glycogen matabolism-mitsouras

Question 1

What transporters are responsible for glucose uptake into the liver?

Answer 1

GLUT2
low affinity, high capacity transporters
—> will uptake and lose glucose first. not likely to hold onto them

Question 2

What transporters are responsible for glucose uptake in muscles?

Answer 2

GLUT 4

Question 3

What is the structure of glycogen?

Answer 3

branches every 8-12 residues
alpha (1,4) bonds between glucose in linear chain
alpha (1, 6) bonds between glucose at branch points

glycosidic bonds occur between the C1 of free glucose and a free OH group in glucose in glycogen

each glycogen has 1 reducing end (free OH at C1, where glycogen initiated) and many non-reducing ends (free OH groups of glucose in glycogen) where glucose will be added or removed.

Question 4

How does glycogenesis occur?

Answer 4

addition of UDP-glucose to non-reducing ends of glycogen –> energy for formation of glycosidic bond provided by the hydrolysis of the UDP

• glycogen synthase allows chain elongation (creation of alpha (1, 4) bonds
• branching enzyme creates alpha (1, 6) bonds

Question 5

What are the 2 ways that UDP glucose can be formed?

Answer 5

from UDP galactose (via UDP-hexose 4 epimerase)

from glucose 1 phosphate (from either glucose 6 P from glucose or from galactose 1P from galactose). enzyme=UDP glucose pyrophospphorylase

Question 6

What is needed for initial glycogen elongation?

Answer 6

glycogen synthase needs a primer for elongation primers:

1. existing glycogen molecule (at least 4 glucose residues long)
2. glucose chain attached to glycogenic

glycogenin autoglycosylates a tyrosine residue 4X until the chain is long enough to be a substrate for glycogen synthase

Question 7

How does glycogen form branches?

Answer 7

Glycogen synthase catalyzes sequential addition of glucose residues at non- reducing ends (approximately 11x)

branching enzyme hydrolyze the alpha 1,4 bond and will transfer a 6-8 glucose fragment from the straight chain to form an alpha (1, 6) bond in an internal position
–> new non-reducing site for glycogen synthase to add more glucose

Question 8

Regulation of glycogenesis

Answer 8

fed state:

Insulin activates protein phosphatase-1 => dephosphorylates glycogen synthase => glycogen synthase ON => glycogenesis ON
Allosteric effectors:
Glucose-6P => Glycogen synthase ON (feed-forward stimulation)
Glucose => Protein phosphatase 1 ON (liver only)

fasting state:

Glucagon activates protein kinase A => phosphorylates glycogen synthase => glycogen synthase OFF => glycogenesis OFF

Question 9

What enzymes are responsible for glycogenolysis? How do these enzymes function in glycogenolysis?

Answer 9

enzymes degrade glycogen at the non-reducing ends

glycogen phosphorylase degrades alpha (1, 4) bonds==>produces glucose-1-P (most glucose in glycogen-92%)
breaks bonds by phosphorlytic cleavage (using Pi)
*requires pyridoxal phosphate (PLP; vitamin B6)

debranching enzyme degrades alpha (1,6) bonds==> produces glucose (only 8% in glycogen)
*debranching enzyme is NOT regulated

glycogen phosphorylase will remove glucose from non-reducing ends until 4 glucoses away from a branch point
debranching enzyme will transfer 3 glucose from a branch point to a non-reducing end (forming more linear chain) and then will hydrolyze the alpha (1, 6) bond –> produces glucose

Question 10

Regulation of glycogenolysis

Answer 10

in the fasting state:
-Glucagon activates protein kinase A=> phosphorylates phosphorylase kinase => phosphorylase kinase ON => phosphorylates glycogen phosphorylase => glycogen phosphorylase ON ( from inactive g. phosphorylaase b–> active g. phosphorylase a)=> glycogenolysis ON

• glucagon phosphorylates glycogen synthase, inactivating it and inhibiting glycogenesis
• ATP, glucose-6P & glucose => Glycogen phosphorylase OFF (feed-back inhibition)–> glycogenolysis OFF

in the fed state:
Insulin activates protein phosphatase 1=> dephosphorylates glycogen phosphorylase => glycogen phosphorylase OFF => glycogenolysis OFF
Protein phosphatase 1 also directly dephosphorylates phosphorylase kinase => phosphorylase kinase OFF => glycogen phosphorylase OFF=>glycogenolysis OFF
==> ensures no glycogen degradation in the fed state

Question 11

What stimulates glycogenolysis in muscle?

Answer 11

muscle contraction and neurotransmitter signaling activate glycogen phosphorylase

*glucagon does not affect skeletal mm

epinephrine activates PKA to phosphorylate and turn on phosphorylase kinase

Ca2+ (bound to calmodulin) activates phosphorylase kinase

AMP activates glycogen phosphorylase

Question 12

What are the common glycogen storage diseases and what enzyme are they deficient in?

Answer 12

Type 1: glucose-6-phosphatase 
type 2: alpha (1,4) glucosidase (lysosomal) 
type 3: debranching enzyme 
type 4: branching enzyme 
type 5: glycogen phosphorylase 
type 6: glycogen phosphorylase 
type 7: PFK 
type 8: PFK