Chapter 25: Glycogenesis

glucose --> glycogen

Glycogenesis Pathway

glucose —> G6P —> G1P —> UDP- glucose —>Glycogen

Hexokinase/ Glucokinase

phosphorylates/ adds phosphate group to glucose to make it glucose-6-phosphate

hexokinase: most tissue (high km, low affinity)

glucokinase: liver (low km, high affinity)

step 1

Phosphoglucomutase

converts G6P to G1P to eventually be converted to UDP-glucose

reversible

UDP-glucose Pyrophosphorylase

converts G1P to UDP glucose; attaches UPD to G1P

Glycogen Synthase

transfers glucose from UDP-glucose onto a growing glycogen chain

forms α-1,4 bonds (only)

active when dephosphorylated (synthase a)
inactive/less active: b form —> allosterically activated by G6P

Branching Enzyme

forms α(1,6) bonds + chains by moving 7 glucose residues

Step 1

Hexokinase/ Glucokinase phosphorylate glucose to form G6P

Step 2

phosphoglucomutase converts G6P to G1P

Step 3

UDP-glucose pyrophosphorylase joins UTP+G1P

releases PPi in the process

Step 4

Glycogen synthase transfers glucose from UDP-glucose onto a growing glycogen chain using a-1,4 bonds

Glycogenin

created inital 8-10 glucose chain

autocatalytic/autoglucosylation; adds glucose on its own

Step 5

Branching enzyme transfers 7 glucose segments to form a branch with a 1,6 bond to form a branch

every ~12 residues

increases surface area

Futile Cycle

glucose synthesis and glucose breakdown cannot occur simultaneously

everytime a glucose is stored, 1 ATP would be spent so it would get wasted

Hormonal Regulation (Activating)

glucagon/epinephrine (fasted/stress state) —> activates pKA —> phosphorylase kinase phosphorylates

glycogen synthase: OFF

Glycogen Synthase Kinase

keeps glycogen synthase in inactive b form

Hormonal Regulation: Switching to Glycogenesis

PKa OFF

Akt on —> turns off phosphorylase (b state; dephosphorylated)

PPi dephosphorylates everythigng —> synthase active state (dephos)

Akt

turns off phosphorylase

Protein Phosphatase (PP1)

desphosphorylates the phosphorylated enzymes;

turns on Synthase

glucose is stored as glycogen

PP1 Regulation in Muscle

default = off state

exersise/ stress state: Pka = ON, PPi off —> phosphorylase ON

PP1 Regulation Liver

fed state: phosphorylase on (default)

glucose binding: PPi released —> synthase ON

von Gierke Disease (GSD 1)

Liver Dysfunction

G6P definciency

Liver cannot release free glucose to blood (bc G6P acumulates so theres no glucose export)

Fasting hypoglycemia, massive hepatomegaly (liver gets huge)

McArdle Disease (GSD V)

Muscle Dysfunction

Muscle Phosphorylase definiciency

muscle cannot breakdown its own glucose (no msucle glycogen mobilization so must rely on blood glucise + alt fuels)

excersise intolerance, “second wind phenomenon”, normal resting metabolism

“Second Wind” Phenomenon

exercise suddenly starts feeling easier after an initial period of fatigue or muscle pain

Glycogen synthase ON

insulin —> active —> dephosphorylated (a)

fed state/ ppi

Glycogen synthase OFF

G6P —> inactive —> phosphorylated (b)

exercise / glucagon / epinephrine

PKA

inhibits PPI

stress/ excersise state