BCH 400- Lecture 26 Glycogen degradation and synthesis

Phosphorylase b and phosphorylase a exist in equilibrium between

an active R state and less active T state

Phosphorylase b is usually inactive because

the equilibrium favors the T state

Phosphorylase a is usually active because

the equilibrium favors the R state

In the T state,

the active site is partly blocked by a regulatory structure

active site is

unobstructed in the R state

Key role of the liver is to

maintain adequate blood levels of glucose
as a result, the default state of liver phsophorylse

liver phosphorylase

prepared to generate blood glucose unless signaled otherwise

negative regulator of liver phosphorylase

glucose
it facilitates the transition from the R state to the T state

Muscle phosphorylase

regulated by the intracellular energy charge

default form of phosphorylase in muscle is the

b form in the T state
when energy is needed, as signaled by an increase in the concentration of AMP the phosphorylase binds AMP which stabilizes the R state

T state of muscle phosphorylase is stabilized by

ATP and glucose 6 phosphate

What enzyme is responsible for the conversion of glycogen phosphorylation from the unphosphorylated b state to the a state

phosphorylase kinase

how is phosphorylase kinase activated

by both phosphorylation and Ca2+ binding

What is phosphorylase kinase phosphorylated by

protein kinase A

What is the delta subunit of phosphorylase

calcium sensor calmodulin

When is phosphorylase kinase maximally active?

when phosphorylated and
bound to calcium

Glucagon (Liver) and Epinephrine (Muscle) initiate protein cascades that result in what

production of cAMP

what is adenylate cyclase activated by

G alpha

What does cyclic AMP activate

protein kinase A (PKA) which phosphorylates and completes the activation of phosphorylase kinase

What activates glycogen degradation

phosphorylase kinase converting glycogen phosphorylase b to the a form

Glycogen breakdown =

must be rapidly turned off when necessary

How is glycogen degradation turned off

1) the inherent GTPase activity of the G protein renders these proteins inactive
2) Phosphodiesterase converts CAMP to AMP which does not stimulate protein kinase A
3) Protein phosphatase 1 ( activated by insulin signaling ) removes phosphoryl groups from phosphorylase kinase and glycogen phosphorylase, thereby inactivating the enzymes

Glycogen synthesis proceeds via an activated form of glucose:

UDP glucose

What is UDP glucose synthesized by

UDP glucose pyrophosphorylase
reaction is subsequently irreversible by the hydrolysis of pyrophosphate

Glycogen synthase catalyzes the transfer of what

glucose from UDP glucose to a growing chain

key regulatory enzyme in glycogen synthesis

glycogen synthase

What does glycogen synthase do

transfers a glucose moiety from UDP glucose to the C4 terminal residue of glycogen chain to form an alpha 1-4 glycosidic bond
extends primer
can extend the branched polymer

What does glycogen synthase require

an oligosaccharide glucose residues as primer
primer is synthesized by glycogenn

What is glycogenin

a dimer of two identical subunits
each subunit generates an oligosaccharide of glucose residues 10-20 molecules long

Glycogen branching enzyme remodels the growing glycogen chain and introduces what

alpha 1,6 linked branches

A branching enzyme generates what

branches by cleaving an alpha 1-4 linkage and taking a block of approximately 7 glucoses and synthesizing an alpha 1,6 linkage

An efficient way to store glucose

making glycogen

Glycogen

highly branched homopolymers of glucose present in all tissues

Largest stores of glycogen are in the

liver and muscle

What does the liver do?

it breaks down glycogen and releases glucose to the blood to provide energy for brain and RBCs

Muscle glycogen stores are mobilized to

provide energy for muscle contraction

Glycogen storage particle storage:

glycogenic protein at center
alpha 1,4 linked glucose chains with alpha 1,6 branch every 10 residues
non reducing end glycogen molecule exposed on the surface

Why is glycogen highly branched?

glycogen particle structure allows for rapid mobilization of glucose reserves

what 4 enzymes are needed for complete glycogen breakdown

Glycogen phosphorylase
Glucosyltransferase

Glycogen phosphorylase

degrades glycogen from the nonreducing ends of the glycogen molecule
catalyzes a phosphorolysis reaction that yields glucose 1- phosphate
specific for the hydrolysis of alpha 1,4 glycosidic linkages and it cannot cleave near branch points

Complete breakdown of glycogen requires what

remodeling of the glycogen molecule

Glucosyltransferase (GT)

shifts a small oligosaccharide near the branch point to a nearby chain, thereby making the glucose moieties accessible to the phosphorylase

alpha-1,6-glucosidase

deb ranching enzyme
cleaves the alpha 1-6 bond at the branch point releasing a free glucose

Phosphoglucomutase form glucose 6 phosphate from glucose 1 phosphate via what

a glucose 1,6 bisphosphate intermediate

Glucose 6 phosphatase generates what

free glucose from glucose 6 phosphate in liver

Glucose 6 phosphatase is absent in most other tissues:

in muscle tissue, the glucose 6 phosphate generated by the breakdown of glycogen feeds into glycolysis and ATP production

Glycogen phosphorylase is regulated by:

reversible phosphorylation and by allosteric effectors

Key regulator enzyme for glycogen degradation

glycogen phosphorylase

The liver and muscle express different isoforms of

glycogen phosphorylase with different regulation

Glycogen phosphorylase exists in two forms:

a less active b form and a more active a form

A form of glycogen phosphorylase

differs from B form in that a serine residue (14) is phosphorylated

Both the a form and b form of glycogen phosphorylate display

R to T equilibrium

B form of glycogen phosphorylase

the T state is favored while in the a form the R state is favored
unphosphorylated

Phosphorylation is stimulated by what 2 hormones

glucagon and epinephrine (adrenaline)

Phosphorylation alters the active site such that

alpha helices that partially block the active site in the b form are removed

How many molecules of ATP are required to incorporate dietary glucose into glycogen

2

complete oxidation of glucose derived from glycogen yields how many ATP

31

Glycogen synthase is inactive where

in the phosphorylated form
opposite of glycogen phosphorylase

Keyallosteric effector for glycogen synthase

is the conversion of the b form in the T state to the active R state of the b form by binding glucose 6 phosphate

What does glycogen synthase kinase do

phosphorylase glycogen synthase, inactivating it

What does protein phosphatase 1 do

dephosphorylates glycogen synthase , activating it

Glycogen synthesis is inhibited by the same glucagon and epinephrine signaling pathways that stimulate what

glycogen breakdown

glucagon or epinephrine

unregulated glycogen phosphorylase
and downregulate glycogen synthase

What inhibits glycogen synthesis

phosphorylation of glycogen synthase by protein kinase A to form glycogen synthase

In liver, high glucose hind to what

glycogen phosphorylase a and inhibits it

High blood glucose levels

glycogen degradation in the liver is inhibited
glycogen synthesis is stimulated

How is PP1 activated?

by the conversion of glycogen phosphorylase a from the R state to the T state by the binding of glucose

What does PP1 do

converts glycogen metabolism from a degradation mode to a synthesis mode