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b R

Fat mobilization in adipocytes. b R. Note: insulin inhibits TAG mobilization. PKA. PKA. P. Hormone-sensitive lipase. Hormone-sensitive lipase. glycerol. MAG. DAG. TAG. FFA. FFA. FFA. See Fig 16.7 Horton. Fatty acid oxidation. Activation Transport into mitochondria

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b R

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  1. Fat mobilization in adipocytes bR Note: insulin inhibits TAG mobilization PKA PKA P Hormone-sensitive lipase Hormone-sensitive lipase glycerol MAG DAG TAG FFA FFA FFA See Fig 16.7 Horton

  2. Fatty acid oxidation • Activation • Transport into mitochondria • b oxidation cycle • Acyl CoA synthetase (thiokinase) • acylcarnitine transferase/acylcarnitine translocase • acyl CoA dehydrogenase • enoyl CoA hydratase • L-3-hydroxy CoA dehydrogenase • Thiolase

  3. R-COO- + CoA-SH + ATP R-C- S-CoA + AMP + PPi O Acyl CoA synthetase Note: 4 different enzymes specific for FA of differing chain length. location: outer membrane of mitochondria, ER membranes

  4. Transport of fatty acyl CoA into mitochondria Carnitine Malonyl CoA Carnitine acyltransferase I Fatty AcylCoA + carnitine acylcarnitine + CoA translocase Mito matrix Fatty AcylCoA + carnitine acylcarnitine + CoA Carnitine acyltransferase II

  5. Net yield of ATP C16 FA + CoA + ATP C16 acyl CoA + AMP + PP1 C16 acyl CoA + 7 NAD + 7 FAD 8 AcCoA + 7 NADH + 7 FADH2 8 AcCoA 24 NADH + 8 FADH2 + 8 GTP + 16 CO2 31 NADH 77.5 ATP 15 FADH2 22.5 ATP 8 GTP 8 ATP 108 ATP - 2 ATP Net = 106 ATP

  6. b-oxidation of unsaturated fatty acids • 2,4 dieonyl-CoA reductase: converts cis to trans double bond • Enoyl-CoAisomerase: converts diene to single double bond

  7. 3 rounds of b-oxidation 3 Ac-CoA CO-S-CoA H C C C C C C C C C C C 3 16 18 14 8 12 10 Enoyl-CoA isomerase 1round of b-oxidation Ac-CoA C10 cis-D4 CO-S-CoA H C C C C C C C C C 3 12 6 8 4 2 b-oxidation of unsaturated fatty acids e.g. Linoleic acid: C18 cis,cis-D9,12 CO-S-CoA C C H C C C C C C C C C C C C C C C 3 16 2 18 14 8 4 12 6 10 C12 cis,cis-D3,6 g b a C12 trans,cis-D2,6 g b a CO-S-CoA H C C C C C C C C C C C 3 10 12 8 2 6 4

  8. C10 cis-D4 CO-S-CoA H C C C C C C C C C 3 12 6 8 4 2 Acyl-CoA dehydrogenase C10 trans,cis-D2,4 CO-S-CoA H C C C C C C C C C 3 12 6 8 4 2 2,4 dieonyl-CoA reductase NADP C10 trans-D3 CO-S-CoA H C C C C C C C C C 3 12 6 8 4 2 Enoyl-CoA isomerase C10 cis-D2 CO-S-CoA H C C C C C C C C C 3 12 6 8 4 2 continued b-oxidation

  9. b-oxidation of odd numbered fatty acids • Requires: • Propionyl CoA carboxylase (biotin) • - adds CO2 • methyl malony CoA racemase • - converts D isomer of methyl malonyl CoA to L isomer • methyl malonyl CoA mutase (adenosylcobalamin) • - rearranges MMCoA to yield succinyl CoA

  10. Oxidation of odd-numbered fatty acids O CH3-CH2-C-S-CoA CH3 O -OOC-CH C-S-CoA O -OOC-CH C-S-CoA CH3 -OOC-CH2 O CH2 C-S-CoA Proprionyl CoA CO2 Biotin, ATP D-methylmalonyl CoA racemase L-methylmalonyl CoA adenosylcobalamin mutase succinyl CoA

  11. Cobalamin B12 methylcobalamin R = CH3 - transfer of methyl groups adenosylcobalamin R = 5’-deoxyadenosinyl - intramolecular rearrangements See fig 7.24 Horton

  12. Fatty acid biosynthesis • Where: cytoplasm • liver, fat cells • When: good energy charge, insulin • Process: • Transfer of AcCoA from mito to cyto • Acetyl CoA carboxylase • Fatty acid synthase

  13. Citrate lyase Citrate + ATP + + CoA OAA + AcCoA + ADP + Pi NADH Citrate lyase NADPH AcCoA malate OAA Pyruvate citrate cyto Antiport with pyr or Pi mito OAA H+ citrate Pyruvate AcCoA • Transfer of AcCoA from mito to cyto

  14. Question: Incubation of tissue using the above pathway with only one of succinate-2,3-14C or succinate-1,4-14C will result in the production of radiolabeled fatty acid. Identify which substrate will yield 14C-fatty acids.

  15. CH2 C - SCoA -OOC O Acetyl-CoA carboxylase 1 (ACC 1) biotin AcCoA + CO2 + ATP malonyl CoA + ADP + Pi • Regulation: • Hormonal control • - AMP kinase • - inhibited by PKA mediated phosphorylation • - enhanced by insulin • Allosteric regulation • - citrate activates phospho form • - inhibited by palmitoyl CoA • glucagon (liver) • adrenalin (adipocytes) • Nutritional status

  16. Regulation of FA metabolism by phosphorylation Adrenalin Glucagon activates inhibits cAMP ACT PKA FA synthesis Malonyl CoA TAG lipase (inactive) ACC(active) AMP- activated kinase phosphatase PP2A TAG lipase-PO4 (active) ACC-PO4(inactive) Note: insulin activates ACC by stimulating the dephosphorylation reaction

  17. + ACP-SH i. C – S-ACP C - SCoA CH2 CH2 -OOC- -OOC- CH3 C - SCoA CH3 C – SACP + CoASH ii. + S-Synthase O O O O O O CH3 C - ACP CH3 C – S-Synthase + ACP-SH iii. ACP-SH CoASH Steps in FA biosynthesis 1. Loading: transfer to ACP and ketoacyl-ACPsynthase

  18. HS-Synthase CO2 O O CH3 C – CH2 C – S-ACP O O 2. Condensation: + CH3 C – S-Synthase CH2 CH2 C – S-ACP C – S-ACP -OOC-

  19. 3. reduction H H CH2 CH3 C CH3 C – OH OH C – S-ACP C – S-ACP C – S-ACP C – S-ACP C – S-ACP C – S-ACP NADP NADPH 4. dehydration O O O O O O O H H CH3 CH3 C C CH2 CH2 CH CH CH3 C – H2O 5. reduction CH3 CH2 CH NADP NADPH

  20. C – S-ACP C C – S-ACP C-SACP O O O O CH3 CH2 CH2 C – S-synthase O CH3 CH2 CH2 Subsequent rounds of synthesis - transfer of growing FA to S-Synthase - addition of 2 carbon units from malonyl-S-ACP Synthase-SH ACP-SH -OOC- CH2 CO2 + Synthase-SH CH CH3 CH2 CH2

  21. Chain elongation • introduction of double bonds • linoleic and linolenic acids • synthesis of arachidonic acid – an important precursor of • several biologically active molecules

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