Glycogen Metabolism

Question 1

glycogen stored where and percent weight?
depleted how quickly?

Answer 1

10% of liver, 1-2% weight of muscle
also stored in astrocytes, heart, adipose tissues
depleted after 1 hour of vigorous exercise or 12-24 hours of fasting

Question 2

how glycogen is stored

Answer 2

granules in the cytosol
beta-particles contain 55,000 glucoses with 2000 non-reducing ends
alpha-rosettes contain 20-40 beta particles

Question 3

Enzymes of glycogenolysis

Answer 3

Glycogen phosphorylase (+ pyridoxal phosphate cofactor)
Glycogen debranching enzyme
Phosphoglucomutase

Question 4

Glycogenolysis at alpha 1,4 linkage

Answer 4

Release of 1 glucose-1-phosphate molecule
Enzyme: glycogen phosphorylase
Cofactor: pyridoxal phosphate (active form B6) + Pi
Works on non-reducing ends until it reaches a branch

Question 5

Glycogenolysis at alpha 1,6 linkage

Answer 5

Enzyme: debranching enzyme
2 activities: transferase and glucosidase

Transferase activity: moves 3 glucose molecules to nonreducing end from branch and reattaches with a-1,4

Glucosidase activity: cleaves remaining branched glucose (no Pi added)

Question 6

Formation pf Glucose-6-phosphate in Glycogenolysis

Answer 6

Enzyme: phosphoglucomutase
Conversion of Glu-1-phosphate –> Glu-6-phosphate

Serine residue adds phosphate to C6, C1 re-phosphorylates serine residue (ready to work again)

Question 7

Dephosphorylation of glu-6-phos

Answer 7

Occurs in liver ER lumen
Enzyme: glucose-6-phosphatase
Release of glucose via GLUT2 receptors, which are NOT insulin dependent

Question 8

Glucose-6-phosphatase in muscle

Answer 8

Expression is very low
Muscle is not a contributor to blood glucose concentration

Question 9

Glycogenesis overview steps

Answer 9

1) Formation of UDP-glucose
2) Initiation short-chain synthesis
3) Elongation
4) Branching

Question 10

Enzymes of glycogenesis

Answer 10

1. NDP-sugar pyrophosphorylase
2. Glycogenin (glycosyltransferase and chain-extending activity)
3. Glycogen synthase (a-1,4 chain extending)
4. Branching enzyme

Question 11

Glycogenesis step 1

Answer 11

Glucose-1-phosphate + NTP –> pyrophosphate/2Pi + NDP-sugar (sugar nucleotide ex. uracil diphosphate)
Enzyme: NDP-sugar pyrophosphorylase
Mechanism: Phosphate on sugar attackes alpha phosphate on NTP

Question 12

Glycogenesis step 2

Answer 12

Enzyme: Glycogenin (dual function glucosyltransferase and chain-extending)
Glucosyltransferase: OH on Tyr of glycogenin attacks C1 of sugar, releasing UDP
Chain-extending: 4’ OH of previous sugar attacks C1 of incoming UDP-glucose, releasing UDP and so on up to 6x
And then glycogen synthase takes over job

Question 13

Glycogenesis Step 3

Answer 13

Enzyme: glycogen synthase
Glycogen synthase adds glucose to non-reducing end with alpha 1,4 linkage and UDP is released

Question 14

Glycogenesis step 4

Answer 14

Enzyme: glycogen-branching enzyme
Creates alpha 1,6 branching linkages
Increases water solubility and number of non-reducing ends

Question 15

phosphoglucomutase

Answer 15

Converts Glu-6-P to Glu-1-P and vice versa
Role in glycogenolysis and glycogenesis

Question 16

From glucose –> glycogen enzymes

Answer 16

Glycogenesis:
Hexokinase
Phosphoglucomutase
UDP-glucose pyrophosphatase
Glycogenin
Glycogen synthase
Glycogen branching enzyme

Question 17

From glycogen –> glucose

Answer 17

Glycogenolysis:
Glycogen phosphorylase
Debranching enzyme: transferase and glucosidase
Phosphoglucomutase
Glucose-6-phosphatase

Question 18

Glycogen phosphorylase beta vs alpha forms

Answer 18

Beta - unphosphorylated on serine side chains, less active
Alpha - phosphorylated serine residues, more active

Question 19

Hormonal regulation of glycogenolysis

Answer 19

Hormones: glucagon (liver only) and epinephrine
Pathway: GPCR, cAMP, PKA –> Active phosphorylase beta kinase –> active glycogen phosphorylase alpha (from beta form) –>glycogenolysis

Question 20

Stimulators of glycogenolysis

Answer 20

Glucagon (liver only) and epinephrine via GCPR cAMP pathway

↑ [Ca2+] - activate phosphorylase beta kinase

↑ [AMP] - activates glycogen phosphorylase alpha

Question 21

muscle does not contain

Answer 21

glucagon receptors

Question 22

hormonal regulation of glycogenesis

Answer 22

Insulin, pathway: RTK receptor, IRS-1, PI3K, PIP2–> PIP3, PDK-1, PKB, GSK3 inactivated, glycogen synthase alpha operational

Insulin, ↑[glucose]/↑[G-6-P] activates PP1 –> active alpha glycogen synthase

Glucagon/epinephrine blocks PP1 –> blocks activation of beta glycogen synthase

Question 23

PP1

Answer 23

protein phosphatase

Question 24

Regulation of glucose metabolism in liver vs muscle

Answer 24

Liver:
Receptors for glucagon and epinephrine
↑ Glycogenolysis and ↑ conversion of pyruvate –> Glucose
Glycolysis ↓
↑ gluconeogenesis

Muscle:
receptors only for epinephrine
↑ glycogenolysis and glycolysis (conversion of Glu-6-phos –> pyruvate for glycolysis)

Question 25

When glucagon and epinephrine are bound in liver and muscle

Answer 25

In liver glycolysis ↓, in muscle glycolysis ↑

In liver gluconeogenesis occurs, none in muscle

In liver pyruvate is used for gluconeogenesis (converted to Glu-6-phos for export to bloodstream), in muscle glycogen is broken down to undergo glycolysis –> pyruvate for TCA

Question 26

Muscle differences from liver

Answer 26

Lacks glucagon receptors (epinephrine signaling)
PKA does not phosphorylate pyruvate kinase (glycolysis continues)
No production of Fructose-2,6-bisphosphate