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V. De novo Synthesis of Fatty Acids

Overview Overview: Tissue locations Overview: Reaction sum     Enzymes and Isolated Reactions Enzymes and Isolated Reactions: Acetyl CoA carboxylase Enzymes and Isolated Reactions: Activities of FA Synthase Enzymes and Isolated Reactions: Characteristics of Fatty Acyl Synthase     Acetyl Groups and Reducing Equivalents     Previous Page Next Page

Enzymes and Isolated Reactions: Activities of FA Synthase

The first iteration of the sequence catalyzed by this enzyme can be represented by the seven following reactions.

  1. In the first reaction acetyl CoA is added to a cysteine -SH group of the condensing enzyme (CE) domain:
    acetyl CoA + CE-cys-SH -> acetyl-cys-CE + CoASH

    Mechanistically this is a two step process, in which the group is first transferred to the ACP (acyl carrier peptide), and then to the cysteine -SH group of the condensing enzyme domain.

  2. In the second reaction malonyl CoA is added to the ACP sulfhydryl group:
    malonyl CoA + ACP-SH -> malonyl ACP + CoASH

    This -SH group is part of a phosphopantethenic acid prosthetic group of the ACP.

  3. In the third reaction the acetyl group is transferred to the malonyl group with the release of carbon dioxide:
    malonyl ACP + acetyl-cys-CE -> beta-ketobutyryl-ACP + CO2
  4. In the fourth reaction the keto group is reduced to a hydroxyl group by the beta-ketoacyl reductase activity:
    beta-ketobutyryl-ACP + NADPH + H+ ->
    beta-hydroxybutyryl-ACP + NAD+
  5. In the fifth reaction the beta-hydroxybutyryl-ACP is dehydrated to form a trans- monounsaturated fatty acyl group by the beta-hydroxyacyl dehydratase activity:
    beta-hydroxybutyryl-ACP -> 2-butenoyl-ACP + H2O
  6. In the sixth reaction the double bond is reduced by NADPH, yielding a saturated fatty acyl group two carbons longer than the initial one (an acetyl group was converted to a butyryl group in this case):
    2-butenoyl-ACP + NADPH + H+ -> butyryl-ACP + NADP+

    The butyryl group is then transferred from the ACP sulfhydryl group to the CE sulfhydryl:

    butyryl-ACP + CE-cys-SH -> ACP-SH + butyryl-cys-CE

    This is catalyzed by the same transferase activity as was used previously for the original acetyl group.

    The butyryl group is now ready to condense with a new malonyl group (third reaction above) to repeat the process.

  7. When the fatty acyl group becomes 16 carbons long, a thioesterase activity hydrolyses it, forming free palmitate:
    palmitoyl-ACP + H2O -> palmitate + ACP-SH

Reference: Smith S. The animal fatty acid synthase: one gene, one polypeptide, seven enzymes. FASEB J 1994 Dec;8(15):1248-1259


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