glycogen metabolism part-2

Glycogen metabolism- Part-2(Glycogen degradation)

Namrata Chhabra, M.D., Biochemistry

Learning objectives

To understand: The Purpose Role of Enzymes and coenzymes, and The steps involved in the pathway of Glycogenolysis

Introduction

Glycogen is a storage form of glucose. It is a very large, branched polymer of glucose residues that

can be broken down to yield glucose molecules when energy is needed.

Most of the glucose residues in glycogen are linked by -1,4-αglycosidic bonds.

Branches at about every tenth residue are created by -1,6-αglycosidic bonds.

05/01/2023Namrata Chhabra, M.D., Biochemistry 4

Glycogen structure

Purpose of Glycogenolysis

The controlled breakdown of glycogen and release of glucose increase the amount of glucose that is available between meals. Hence, glycogen serves as a buffer to maintain blood-glucose levels.

Glycogen's role in maintaining blood glucose levels is especially important because glucose is virtually the only fuel used by the brain, except during prolonged starvation.

Purpose of Glycogenolysis

The glucose from glycogen is readily mobilized and is therefore a good source of energy for sudden, strenuous activity.

Unlike fatty acids, the released glucose can provide energy in the absence of oxygen and can thus supply energy for anaerobic activity.

Enzymes involved in Glycogenolysis

The efficient breakdown of glycogen requires four enzyme activities:

one to degrade glycogen, two to remodel glycogen so that it remains a

substrate for degradation, and one to convert the product of glycogen breakdown

into a form suitable for further metabolism.

Enzymes of Glycogenolysis

Phosphorylase

Bifunctional-Debranching

enzyme

Phospho- glucomutase

Glucose-6-Phosphatase

Major coenzyme of Glycogenolysis

Pyridoxal phosphate (PLP), a derivative of vitamin B6, is the major coenzyme involved in the glycogen degradation.

serves as prosthetic group for Glycogen Phosphorylase. It is held at the active site of Phosphorylase enzyme by

a Schiff base linkage, formed by reaction of the aldehyde group of PLP with the ε-amino group of a lysine residue.

Glycogen degradation is not just the reverse of glycogenesis

Glycogenesis

Glucose-> Glucose-6-P

Glucose-6-P –> Glucose-1-P

Polymerization

Branching

Polymerization

Glycogenolysis Depolymerization- Removal of

glucose as glucose-1-P Debranching Depolymerization Conversion of Glucose-1-P to

Glucose-6-P Conversion of Glucose-6-P to

free Glucose

Specific steps of Glycogenolysis

Step-1- Depolymerization (Release of Glucose-1-P from Glycogen)

Enzyme- Phosphorylase Coenzyme– Pyridoxal phosphate Reaction involved :

Step-1- Reaction catalyzed by Phosphorylase

Phosphorylase catalyzes the sequential removal of glucosyl residues from the nonreducing ends of the glycogen molecule (the ends with a free 4-OH group.

Orthophosphate splits the glycosidic linkage between C-1 of the terminal residue and C-4 of the adjacent one.

Phosphoroyltic cleavage Why not hydrolytic cleavage ?

Advantages of Phosphoroyltic cleavage

The phosphoroylytic cleavage of glycogen is energetically advantageous because the released sugar is already phosphorylated.

In contrast, a hydrolytic cleavage would yield glucose, which would then have to be phosphorylated at the expense of the hydrolysis of a molecule of ATP to enter the glycolytic pathway.

An additional advantage of phosphoroylytic cleavage for muscle cells is that glucose 1-phosphate, negatively charged under physiological conditions, cannot diffuse out of the cell.

Problem with Phosphorylase

The α-1,6-glycosidic bonds at the branch points are not susceptible to cleavage by phosphorylase.

Glycogen phosphorylase stops cleaving α -1,4 linkages when it reaches a terminal residue four residues away from a branch point.

Because about 1 in 10 residues is branched, glycogen degradation by the phosphorylase alone would come to a halt after the release of six glucose molecules per branch.

Step-2- Remodeling and Debranching

Special Bifunctional enzyme with two enzyme activities

Transferase and Debranching (α-1,6-glucosidase)

Both these enzymes remodel the glycogen for continued degradation by the phosphorylase.

Role of Transferase

Transferase shifts a block of three glucosyl residues from one outer branch to the other.

This transfer exposes a single glucose residue joined by an α-1,6-glycosidic linkage.

Debranching enzyme, hydrolyzes the α -1, 6-glycosidic bond, resulting in the release of a free glucose molecule.

The transferase and α-1,6-glucosidase convert the branched structure into a linear one, which paves the way for further cleavage by phosphorylase.

Phosphorylase versus debranching enzyme- Outcomes

Glucose-1-P is released as an outcome of reaction catalyzed by Phosphorylase

Free glucose is released by the action of debranching enzyme

Step-3- Conversion of Glucose-1-P to Glucose-6-P

Phosphoglucomutase converts glucose 1-phosphate into glucose 6-phosphate in a reversible reaction.

The catalytic site of an active mutase molecule contains a phosphorylated serine residue.

The phosphoryl group is transferred from the serine residue to the C-6 hydroxyl group of glucose 1-phosphate to form glucose 1,6-bisphosphate.

The C-1 phosphoryl group of this intermediate is then shuttled to the same serine residue, resulting in the formation of glucose 6-phosphate and the regeneration of the phosphoenzyme.

Reaction catalyzed by Phosphoglucomutase

Step-4- Fate of Glucose-6-P

Glucose 6-phosphate derived from glycogen can

(1) be used as a fuel for anaerobic or aerobic metabolism as in, for instance, muscle;

(2) be converted into free glucose in the liver and subsequently released into the blood;

(3) be processed by the pentose phosphate pathway to generate NADPH or ribose in a variety of tissues.


The fate is different in liver and muscle

The liver contains a hydrolytic enzyme, glucose 6-phosphatase, which cleaves the phosphoryl group to form free glucose and orthophosphate.

Glucose 6-phosphatase is absent from most other tissues. Consequently, glucose 6-phosphate is retained for the generation of ATP.

In contrast, glucose is not a major fuel for the liver. The liver releases glucose into the blood during muscular activity and between meals to be taken up primarily by the brain and skeletal muscle.


Reaction catalyzed by Glucose-6-Phosphatase


Glycogenesis versus Glycogenolysis

• Glycogenolysis and Glycogenesis are not the just the reverse of each other.

• The reaction pathways, enzymes and coenzymes are all different and,

• both the ways are reciprocally regulated.


Regulation of glycogen metabolism

To be continued in the next section…


Thank you

glycogen metabolism part-2

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