Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Glycogen metabolism

Biochemistry

2017Hayder A Giha

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Glycogen metabolism

l Glycogen found mainly in Liver (blood) and muscle (local)

l Synthesis of glycogen, (glycogenesis)

l Degradation of glycogen (glycogenolysis)

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Glycogen synthesisl Liver glycogen is for storage and maintenance of

blood glucose between mealsl After 12-18 hours of fasting the liver completely

depleted of glycogenl Muscle glycogen for local use, depleted only after

vigorous exercise. It is not affected short-term fasting (few days), and only moderately affected by prolonged starvation (few weeks)

l Glycogen storage diseases are inherited disorders, either abnormal glycogen or deficient mobilization cause muscle weakness or even death

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Glycogen synthesisl The substrate is UDP-glucosel Enzyme glycogen synthase (a1-4)l Branching enzyme (a1-6)l Initiation need either: a. a. Pre-existing short chains of glycogen or b. b. Glycogenin (protein found in center of

glycogen granule) l Progress at non-reducing end (c4 or c6)

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

UDP-glucose

• Glucose 6-P Glucose 1-P

• Glucose1-P + UTP UDP-Glucose + PPi

Phosphoglucomutase

UDP-glucose pyrophosphorylase

C1 of activated Glu form a glycosidic bond with C4 of terminal Glu residue of glycogen primer or OH of tyrosine of glycogenin primer. In the later, glycogen initiator synthase enzyme is used.

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Branchingl When chain length 10 – 12 glucosyle residuesl Branching enzyme remove 5 – 8 residues to

another glucose in original chain l Link it through a1-6 (branch)l The branch grow by a1-4 linkagel The free C4 and C6 are reactive sites (non-

reducing site or terminal) l The increasing number of branches enhance both

synthesis and degradation

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Glycogenolysis (degradation) l Removal of glucose from glycogenl It is not the reverse of glycogenesisl Enzymes are:* glycogen phosphorylase* debranching enzyme

l Site: non-reducing end (C4/C6)l i P is used to break a1 -4 linkl Product: * glucose 1-P * glycogen – smaller by one glycosyle residue

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Debranching l When branch became only 4 residues (limited

dextrin)l Debranching enzyme remove 3 residues to another

branchl The elongated chain can be shortened by

phosphorylase until ONE residue linked by a1-6 is left

l The a1-6 residue is removed by debranching enzymel All G-1P converted to G-6P, in liver (kidney) G-6P

can be converted to Glu by glucose-6-phosphatase

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Regulation l Different between liver and muscles due to diff.

goalsl Breakdown and synthesis are opposing, so that

they are reciprocally regulated i.e. when one activated other inhibited. To avoid futile cycles (waste of energy in form of heat)

l In muscles: a. When four Ca++ bind calmodulin, the later

undergoes conformational changes, that leads to activation of phosphorylase (glycogenolysis) by phosphorylase kinase

b. High level of AMP increase glycogenolysisl In liver:

- Glucose inhibit phosphorylase

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Regulation l Phosphorylase a [P] – active form:

- Activated by phosphorylase kinase- Inhibited by protein phosphatase-1

l Glycogen synthase a [de-P] – active forml - activated by protein phosphatase-1 l - inhibited by phosphorylase kinase

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005

Harvey RA, Champe PC. Lippincott Illustrated Biochemistry 3rd Edition, 2005