Fundamentals of Biochemistry

Third Edition

Donald Voet • Judith G. Voet • Charlotte W. Pratt

Chapter 16

Glycogen Metabolism and Gluconeogenesis

Copyright © 2008 by John Wiley & Sons, Inc.

Glycogen Breakdown

Enzymes for Glycogen Breakdown • Glycogen phosphorylase – Glycogen + P

i

 Glycogen (n-1) + G1P • Glycogen Debranching Enzyme • Phosphoglucomutase – G1P  G6P

• Glycogen Phophorylase – Homodimer – Regulation • -- ATP, G6P, glucose • + AMP • Phosphorylation – R & T states – Crevase that holds 4-5 linear carbohydrates – Cofactor of PLP, a B 6 derivative

Debranching Enzyme

Phosphoglucomutase

Diseases • G6P generated via glycogen has multiple fates – Glycolysis – Pentose phosphate – Transport to other tissues • In liver, G6Pase, removes phosphate for transport out of cell • G6Pase is in the ER, but G6P is in cytosol – G6P translocase • Glucose exits cell via GLUT2 – Muscles lack G6Pase and therefore retain G6P

Glycogen Synthesis • G’ for glycogen phosphorylase is +3.1 kJ/mol – Under physiological conditions it is -5 to -8 kJ/mol – This reaction then, cannot go both directions spontaneously via the same enzymes

UDP-Glucose Pyrophosphorylase • Since synthesis is thermodynamically unfavorable, we must put in energy.

G1P + UTP ↔ UDPG + PP

i

H 2 O + PP

i

 2 P

i

= 0 kJ/mol = -19.2 kJ/mol Net G1P + UTP  UDPG + 2 P

i

= -19.2 kJ/mol

Glycogen Synthase The second step is spontaneous under physiological conditions. It comes at a cost of 1 ATP (UTP) Glycogen synthase only adds to a chain Need Glycogenin to build initial starting chain

Branching Enzyme Must transfer 7 carbohydrates at a time (only). There must be at least 4 left over.

PP1c

Activated by phosphorylation and Ca 2+ Calcium is regulated by calmodulin

Hormonal Control

Increase Glycogen Breakdown

• Low Glucose • ↑ Glucogon • ↑ Epinephrine – B-adrenergic receptor (muscle) • ↑cAMP – A-adrenergic receptor (liver) • ↑ Glucogon • ↑ cAMP • ↑ Ca2+

Increase Glycogen Synthesis

• High Glucose • Insulin – GLUT4 • Muscle, fat • ↓ cAMP

Gluconeogenesis • Most of Gluconeogenesis is Glycolysis in reverse.

• Only irreversible steps must be different • Oxaloacetate is the required molecule to start gluconeogenesis

Step 1 – Make oxaloacetate

normal

Oxaloacetate is only formed in the mitochondria, remaining steps occur in cytosol.

anaerobic

F1,6BP PFK Same enzyme different domains

N-linked O-linked

N-linked