Gluconeogenesis

By

Amr S. Moustafa, M.D.; Ph.D.

Assistant Prof. & Consultant, Medical Biochemistry Dept.

College of Medicine, KSUamrsm@hotmail.com

Gluconeogenesis: An Overview

• Liver (mainly) and Kidneys

• Both mitochondria and Cytosol

• Exception: Glycerol, only cytosol

• Gluconeogenic substrates:

GlycerolLactateGlucogenic amino acidsPropionyl CoA

Gluconeqgenic Substrate: Glycerol

Glycerol Glycerol 3-phosphate*GK

Dihydroxyacetone phosphate

Glycerol 3-phosphate dehydrogenase

NAD+

NADH

Glucose

*GK: Glycerol kinase only in liver & kidneys

ATP ADP

Glucogenic Amino Acids

Glu, GlnPro, HisArg

MetValIle

PheTyr

Aminoacids

AspAsn

Gluconeogenic

Substrates

Glu, GlnPro, HisArg

MetValIle

PheTyr

Aminoacids

AspAsn

PyruvateGly, Ala, SerThr, Cys, TryAmino

acids

Propionyl CoA +

Lactate

Gluconeogenic Substrate: Lactate

(Cori Cycle)

Aerobic Glycolysis

Gluconeogenesis Pathway

Carboxylation of pyruvateTransport of OAA

Dephosphorylation of F 1,6-P

Dephosphorylation of G-6-P

Pruvate Carboxylase and PEP-CK

Fasting:Acetyl CoA(FAO)OAA(Gluconeogensis)

Pyruvate carboxylase + PEP-CK = Pyruvate kinase

Fructose 1,6-Bisphosphatase

Fructose 1,6-bisphosphatase = PFK-1

Glucose 6-Phosphatase

Glucose 6-phosphatase = GlucokinaseGlucose 6-phoshate translocase: G 6-P across ER membrane

(ER-Enzyme)

F – 2,6 – Bisphosphate and PFK-2: Fasting State

(high glucagon)

F – 2,6 – Bisphosphate and PFK-2: Well-fed State (high insulin)

Gluconeogensis:E-

Consumed

Six High-Energy Phosphate BondsFor Pyruvate toGlucose

2 ATP

2 ADP

Gluconeogenesis: Regulation

• Reciprocal control Gluconeogenesis & Glycolysis

• Allosteric: Acetyl CoA (Pyruvate carboxylase)

AMP or ATP F 2,6-Bisphosphate

• Glucagon ( I/G ratio)Allosteric ( F 2,6-Bisphosphate)

Covalent modification (Pyruvate kinase)

Induction (PEP-CK)

F 1,6-bisphosphatase