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GLYCOGEN METABOLISM

GLUCONEOGENESIS

GLUCONEOGENESIS synthesis of glucose from noncarbohydrate

precursors during longer periods of starvation

a very important pathway since the brain depends on glucose as its primary fuel (120g of the 160g daily need for glucose)and RBCs use only glucose as fuel

amount of glucose in body fluids is 20g and the amount that can be derived from glycogen is 190g

major noncarbohydrate sources are lactate, amino acids, and glycerol

noncarbohydrate sources need to be first converted to either

pyruvate,oxaloacetate or dihydroxyacetone phosphate (DHAP)

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

place in the kidneys gluconeogenesis in the liver and kidneys helps

maintain the glucose demands of the brain and muscles by increasing blood glucose levels

little occurs in the brain, skeletal muscle or heart muscle

not a reversal of glycolysis

NONCARBOHYDRATE SOURCES Pyruvate is converted to glucose in the

gluconeogenetic pathway

Lactate is formed by active skeletal muscle when glycolytic rate exceeds oxidative rate; becomes glucose by first converting it to pyruvate

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

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

IRREVERSIBLE STEPS of GLYCOLYSIS Causes of most of the decrease in free energy

in glycolysis

Bypassed steps during gluconeogenesis

Steps catalyzed by the enzymes Hexokinase

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

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

(PEP + ADP Pyruvate + ATP)

NEW STEPS in GLUCOSE FORMATION from PYRUVATE via GLUCONEOGENESIS

PEP is formed from pyruvate by way of oxaloacetate Pyruvate + CO2 + ATP + HOH ------------ oxaloacetate + ADP + Pi + 2H+

Oxaloacetate + GTP ------------- PEP + GDP + CO2

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

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

Glucose is formed by hydrolysis of G-6-P

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

Pyruvate carboxylase

PEP carboxykinase

Fructose-1,6-bisphosphatase

Glucose-6-phosphatase

RECIPROCAL REGULATION OF GLYCOLYSIS & GLUCONEOGENESIS

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

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

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

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

serves as buffer to maintain blood sugar levels

Released glucose from glycogen can provide energy anaerobically unlike fatty acids

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

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

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

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

GLYCOGENOLYSIS Consists of three steps

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

2. remodeling of glycogen substrate to permit further degradation with a transferase and α-1,6 glucosidase

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

Fates of Glucose-6-Phosphate Initial substrate for glycolysis

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

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

GlycogenGlycogen n-1

Glucose-1-phosphate

Glucose-6-phosphate

Glycolysis PPP

Pyruvate Glucose Ribose + NADPH

Lactate CO2 + HOHBlood for use by

other tissues

Muscle,Brain

Liver

Glycogen phosphorylase

Glucose-6-phosphatase

Phosphoglucomutase

GLYCOGENESIS Regulated by a complex system and requires a

primer, glycogenin

Requires an activated form of glucose, theUridine diphosphate glucose (UDP-glucose) formed from UTP and glucose-1-phosphate

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

regulatory enzyme in glycogen synthesis

Glycogen is then remodeled for continued synthesis

GLYCOGEN BREAKDOWN & SYNTHESIS ARE RECIPROCALLY REGULATED

Glycogen breakdown Glycogen synthesisEpinephrine

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 DISEASETYPE DEFECTIVE

ENZYMEORGAN AFFECTED GLYCOGEN IN

AFFECTED ORGANCLINICAL FEATURES

I (Von Gierke) Glucose-6-phosphatase

Liver & kidney Increased amount; normal structure

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

II (Pompe dse) α-1,4 glucosidase All organs Massive increase in amount; normal structure

Cardiorespiratory failure causes death usually before age 2

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

Muscle & liver Increased amount; short outer branches

Like type 1 but milder

IV (Andersen dse)

Branching enzyme (α-1,4 & 1,6)

Liver & spleen Normal amount; very long outer branches

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

V (McArdle dse) Phosphorylase muscle Moderately increased amount; normal structure

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

VI (Hers dse) Phosphorylase liver Increased amount Like type 1 but milder

VII Phosphofructokinase

muscle Increased amount; normal structure

Like type V

VIII Phosphorylase kinase

liver Increased amount; normal structure

Mild liver enlargement. Mild hypoglycemia

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