section 3: part 1 - glucose metabolism overview/glycogen breakdown

very generally give an overview of glycogen breakdown

1. glycogen phosphatase

- degrades glycogen to glucose-1-phosphate

2. glycogen debranching enzyme

- acts as a glucosyltransferase

3. phosphoglucomutase

- interconverts glucose-1-phoshate and glucose-6-

phosphate

what are the functions of glycogen

stockpile glucose for later use

provide a constant supply of glucose

- essential for brain and RBCs

mobilization of glucose from glycogen stores (in skeletal muscle and liver))

- provides a constant supply of glucose to all tissues

describe glycogen synthesis when [glucose] is high

glycogen synth. accelerates

liver's glycogen storage holds enough glucose to do what

supply the brain with glucose for half the day

during fasting conditions, how are most of the bodies glucose needs met

by gluconeogenesis from non-carb precursors such as aas

Describe McArdle's disease

lack of glycogen phosphorylase (needed to break down glycogen to yield glucose)

leads to insufficient glycolysis to keep up with demand for ATP

and painful muscle cramps on exertion

Describe glucose-6-phosphate (G6P)

key branch point

derived from free glucose through the action of hexokinase (HK)

or is a product of glycogen breakdown or gluconeogenesis

Describe the structure of glycogen

α(1->4)-linked D-glucose with α(1→6)-linked branches every 8-14 residues

occurs as intracellular granules

each spheroidal molc. of glycogen can hold how many glucose units

120,000 glucose units

Describe glycogen granules

prominent in cells that make the greatest use of glycogen

- muscle = up to 1-2% glycogen by weight

- liver cells = up to 10% glycogen by weight

contain enzymes that catalyze glycogen synth and degradation

how are glucose units mobilized

by their sequential removal from non-reducing end

complete the sentence: glycogen has only ___________________, and there is a _______________________ on every branch

one reducing end, non-reducing end

glycogens highly branched structure allows for what

simultaneous release of glucose units from the end of every branch

permits rapid glucose mobilization

what are the 3 enzymes glycogenolysis requires

glycogen phosphorylase

glycogen debranching enzyme

phosphoglucomutase

Describe glycogen phosphorylase

catalyzes glycogen phosphorolysis to yield glycogen-1-Phosphate (G1P)

glycogen + Pi <-> glycogen + G1P

releases a glucose unit only if at least 5 units away from a branch point

describe glycogen debranching enzyme

removes glycogens branches

- makes additional glucose residues accessible to

glycogen phosphorylate

Describe phosphoglucomutase

converts G1P to G6P

what catalyzes the rate controlling step in glycogen breakdown

glycogen phosphorylase

what are the regulators of glycogen phosphorylase

allosteric interactions

covalent modification (phos/dephos)

Describe the allosteric interaction regulators of glycogen phosphorylase

allosteric inhibs:

- ATP

- G6P

- glucose

allosteric activator

- AMP

Describe the active site (AS) of glycogen phosphorylase

small opening on surface of phosphorylase monomer

- connects glycogen storage site active site

- can accommodate 4/5 sugar residues in a chain

- too narrow to admit branched oligosaccs.

phosphorylase cleaves only glycosyl residues ≥five units from branching point

Describe the cofactor of glycogen phosphorylase

PLP

- pyridoxa-5'-phosphate

is a vitamin B6 derivative

required for activity

Describe the T state of glycogen phosphorylase

inactive

enzyme has buried active site

low affinity for its substrates

describe the R state of glycogen phosphorylase

active

enzyme has accessible catalytic site

high affinity phosphate binding site

How does AMP affect the conformational state of glycogen phosphorylase

promotes shift from T -> R

binds to R state of enzyme at its allosteric effector site

- disordering loop of residues that would block AS

- increased access of substrate to AS

How does ATP affect the conformational state of glycogen phosphorylase

inhibits shift of T -> R

binds to T state of enzyme at its allosteric effector site

what does glycogen debranching enzyme act as

glucosyltransferase

Describe the phosphorolysis process of glycogen debranching enzyme

proceeds along glycogen branch

stops when within 4 or 5 residues of an α(1→6)branch point to limit the branch

how does Glycogen Debranching Enzyme Acts as Glucosyltransferase

it is an α(1->4)transglycosylase

transfers an α(1→4)-linked trisaccharide unit from limit branch to nonreducing end of another branch

what happens to the α(1→6) bond linking remaining glycosylresidue in the branch to the main chain after the removal of the α(1→4)-linked trisaccharide unit from GDE

it is hydrolyzed by a same debranching enzyme

to yield glucose + debranched glycogen

What percentage of residues in glycogen at the branch points are converted to glucose rather than G1P

10%

Describe the GDE AS

has separate active sites for transferase and the α(1→6)-glucosidase reaction

2 independent catalytic AS on same enzyme improves debranching efficiency

which is faster, glycogen phosphorylase rate or glycogen debranching rate

glycogen phosphorylase rate is much faster

limits maximum exertion a muscle can sustain for only a few seconds

describe what affects conditions of high metabolic demand in muscle have on debranching/branches

outermost branches of glycogen ( constitute nearly half of its residues) degraded in seconds

glycogen degradation beyond this point requires debranching and hence occurs slower

limits maximum exertion a muscle can sustain for only a few seconds

what is moved to make G6P

phosphoryl group transferred from the active phosphoenzyme to G1P making it become G6P

G6P produced by glycogen breakdown can continue along what pathways

glycolytic pathway

or pentose phosphate pathway

- glucose is already phos.

- ATP consuming HK-catalyzed phosphorylation

of glucose is bypassed

where can G6P be made

liver

can G6P pass through cell membranes

no

What is G6P first hydrolyzed by

G6Pase to make glucose + Pi

Describe the process of G6P generation/hydrolysis and glucose export within a liver cell

G6P produced in cytosol

G6P imported to ER by G6P translocase

G6Pase in ER mem hydrolyzes G6P and glucose and Pi are returned cytosol specific transport proteins

glucose leaves cell via GLUT2 carried by blood to other tissues

defect in components of G6P hydrolysis system have what

type 1 glycogen storage disease

muscles and other tissues that lack G6Pase do what

retain their G6P