-glucose is added to the nonreducing end of end of glycogen glycogen using using glycogen synthaseglycogen synthase, the key , the key

regulatory enzyme in glycogen synthesisregulatory enzyme in glycogen synthesis

Glycogen is then remodeledGlycogen is then remodeled for continued for continued synthesissynthesis

GLYCOGEN BREAKDOWN & SYNTHESIS ARE GLYCOGEN BREAKDOWN & SYNTHESIS ARE RECIPROCALLY REGULATEDRECIPROCALLY REGULATED

Glycogen breakdownGlycogen breakdown Glycogen synthesisGlycogen synthesis Epinephrine

Adenylate cyclase Adenylate cyclase

ATP cAMP

Protein kinase A Protein kinase A

Phosphorylase kinase Phosphorylase kinase

Phosphorylase b Phosphorylase a

Glycogen synthase a Glycogen synthase b

PINK – inactive GREEN - active

GLYCOGEN STORAGE DISEASEGLYCOGEN STORAGE DISEASETYPETYPE DEFECTIVE DEFECTIVE

ENZYMEENZYMEORGAN AFFECTEDORGAN AFFECTED GLYCOGEN IN GLYCOGEN IN

AFFECTED ORGANAFFECTED ORGANCLINICAL FEATURESCLINICAL FEATURES

I (Von Gierke)I (Von Gierke) Glucose-6-Glucose-6-phosphatasephosphatase

Liver & kidneyLiver & kidney Increased amount; Increased amount; normal structurenormal structure

Hepatomegaly, failure to thrive, Hepatomegaly, failure to thrive, hypoglycemia, ketosis, hypoglycemia, ketosis, hyperuricemia, hyperlipidemiahyperuricemia, hyperlipidemia

II (Pompe dse)II (Pompe dse) αα-1,4 glucosidase-1,4 glucosidase All organsAll organs Massive increase in Massive increase in amount; normal amount; normal structurestructure

Cardiorespiratory failure causes Cardiorespiratory failure causes death usually before age 2death usually before age 2

III (Cori dse)III (Cori dse) Amylo-1,6-Amylo-1,6-glucosidase glucosidase (debranching)(debranching)

Muscle & liverMuscle & liver Increased amount; Increased amount; short outer branchesshort outer branches

Like type 1 but milderLike type 1 but milder

IV (Andersen IV (Andersen dse)dse)

Branching enzyme Branching enzyme ((αα-1,4 & 1,6)-1,4 & 1,6)

Liver & spleenLiver & spleen Normal amount; very Normal amount; very long outer brancheslong outer branches

Progressive cirrhosis of the liver; Progressive cirrhosis of the liver; liver failure causes death before liver failure causes death before age 2age 2

V (McArdle dse)V (McArdle dse) PhosphorylasePhosphorylase musclemuscle Moderately Moderately increased amount; increased amount; normal structurenormal structure

Limited ability to perform Limited ability to perform strenuous exercise because of strenuous exercise because of painful muscle cramps. painful muscle cramps. Otherwise patient is normal or Otherwise patient is normal or well-developed.well-developed.

VI (Hers dse)VI (Hers dse) PhosphorylasePhosphorylase liverliver Increased amountIncreased amount Like type 1 but milderLike type 1 but milder

VIIVII PhosphofructokinPhosphofructokinasease

musclemuscle Increased amount; Increased amount; normal structurenormal structure

Like type VLike type V

VIIIVIII Phosphorylase Phosphorylase kinasekinase

liverliver Increased amount; Increased amount; normal structurenormal structure

Mild liver enlargement. Mild Mild liver enlargement. Mild hypoglycemiahypoglycemia

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