Gluconeogenesis ط Definition and Importance, ط Reactions and irreversibility ط Substrates : Glycerol, Lactate, Glucogenic amino acids, Odd chain fatty acids D

Introduction § Gluconeogenesis is formation of glu from non-carbohydrate (CHO) source § Main tissues: liver, kidneys § Substrates: lact, pyr, glucogenic AA (T7.2), glycerol, propionate § Other sugars: Fru, Gal, Man § Opposite of glycolysis: * GK/HK َ G6P-tase (located on surface of endo retic fig7.37) * PFK1 َ F1,6BP-tase * PK َ PC + PEPCK § Occur during starvation, diabetes, Cushing's syndrome, intense exercise & high cortisone dose § Inhibited: - during shortage of oxygen & use of uncouplers: pathway goes towards glycolysis - by ethanol (produce NADH), opposite use: * LDH (pyr => lact) * MDH (OA => M-ate) § Regulation by hormonal (INS/GLG ratio), allosteric & substrate

Importance 1. When glu is not sufficient in diet: § Glu is main source of energy in brain (aerobically) § Glu is main source of energy in muscle & RBCs (anaerobically) § Glu is main source of glycerol-3-phosphate in adipose tissue (no glycerol kinase) § Glu is source of intermediates for TCA cycle § Glu is precursor for lactose (milk sugar) 2. To clear tissue metabolites: Lact from muscle & RBCs Glycerol from adipose tissue (AT)

Reactions 1. fig7.33, fig7.33 (2) Lactate  (2) Pyr  (2) OA  PEP  Asp  OA  PEP fig7.32a, Cori Cycle: Glu in RBCs (glycolysis) => +2 ATP & 2 Lact => TableTable Lact in Liver (gluconeogenesis) => –6 ATP & 1 Glu => Glu in RBCs (glycolysis) + 2 ATP + 2 Lact 2. fig7.38, fig7.38 (2) alanine  (2) Pyr  (2) OA  M-ate  OA  PEP  Asp  M-ate  OA  PEP fig7.32b, Alanine Cycle : Glu in RBCs (glycolysis) => 2 Pyr => +8 ATP & 2 ala => TableTable ala in Liver (gluconeogenesis)=> 2 Pyr => –6 ATP & 1 Glu => Glu in RBCs (glycolysis) => 2 Pyr => +8 ATP + 2 Ala

Alanine Cycle Energy efficient cycle Cori Cycle Energy inefficient cycle 1. Ala-Glu cycle between liver & muscle 2. Glycolysis in muscle, produce 2 NADH (4-6ATP) 3. NADH are transported to mitoch for ATP production 4. In liver, gluconeogenesis forms Glu from 2 Ala 1. Lact-Glu cycle between liver & RBCs 2. Glycolysis in RBCs, produce 2 NADH (6ATP) 3. NADH are used to red 2 Pyr to 2 Lact 4. In liver, gluconeogenesis forms Glu from 2 Lact 6-8 ATP produced by glycolysis (shuttles & PGK) 6 ATP used by gluconeogenesis 2 ATP produced by glycolysis (PGK) 6 ATP used by gluconeogenesis

3. Glucogenic AA  1- Pyr  OA  M-ate  OA  PEP (not leu & lys) 2- α-KG  SCoA  S-ate  F-ate  M-ate  OA  PEP 3- SCoA  S-ate  F-ate  M-ate  OA  PEP 4- F-ate  M-ate  OA  PEP 5- OA  M-ate  OA  PEP 6- 3PG  2PG  PEP  Pyr  OA  M-ate  OA  PEP 4. fig7.40, (2) Propionate  (2) MCoA  (2) SCoA => (2) OA  (2) PEPfig fig7.41, (2)Glycerol  (2) G3P  (2) DHAP  DHAP + GAP  F1,6BPfig fig7.42, Fructose  F1P  DHAPfig7.42 Glyceraldehyde  Glycerol  G3P  DHAP  GAP 7. fig7.43, Glucose  Sorbitol / Sucrose  Fructosefig fig7.44, Galactose  Gal 1 P  G1P  G6P  Glu fig Mannose  M6P  F6P  G6P  Glu

Regulation of Gluconeogenesis ط Hormonal regulation ط reciprocality with glycolysis ط Factors affecting gluconeogenesis ط Cori and Alanine cycles D

Regulation 1. Regulation of glycolytic enzymes a) Glu  GK/HK  G6P GK (–) by F6P (GKRP), GLG (+) by F1P (GKRP), INS * HK (–) by G6P b) F6P  PFK1  F1,6P2 (–) by ATP, citrate (FA oxid/CAC), GLG (+) by AMP, F2,6BP c) PEP  PK  Pyr (–) by ATP, ala, ACoA, GLG (+) by F1,6BP

Regulation 2. Regulation of gluconeogenic enzymes a) Pyruvate  PC  OA (+) ACoA (FA oxid) b) OA  PEPCK  PEP (–) by INS * (+) GLG *, ala fig7.46 c) F1,6BP  F1,6BP-tase  F6P (–) by AMP, F2,6BP (+) by F1,6BP d) G6P  G6P-tase  Glucose (+) GLG Note: * INS & GLG regulate gene expression (synthesis) NOT by phosph/dephosphorylation