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Gluconeogenesis ط Definition and Importance , ط Reactions and irreversibility ط Substrates : Glycerol, Lactate, Glucogenic amino acids, Odd chain fatty acids D4 299-308. Introduction
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Gluconeogenesis ط Definition and Importance , ط Reactions and irreversibility ط Substrates : Glycerol, Lactate, Glucogenic amino acids, Odd chain fatty acids D4 299-308
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, • (2) Lactate (2) Pyr (2) OA PEP Asp OA PEP • fig7.32a, Cori Cycle: • Glu in RBCs (glycolysis) => +2 ATP & 2 Lact => .........Table • Lact in Liver (gluconeogenesis) => –6 ATP & 1 Glu=> • Glu in RBCs (glycolysis) + 2 ATP + 2 Lact • 2. 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 => .........Table • ala in Liver (gluconeogenesis)=> 2 Pyr => –6 ATP & 1 Glu=> • Glu in RBCs (glycolysis) => 2 Pyr => +8 ATP + 2 Ala
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) PEP 5. fig7.41, (2)Glycerol (2) G3P (2) DHAP DHAP + GAP F1,6BP 6. fig7.42, Fructose F1P DHAP Glyceraldehyde Glycerol G3P DHAP GAP 7. fig7.43, Glucose Sorbitol / Sucrose Fructose 8. fig7.44, Galactose Gal 1 P G1P G6P Glu 9. Mannose M6P F6P G6P Glu
Regulation of Gluconeogenesis ط Hormonal regulation ط reciprocality with glycolysis ط Factors affecting gluconeogenesis ط Cori and Alanine cycles D4 308-312
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