Glycogen metabolism

Question 1

glycogen is made from what form of glucose

Answer 1

alpha-D-glucose

Question 2

the primary bond

Answer 2

alpha-1,4-glycosidic linkage

Question 3

the branch bond

Answer 3

alpha-1,6-glycosidic linkage

Question 4

glycogen is store in…as…

Answer 4

cytoplasm of the liver and muscle (primarily) as large hydrated granules

Question 5

function of liver vs muscle glycogen

Answer 5

liver - maintain blood glucose concentration

muscle - contraction

Question 6

blood glucose can be obtained from what sources?

Answer 6

diet - sporadic
degradation of glycogen - less than 24 hr supply
gluconeogenesis - slow

Question 7

function of muscle glycogen

Answer 7

fuel reserve for synthesis of ATP to power mm contraction
glucose can not leave cell because it remains phosphorylated
mm lacks; glucose-6-phosphatase

Question 8

important enzyme in the liver

Answer 8

glucose-6-phosphatase

“frees” glucose so that it can leave cell and enter blood

Question 9

special enzymes of glycogenesis

Answer 9

1. glycogen synthase
   - requires a primer (glycogen or glycogenin protein)
2. branching enzyme
   - breaks alpha 1,4 -> transfer to alpha 1,6

(first glucose must become activated = UDP-Glucose)

Question 10

what must happen to glucose before it can be used in glycogenesis?

Answer 10

must be activated w a nucleotide sugar

uridylyltransferase / UDPFle pyrophosphorylase

UTP + Glucose-1-P -> UDP-Glucose + PPi

note the subsequent hydrolysis of PPi by Pyrophosphatase makes this rxn favorable

Question 11

what enzyme is equivalent to glucokinase but acts in the reverse direction?

Answer 11

glucokinase = in liver, phosphorylates glc -> G-6-P

glucose-6-phosphatase (liver only) removes that P group

Question 12

significance of alpha-D-glucose attached to uridine diphosphate (UDP)

Answer 12

the soucre of all the glucosyl residues added to the growing glycogen molecule

Question 13

why can’t free glucose accept a mol of glucose from UDP-glucose to initiate chain synthesis?

Answer 13

the smaller the glycogen the larger the Km of the synthase, so at its physiologic conc glucose can’t serve as a primer for glycogen synthesis
glycogen frament can serve as a primer

Question 14

what is glycogenin? what does it do?

Answer 14

protein that acts as a primer via autoglucosylation
OH grp of Tyr-194 accepts initial glucosyl unit
both enzyme and substrate
after ~ 7 residues glycogen synthase takes over

Question 15

does glycogen synthase require ATP?

Answer 15

no - a synthetase normally would

a synthase - catalyzes a synthetic rxn in which two units are joined wo the direct participation of ATP

Question 16

glycogen synthase, what does it do?

Answer 16

transfers glucose from UDP-glc to the non-reducing end of the growing chain

Rate limiting and Regulated step
a homotetramer

Question 17

branching enzyme

Answer 17

glucosyl 4:6 transferase

clease an alpha-1,4 bond, transfers chain (6-8residues) to another residue on chain and forms a alpha-1,6-bond

results in two nonreducing ends that can be added to by glycogen synthase

Question 18

why branching?

Answer 18

increased solubility

increased number of nonreducing ends to which new glycosyl residues can be added

Question 19

what limits glycogen synthesis?

Answer 19

feedback control by glycogen

not well understood

Question 20

glycogen phosphorylase

Answer 20

first step in glycogen degradation
uses Pi to cleave the alpha-1,4- bonds -> G-1-P + remaining glycogen
stops 4 residues from branch pt => limit dextrin

alpha-1,4-glucosidase, phosphorlysis, rate-limiting
requires: PLP pyridoxal phosphate (B6)

Question 21

phosphoglucomutase

Answer 21

coverts G-1-P -> G-6-P

Question 22

debranching enzyme

Answer 22

second step in glycogen
bifunctional enzyme:
1. 4-alpha-D-glucantransferase
transfers 3 outer residues of the limit dextrin to a nonreducing end, leaving only 1 glucosyl residue in an alpha-1,6-linkage

2. amylo-alpha-1,6 glucosidase
   cleaves the 1 remaining residue
   => free glucose! (not phosphorylated)

Question 23

lysosomal glycogen degradation pathway

Answer 23

quantitatively less significant
1-3% glucogen degraded in lysosom by the acid hydrolase:
alpha-glucosidase

Question 24

forms that glycogen phosphorylase exists in, what enzyme(s) cause these changes?

Answer 24

Glycogen Phosphorylase
a = active form: Phosphorylated (phosphorylase kinase)
b= inactive form: de-phosphorylated (phosphorylase phosphatase)

Question 25

how is Phosphorylase Kinase activated? what does it do?

Answer 25

Phosphorylase Kinase
activated by Protein Kinase A
a = active form is Phosphorylated

phosphorylase kinase can now phosphorylate (activate) glycogen phosphorylase (glycogenolysis)

Question 26

how is phosphorylase kinase inactivated?

Answer 26

phosphoprotein phosphatase removes Pi thus inactivating posphorylase kinase

Question 27

summarize the activation of Glycogen Phosphorylase (glycogenolysis)

Answer 27

hormone signal (glucagon, epinephrine)
increase cAMP
activation of Protein Kinase A
Phosphorylase kinase (active -P'ated)
Glycogen phosphorylase (active - P'ated)

Question 28

hormone signals that initiate glycogenolysis and where?

what processes do they inhibit?

Answer 28

Both activate Protein Kinase A

Glucagon;

• pancreatic alpha cells
• LIVER

Epinephrine:

• adrenal medulla, synth from tyr, stress
• binds beta-adrenergic receptors
• Liver & Muscle

both Inhibit: conversion of UDP-Glucose -> glycogen & G-6-P -> Pyruvate (aka storage)

Question 29

forms of Glycogen Synthase, enzymes that act on it

Answer 29

a = active; DePhosphorylated - several Kinases (opp of glycogenolysis - Glucogen Phosphorylase)
b = inactive, Phosphorylated form - Phosphoprotein Phosphatase

Question 30

how does cAMP regulate glycogen metabolism?

Answer 30

simultaneously
activates glycogenolysis
inhibits glycogenesis
all this via protein phosphorylation by cAMP-dependent PKA

Question 31

protein phosphatase inhibitor

Answer 31

this is also phosphorylated and thus activated by PKA along with glycogen phosphorylase kinase (activates glycogen phosphorylase)

this prevents the dephosphorylation (inactivation)

Question 32

for synthase the deP form is the active/inactive form

Answer 32

for synthase the deP is the Active form

Question 33

for phosphorylase kinase & phosphorylase the deP form is the active/inactive form

Answer 33

for phosphorylase kinase & phosphorylase the deP is the Inactive form

Question 34

insulin’s role in glycogen metabolism

Answer 34

1. inhibits several kinases = prevents P’lation of Synthase
   activates Phosphoprotein Phosphatase = Activates Synthase
2. promotes conversion of cAMP -> 5’ AMP
   Net: activation of Glycogen Synthase (to its deP form)
   and thus Glycogen synthesis (storage)

Question 35

what are the allosteric effectors involved in glycogen metabolism?

Answer 35

Ca 2+
AMP
glucose
G-6-P

Question 36

Ca2+ allosterically acts on…

Answer 36

phosphorylase kinase b (deP inactive form)
Activating it

Note: Ca also phosphorylates and inhibits Glycogen Synthase
thus, Ca+ increases degradation and decreases synthesis of glycogen

Ca is also required for maximum activation of phosphorylase kinase a

Question 37

AMP allosterically acts on…

Answer 37

glycogen phosphorylase b (mm isozyme)
(inactive deP form)

AMP indicates low energy! so Activates the phosphorylase to breakdown glycogen stores

Question 38

Glucose allosterically acts on

Answer 38

phosphorylase a (liver isozyme)
(a- active, P form)

Glucose = energy available, so Glucose will Deactivate it bc we don’t need to make more energy

Question 39

Glucose 6 -P allosterically acts on

Answer 39

Glycogen Synthase b
(inactive, P form)

G-6-P indicates energy is available => Activates it to store available energy

Question 40

Differences in Ca2+ in muscle and liver

Answer 40

Contracting muscle:
Ach -> depolarization -> release of Ca2+ from sarcoplasmic reticulum

Liver:
Epi -> alpha-adrenergic receptors -> Phospholipase C -> IP3 (and DAG) -> release of Ca2+ from ER

Question 41

Epinephrine binding to beta-adrenergic receptors

Answer 41

in liver and muscle

promotes glycogenolysis via activation of cAMP -> PKA

Question 42

Epinephrine binding to alpha-adrenergic receptors

Answer 42

liver only
promotes glycogenolysis (increase blood sugar)

Question 43

Triacylglyceral/fat (TAG) synthesis and degradation site

Answer 43

synthesis; liver

degradation; fat

Question 44

dihydroxyacetone phosphate (DHAP)

Answer 44

can be converted to GAP (glyceraldehyde 3-phosphate) and sent into glycolysis

or continue on into TAG synthesis

Question 45

key lipase for TAG degradation

Answer 45

Hormone Sensitive Lipase

activated by Epinephrine (some degree glucagon)