Gluconeogenesis

Gluconeogenesis

making glucose from pyruvate

not a direct reversal of glycolysis

COMPARISON OF ENZYMES IN THE GLUCONEOGENIC AND GLYCOLYTIC PATHWAYS

Why can enzymes catalyse the reverse direction?

stabilise the same transition state

dependent on concentrations

OAA shuttle in gluconeogenesis

pyruvate carboxylase + phosphoenolpyruvate carbokinase

replaces pyruvate kinase

regulated down by ADP and up by acetyl-CoA

biotin (vitamin B7 or vitamin H)

CO2 carrier

pyruvate carboxylase

biotin carboxylation → carboxyltransferase

pyruvate carboxylase mechanism

pyruvate enol form

phosphoenolpyruvate carbokinase

makes enolate via decarboxylation → GTP attack

Fructose-1,6-bisphosphatase

key regulatory checkpoint

Fructose-2,6-BP

potent allosteric regulator of PFK-1 and FBPase-1 activity

activates PFK-1 and deactivates FBPase-1

produced by PFK-2 and broken down by FBPase-2

PFK-2/FBPase-2

dual enzyme with a kinase and phosphaste domain

Fructose-2,6-BP produced by PFK-2 and broken down by FBP

depends on phosphorylation state of Ser32

Regulation of PFK-2/FBPase-2

low blood sugar → glucagon → PKA → PFK-2 ON & FBPase-2 OFF

high blood sugar → insulin → PP1 → PFK-2 OFF & FBPase-2 ON

Glycolysis and Gluconeogenesis enzyme separation

don’t compete for the same substrates at the same location

Glycogen Synthesis from Glucose

The glycogen synthase enzyme catalyzes a reaction that links glucose to nonreducing ends of glycogen, using UDP-glucose as the substrate. Generation of UDP-glucose requires the enzymes UDP-glucose pyrophosphorylase and nucleotide diphosphate kinase.

begins with glycogenin core protein Tyr194