аЯрЁБс>ўџ ACўџџџ@џџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџьЅС7 №П”bjbjUU .7|7|q "џџџџџџlЄЄЄЄ$` ` ` ` l ,$7,ЖЄ Є Є Є Є їїїЋ%­%­%­%Gє%аФ(а”+$э,  /pИ+9їЙ>їїїИ+OЄЄЄ Є ё+OOOї.ЄОЄ Є Ћ%OїЋ%OrOСRg$єbЎ—%Є ˜ Иr˜ЬMЦ$<` %–[%—%,07,y%}/Л”}/—%O$$ЄЄЄЄйFATTY ACID AND CHOLESTEROL BIOSYNTHESIS WHERE: LIVER AND ADIPOSE TISSUE (HEPATOCYTES AND ADIPOCYTES CYTOPLASM WHEN: HIGH ENERGY CHARGE REGULATION: PHOSPHORYLATION ( ACETYLCoA CARBOXYLASE ALLOSTEARIC: AcCoA CARBOXYLASE (Phosphorylated form): ( CITRATE GENE EXPRESSION: AcCoA CARBOXYLASE ( DURING STARVATION SUMMARY: 8 AcCoA + 7ATP + 14 NADPH ( C16 SATURATED FA + 14 NADP + 7 ADP + 6 H2O + 8 CoA PATHWAY: 1. MOVEMENT OF AcCoA FROM MITO TO CYTO  NADPH NADH  pyruvate ( malate ( OAA ( citrate ( AcCoA   H+ OAA  pyruvate citrate  AcCoA i. ATP citrate lyase citrate + ATP + CoA ( OAA + AcCoA + ADP + Pi ii. Transfer of e- from NADH to NADP for biosynthesis: accounts for most of glycolytic NADH produced by glycolysis in fat cells. Produces approx 50% of required NADPH for FA synthesis. Rest from HMPS. QUESTION: succinate [2,3 14C] ( 14C FA succinate [1,4 14C] does not. WHY NOT? Acetyl CoA carboxylase AcCoA + ATP + CO2 malonylCoA + ADP + Pi biotin inhibited by phosphorylation (mainly by AMPK. May also be phosphorylated (and inhibited) by PKA) dephosphorylated (and activated) by PP2A activated by insulin (by activating PP2A) allosteric control citrate activates phosphorylated form inhibited by palmitoyl CoA enzyme levels decrease as a result of fasting and increase upon refeeding enzyme levels increase on fat free diet ACC1 present in lipogenic tissues such as liver and adipose tissue ACC2 present in non-lipogenic tissue such as skeletal and heart muscle where it is thought to control FA oxidation; ie by making malonyl CoA to decrease activity of acyl-carnitine transferase. Mice lacking ACC2 have less body fat in spite if increased food intake - consistent with enhanced FA oxidation in these animals. Thus, malonyl-CoA produced by ACC-2 is exclusively involved in regulation of fatty acid oxidation (by inhibiting acycarnitine transferase I) , whereas that produced by ACC-1 is utilized in fatty acid synthesis. Phosphorylation of ACC, for example a result of activation of PKA by stress or exercise switches on fatty acid oxidation (via phosphorylation and inhibition of ACC-2 resulting in decreased malonyl CoA levels) while switching off fatty acid synthesis (via phosphorylation and inhibition of ACC-1). ELONGATION AND INTRODUCTION OF DOUBLE BONDS. see text pages 484 need to know: reaction catalysed by desaturase enzyme mammalian cells cannot introduce double bonds more than 9 carbons from carboxyl end. Therefore, linoleate (18:2D№9,12) and a№-linoleate (18:3D№9,12,15), essential fatty acids, must be obtained from plants. These can however be elongated and additional double bonds added. See fig 16-7 for synthesis of arachidonoylCoA (20:4D№5, 8, 11,14). Elongation occurs in both mitochondria and and E.R. In former, acetyl CoA is donor of 2 carbon units; in latter, malonyl CoA is donor. CHOLESTEROL see text p495 need to know: synthesis of HMGCoA occurs in cytoplasm (for KB synthesis it occurs in mito.) 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