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PHAR150GGlycogensynthesisandDegradation1-2.pptx

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PHAR 150G Biochemistry

Glycogen Synthesis and Degradation

Vicky Mody, PhD

Associate Professor of Pharmaceutical Sciences

Office: Rm 3034,

Email: [email protected]

Phone: 678-407-7386

Objectives

Difference between a-1-4 and a-1-6 glyosidic bonds

Synthesis and degradation of glycogen.

Regulation of glycogen synthesis and degradation in both liver and muscles.

Difference between a-1-4 vs a – 1-6 bonds

1-4 and 1-6 a-glycosidic bonds in Glycogen

1-4 a-glycosidic bonds in Glycogen

Glycogen, the storage form of glucose present in tissues, is a branched glucose polysaccharide composed of chains of glucosyl units linked by a-1,4-glycosidic bonds with a-1,6-branches, every 8 to 10 residues.

The branched structure permits rapid degradation and rapid synthesis of glycogen because enzymes can work on several chains simultaneously.

The enzymes involved in glycogen synthesis and degradation, and some of the regulatory enzymes are bound to the surface of the glycogen particle

1-4 and 1-6 a-glycosidic bonds in Glycogen

Function of Glycogen in Skeletal Muscles and Liver

Glucose utilizations takes place in muscles

But in the liver gluconeogensis

Function of Glycogen in Skeletal Muscles and Liver

Glucose utilizations takes place in muscles

But in the liver gluconeogensis.

Once glucose is synthesized it is transferred to the body.

Glycogen is found in most cell types, where it serves as a reservoir of glucosyl units for adenosine triphosphate (ATP) generation from glycolysis.

Glycogen is degraded mainly to glucose 1-phosphate, which is converted to glucose 6-phosphate (G6P).

In skeletal muscle and other cell types, the G6P enters the glycolytic pathway.

Function of Glycogen in Skeletal Muscles and Liver

In liver glycogen is the first and immediate source of glucose for the maintenance of blood glucose levels.

In the liver, the G6P that is generated from glycogen degradation is hydrolyzed to glucose by glucose 6-phosphatase—an enzyme that is present only in the liver and kidneys.

G6P can then be converted to glucose via gluconeogenesis.

Function of Glycogen in Skeletal Muscles and Liver

Synthesis and Degradation of Glycogen

(S1) G6P is formed from glucose by hexokinase in most cells, and glucokinase in the liver. G6P is converted to G1P via phoshoglucomutase.

(S2) UDP-glucose (UDP-G) is synthesized from glucose 1-phosphate. UDP-G is the branch point for glycogen synthesis and other pathways that require the addition of carbohydrate units.

(S3) Glycogen synthesis is catalyzed by glycogen synthase and the branching enzyme.

(D1) Glycogen degradation is catalyzed by glycogen phosphorylase and a debrancher enzyme.

(D2) Glucose 6-phosphatase in the liver (and, to a small extent, the kidney) generates free glucose from G6P.

Synthesis and Degradation of Glycogen

Synthesis of Glycogen

Glycogen is formed from glucose 1-phosphate.

The high-energy phosphate from UTP is used to activate the Glucose-1-phosphate residues to form uridine diphosphate glucose (UDP-G).

Synthesis of Glycogen

Glycogen synthesis requires the formation of a -1,4-glycosidic bonds to link glucosyl residues in long chains from UDP-G by glycogen synthase.

Synthesis of Glycogen

Every 8 to 10 residues branching takes place.

Synthesis of Glycogen

a-1,6-branch every 8 to 10 residues takes place when 6-UDP-G reacts with the chain in presence of glycogen synthase.

NOTE: the use of 6-UDP-G for branching as compared to UDP-G for straight chain

UDP-G

Synthesis of Glycogen

When the a-1,6-branch chain reaches approximately 11 residues in length, a 6- to 8-residue piece is cleaved by amylo-4,6-transferase (also known as branching enzyme) and reattached to a glucosyl unit by an a-1,6-bond.

Synthesis of Glycogen

1-3 additional units

Both chains continue to lengthen until they are long enough to produce two new branches. Branching is done by transferase enzyme.

This process continues, producing highly branched molecules.

Branching of glycogen serves two major roles: increased sites for synthesis and degradation, and enhancing the solubility of the molecule.

Synthesis of Glycogen

Degradation of Glycogen

Glycogen Phosphorylase

Glycogen degradation is a phosphorolysis reaction (breaking of a bond using a phosphate ion as a nucleophile). Enzymes that catalyze phosphorolysis reactions are named phosphorylase.

Degradation of Glycogen

Glycogen Phosphorylase

However, glycogen phosphorylase cannot act on the glycosidic bonds of the four glucosyl residues closest to a branch point because the branching chain sterically hinders a proper fit into the catalytic site of the enzyme.

Degradation of Glycogen

4:4 transferase

Degradation of Glycogen

The debrancher enzyme, which catalyzes the removal of the four residues closest to the branch point, has two catalytic activities:

Transferase

Glucosidase

As a transferase, the debrancher first removes a unit containing three glucose residues and adds it to the end of a longer chain by an -1,4-glycosidic bond.

Degradation of Glycogen

a 1-6 glucosidase

Glucosidase : The one glucosyl residue remaining at the a-1,6-branch is hydrolyzed by the amylo-1,6-glucosidase activity of the debrancher, resulting in the release of free glucose.

Degradation of Glycogen

Glycogen Phosphorylase

Phosphorylase will then continue the degradation of the glycogen.

Some degradation of glycogen also occurs within lysosomes when glycogen particles become surrounded by membranes that then fuse with the lysosomal membranes.

A lysosomal glucosidase hydrolyzes this glycogen to glucose.

Degradation of Glycogen

Regulation of Glycogen

By Glucagon and Epinephrine

Inactive protein kinase

Active protein kinase

Insulin