gluconeogenesis how to synthesize glucose from noncarbohydrate precursors? p.543
TRANSCRIPT
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