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.

Lactate Glycerol Pyruvate Glucogenic amino acids Animals Stored fats Stored proteins Plants Acetate, lactate, propionate Microorganisms 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 NAD+ ADP G3PGlcG6PF6P F1,6BP DHAP 1,3BPG 3-PGA2-PGA PEP Pyruvate HCO3- Pyruvate OAA ATP NADH NAD+ CO2 PEP Pyruvate carboxylase Pi OAA NADH Mitochondrial malate dehydrogenase malate cytosolic malate dehydrogenase OAA cytosolic PEP carboxykinase ATP ADP G3P NADH Main pathway of the first bypass : pyruvate as precursor

NAD+ Pi G3PGlcG6PF6P F1,6BP DHAP 1,3BPG 3-PGA2-PGA PEP ATP ADP G3P NADH lactate NAD+ NADH Pyruvate Lactate dehydrogenase CO2 OAA PEP Mitochondrial 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 O P F 1,6-BP O P P H2OH2O FBPase-1

Third bypass only happen in liver and kidney Glucose 6- phosphatase Glc T1 Glc T2 Glc GLUT2 Glc T3 ER lumen Cytosol of hepatocyte capillary

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

Pyruvate Alanine Cysteine Glycine Serine Tryptophan Glutamine Arginine Glutamate Histidine proline Isoleucine Methionine Threonine valine Phenylalanine tyrosine Asparagine aspartate

Glycolysis and Gluconeogenesis must be reciprocally regulated ATP + Fructose 6-phosphate  ADP + Fructose 1,6-bisphosphate Fructose 1,6-bisphosphate + H 2 O  fructose 6-phosphate + Pi ATP + H 2 O  ADP + Pi + Heat