1. p.543 Gluconeogenesis How to synthesize glucose from noncarbohydrate precursors?

2. 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.

3. 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.

4. Noncarbohydrate precursors for gluconeogenesis Plants Animals Lactate Glycerol Pyruvate Glucogenic amino acids Stored fats Stored proteins Microorganisms Acetate, lactate, propionate

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

6. 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.

7. DHAP ATP ADP Main pathway of the first bypass : pyruvate as precursor NAD+ G3P Glc G6P F6P F1,6BP G3P 1,3BPG 3-PGA 2-PGA PEP Pyruvate Pi Pi NADH cytosolic PEP carboxykinase PEP GDP CO2 NAD+ OAA cytosolic malate dehydrogenase OAA NADH GTP malate malate Pyruvate OAA Mitochondrial malate dehydrogenase HCO3- Pyruvate carboxylase OAA ADP NAD+ malate Pi ATP NADH

8. DHAP ATP ADP Alternative pathway of the first bypass: lactate as precursor NAD+ G3P Glc G6P F6P F1,6BP G3P 1,3BPG 3-PGA 2-PGA PEP Pi Pi NADH PEP NAD+ lactate Lactate dehydrogenase NADH Pyruvate Mitochondrial PEP carboxykinase Pyruvate Pyruvate PEP Pyruvate carboxylase OAA OAA CO2 CO2

9. O P P F 1,6-BP O P F 6-P 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. H2O Pi FBPase-1

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

11. 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.

12. Many amino acids are glucogenic

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

14. 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