GLYCOGENESIS and GLYCOGENOLYSIS

MARIA ESPERANZA E. UY, MD; FPCP

GLYCOGENOLYSIS & GLYCOGENESIS

Glycogenolysis breakdown of glycogen to glucose or G6P Glycogenesis synthesis of glycogen - these 2 processes are especially occurring in muscle & liver

Glycogen Granules
- abundant in liver of well-fed animals but absent after 24 hrs of fasting; or after heavy exercise - granules also contain the enzymes that catalyze its formation and use.

STORAGE: The polymeric nature of glycogen allows energy to be sequestered without the problems of osmotic effects that glucose would cause. - Primarily stored in the MUSCLE and LIVER. - In humans,liver glycogen stores are typically adequate for up to 12 hrs.without the support of gluconeogenesis

Glycogen - storage form of fuel

- composed of glucosyl residues, mostly linked together by - 1,4 glycosidic linkages. Branches arise from frequent 1,6 glycosidic linkages

Glycogen Tree - branches at every 4th

glucosyl residue within the more central core of the molecule and less in the outer region

Muscle glycogen is a fuel reserved for the production of ATP within that tissue whereas; Liver glycogen is a glucose reserve for the maintenance of blood concentration

Glycogen Synthase transfer the activated glucosyl moiety of UDP glucose to the carbon 4 of a glucosyl residue of the growing chain to form a new glycosidic bond at the hydroxyl group of C1of the activated sugar.
The reducing end of glucose (C1) is always added to the non- reducing end (C4 of a glucosyl residue) of the glycogen chain

- Glycogen synthase cannot form the 1,6- glycosidic linkages - once an amylose chain of at least 11 residues has been formed, a branching enzyme called glucosyl (-4:6) transferase removes a block of about 7 glucosyl residues from a growing chain and transfer it to another chain to produce an 1,6 linkage.

How does this branching enzyme work?

Transfers approximately 5-8 glucosyl residues from the non-reducing end of the glycogen chain to another residue within the chain and attaches the residues via an -1,6 linkage.

The new branch has to be introduced at least 4 glucosyl residues from the nearest branch points

The creation of the highly branched structure of glycogen requires the concerted efforts of glycogen synthase and branching enzyme.

What is the purpose of branching glycogen molecules?

To facilitate the breakdown of glycogen and aid in solubility When used as a fuel during strenuous exercise in muscle and in liver in the fasted state

Glycogenin is Required as a Primer for Glycogen Synthesis

Glycogen Degradation
Glycogen Glycogen n-1 glycogen phosphorylase

Glucose-1-phosphate

phosphoglucomutase
Glucose-6-phosphate glucose 6-phosphatase Glucose

ACTION OF GLYCOGEN PHOSPHORYLASE

HYDROLYTIC ACTION ALWAYS

AT THE NON-REDUCING END 1- 4 GLYCOSIDIC LINK CLEAVED BY PHOSPHOROLYSIS

Debranching Enzyme is Required for Glycogenolysis

Glycogen phosphorylase is specific -1,4 glycosidic linkages It stops attacking -1,4 - glycosidic linkages 4 glucosyl residues from an 1,6- branch point Phosphorylase-limit dextrin is the glycogen molecule that has been degraded to the limit.

Debranching Enzyme:
Allows phosphorylase to continue to degrade glycogen Bifunctional enzyme A. 1,4 1,4-glucan transferase activity B. -1,6 glucosidase activity

The cooperative & repetitive action of phosphorylase & debranching enzyme results in complete breakdown of glycogen to glucose -1- PO4 & glucose.

Special Features of Glycogenolysis & Glycogenesis

Why Store Glucose as Glycogen & NOT FAT?

1. Fat cannot be mobilized nearly as rapidly as glycogen 2. Fat cannot be used as a source of energy in the absence of O2 3. Fat cannot be converted to glucose to maintain blood glucose levels required by the brain

Why not Store it as Free Glucose? Why Waste ATP Making a Polymer Out of Glucose?
- It would cost ATP to pump glucose into a cell against a concentration gradient, and its concentration would have to reach about 400 mm in liver cells to match the glucose reserve provided by the usual liver glycogen content. - Unless balanced by outward movement of some other osmotically active compound accumulation of glucose would cause considerable uptake of water with osmotic lysis of the cell.

Glycogen Synthesis and Degradation are Highly Regulated

Glycogen synthase and glycogen phosphorylase are the regulatory enzymes of glycogen synthesis and degradation respectively. Both catalyze non-equilibrium reactions, & both are subject to control by allosteric effectors and covalent modification

Regulation of Glycogen Synthase and Glycogen Phosphorylase

GLYCOGEN STORAGE DISEASES

Von Gierkes Disease or Type 1

- most common - deficiency of liver, intestinal mucosa & kidney G-6 Phosphatase - diagnosis possible by intestinal biopsy - fasting hypoglycemia, lactic acidemia, hyperlipidemia, & hyperuricemia with gouty arthritis

Pompes Disease Type II

- caused by the absence of - 1,4 glucosidase (or acid maltase), normally found in lysosomes - accumulation of glycogen mostly in lysosomes in virtually every tissue - Severe hypoglycemia, massive cardiomegaly & cardiomyopathy occur & death results from heart failure

Coris Disease or Type III

- caused by deficiency of glycogen debranching enzyme, -1,6 glucosidase. - Glycogen accumulates because only the outer branches can be removed by phosphorylase. - hepatomegally & other clinical manifestation are similar to, but milder than those in Von Gierkes disease

Andersons Disease or Type IV

Deficiency of the branching enzyme, glucosyl 4:6 transferase Normal amount of glycogen but with very long outer branches Liver cirrhosis and death before 2 years of age

McArdles Disease or Type V

- caused by the absence or deficiency of skeletal muscle glycogen phosphorylase - The liver enzyme is normal - patients suffer from painful muscle cramps and are unable to perform strenuous exercise because muscle glycogen stores are not available to the exercising muscle - the normal increase in plasma lactate following exercise is absent

Hers Disease or Type VI

Deficient enzyme is liver phosphorylase Mild hepatomegaly and hyperlipidemia Mild hypoglycemia or no symptoms at all

GSD Type VII

Enzyme deficient is phosphofructokinase Patients have painful muscle cramps with exercise

GSD Type VIII

Phosphorylase kinase (liver) is the enzyme deficient Mild hepatomegaly and hypoglycemia Growth retardation,delayed motor development and increased blood lipids

 THE END