Gluconeogenesis

How to synthesize glucose from noncarbohydrate

precursors?

p.543

Gluconeogenesis

• Gluconeogenesis happens in all animals, plants, and fungi. All the reactions are the same except the regulation.

• In higher animals, gluconeogenesis happens in liver and renal cortex. Gluconeogenesis can also happen in brain, skeletal and heart muscle.

• The gluconeogenesis described here is the mammalian pathway.

Why gluconeogenesis?

• Brain, nervous system, erythrocytes, testes, renal medulla, and embryonic tissues can only utilize glucose from blood as their major or only energy source.

• Between meals and during longer fasts, or after vigorous exercise, glycogen is depleted. In order to keep the above systems functional, organisms need a method for synthesizing glucose from noncarbohydrate precursors.

LactateGlycerolPyruvateGlucogenic amino acids

Animals Stored fatsStored proteins

Plants

Acetate, lactate, propionateMicroorganisms

Noncarbohydrate precursors for gluconeogenesis

Three bypasses in gluconeogenesis

• Because both glycolysis and gluconeogenesis happen in cytosol, reciprocal and coordinated regulation is necessary.

First bypass: from pyruvate to phosphoenolpyruvate

(PEP)• There are two pathways from

pyruvate to PEP.• The major pathway uses

pyruvate/alanine as glucogenic precursor; however the second pathway will dominate when lactate is the glucogenic precursor.

• This step involved both cytosolic and mitochondiral enzymes.

GDP

GTP

NAD+Pi Pi

NAD+ADP

G3PGlc G6P F6P F1,6BP

DHAP

1,3BPG 3-PGA 2-PGA PEP Pyruvate

HCO3-

Pyruvate

OAA

ATP

NADH

NAD+CO2PEP

Pyruvate carboxylase

PiOAAOAA

NADH

Mitochondrial malate

dehydrogenasemalate

malate

malate

cytosolic malate

dehydrogenase

OAA

cytosolic PEP carboxykinase

ATPADP

G3P

NADHMain pathway

of the first bypass :

pyruvate as precursor

NAD+Pi Pi G3PGlc G6P F6P F1,6BP

DHAP

1,3BPG 3-PGA 2-PGA PEP

ATPADP

G3P

NADH

lactate NAD+

NADHPyruvate

Pyruvate Pyruvate

Lactate dehydrogenase

CO2

CO2OAA OAA

PEP

PEPMitochondrial

PEP carboxykinase

Pyruvate carboxylase

Alternative pathway of the

first bypass: lactate as precursor

Pi

Second bypass: conversion of fructose 1,6-bisphosphate to

fructose 6-phosphate• Because the

conversion of fructose 6-phosphate to fructose 1,6-bisphosphate is highly exergonic, the reverse reaction in gluconeogenesis is catalyzed by a different enzyme, FBPase-1.

F 6-P

OP

F 1,6-BP

OP PH2O

FBPase-1

Third bypass only happen in liver and kidney

Glucose 6-phosphatase

Glc

T1

Glc

Glc

T2 Glc GLUT2

Glc

T3

ER lumen

Cytosol of hepatocyte

cap

illa

ry

Gluconeogenesis is energetically expensive, but essential

• For glycolysis, every glucose generate 2ATP and 2NADH (p.548).

• However, 6ATP (4ATP+2GTP) and 2NADH were spent to generate 1 glucose from 2 pyruvate (p.548, eq. 14-9).

• The extra energy spent is to ensure the irreversibility of gluconeogenesis.

Many amino acids are glucogenic

PyruvateAlanineCysteineGlycineSerineTryptophan

GlutamineArginineGlutamateHistidineproline

IsoleucineMethionineThreoninevaline

Phenylalaninetyrosine

Asparagineaspartate

Glycolysis and Gluconeogenesis must be reciprocally regulated

• ATP + Fructose 6-phosphate ADP + Fructose 1,6-bisphosphate

• Fructose 1,6-bisphosphate + H2O fructose 6-phosphate + Pi

• ATP + H2O ADP + Pi + Heat