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Metabolism of lipids II b.

Metabolism of lipids II b. Fatty acid synthesis. Lipogenesis Not a reversal of degradation. Fatty acids – differences in …. Fatty acid synthesis. In Liver Adipose tissue Lactating mammalian gland Ac-CoA è palmitic acid. Comitted Step in Fatty Acid Synthesis. Acetyl-CoA carboxylase

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Metabolism of lipids II b.

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  1. Metabolism of lipids II b.

  2. Fatty acid synthesis • Lipogenesis • Not a reversal of degradation

  3. Fatty acids – differences in …

  4. Fatty acid synthesis • In • Liver • Adipose tissue • Lactating mammalian gland Ac-CoA è palmitic acid

  5. Comitted Step in Fatty Acid Synthesis • Acetyl-CoA carboxylase • ACC • Biotin – prostetic group

  6. v Comitted Step in Fatty Acid Synthesis

  7. REACTION MECHANISM OF ACETYL-CoA CARBOXYLASE

  8. Regulation of Ac-CoA carboxylase

  9. Regulation of Ac-CoA carboxylase Long term adaptation to a carbohydrate rich (lipid-free) diet èThe amout of the enzyme is increased

  10. Prosthetic groups of FattyAcid Synthase include

  11. Fatty acid synthase • Multienzyme compex • dimer of two identical subunists • each with three domains

  12. Fatty acid synthase • Attachment of Ac-CoA to acetyl transferase (AT) (CH3-CO-O-Serine) • Malonyl group to malonyl transferase (MT) • Acetyl unit is transferred to SH – condensing enzyme (CE)

  13. Fatty acid synthase • Malonyl unit is transferred to SH-condensing enyzyme (CE) • Condensation acetoacetyl group on ACP SH-CE restored

  14. Fatty acid synthase • Acetoacetyl group is delivered to domain 2 of the opposite chain to reduction by ß-ketoacyl reductase (KR) dehydratase (DH) enoyl reductase (ER)

  15. Fatty acid synthase • Butyryl unit migrates from SH-ACP to SH-CE • next malonyl group to MT then SH-ACP • Next round • After seven round palmitate is released by thioesterase (TE) of D3

  16. Control of fatty acid synthesis Short term regulation • Ac-CoA á • ATP á .â isocitrate dehydrogenase inhibited citrateá – stimulates Ac-CoA carboxlase Indicates, thea two-carbon units & ATP are available for synthesis

  17. Control of fatty acid synthesis Palmitoyl-CoA Inhibits Ac-COA carboxylase Inhibits translocation of citrate from mitochondria to cytosol Inhibits glucose 6-P dehydrogenase è NADPH â

  18. Control of fatty acid synthesis Glucagon • cAMP áè activation of protein kinases è phosphorylation of Ac-CoA carboxylase è switch off • Long term ~ • – low fat – high carbohxdrate diet • the amount if Acetyl-CoA carboxylase & • fatty acid synthase increased • è ADAPTIVE CONTROL

  19. STOICHIOMETRY Ac-CoA + 7 malonyl-CoA + 14 NADPH + H+ è Palmitate + 7 CO2 + 14 NADP+ + 8 CoA + 6 H2O 7 Ac-CoA + 7 CO2 + 7 ATP è7 malonyl-CoA + 7 ADP + 7 Pi 8 Ac-CoA + 7 ATP + 14 NADPH + H+ è palmitate + 14 NADP+ + 8 CoA + 6 H2O + 7 ADP + 7 Pi

  20. CITRATE CARRIES ACETYL GROUPS FROM MITOCHONDRIA TO THE CYTOSOL FOR FATTY ACID SYNTHESIS Oxaloacetate + AcCoAè citrate + CoA Citrate + ATP + CoA èAcCoA + ADP + P + oxaloacetate ATP – citrate lyase

  21. Sources of NADPH for fatty acid synthesis Oxaloacetate + NADH + H+ çè malate + NAD+ Malate + NADP+èpyruvate + CO2 + NADPH + H+ Diffuses into mitochondria Pyruvate + CO2 + ATP + H2O è oxaloacetat + ADP + Pi

  22. Sources of NADPH for fatty acid synthesis For each Ac-CoA that is transferred from the mitochondria to the cytosol one NADP+ is generated (8 NADPH is formed when 8 molecules of Ac-COA are transferred) The additional six NADPH come from pentose phosphate pathway

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