Synthesis of Triacetic Acid Lactone by the Pigeon Liver Fatty Acid Synthetase Complex

The synthesis of triacetic acid lactone (TAL) is effected by purified soluble pigeon liver fatty acid synthetase.This enzyme system synthesizes TAL from acetyl coenzyme A and malonyl coenzyme A in the absence of TPNH, and synthesizes palmitic acid in the presence of TPNH.The major product of the reaction in the absence of TPNH is TAL, and not free triacetic acid.Presumably triacetic acid, bound as a thioester to the 4'-phosphopantetheine prosthetic group of the fatty acid synthetase, is an intermediate in the formation of TAL.The latter compound is formed from 1 mole of acetyl-CoA and 2 moles of malonyl-CoA in the sequence, acetate-malonate-malonate (proceeding left to right from the methyl end of the molecule).The synthesis of TAL is inhibited by either TPN+ or TPNH.The very strong inhibition by both forms of the nucleotide implies that TAL is not synthesized in vivo by the avian soluble fatty acid synthetase.Lynen (1) concluded in 1961, from a wide variety of data, that the specific arrangement of enzyme activities within the fatty acid synthetase complex determined whether fatty acids, aromatic compounds, or macrolide structures would be formed from malonyl coenzyme A and TPNH in the presence of a suitable "primer," such as acetyl-CoA.Lynen (1) also presented a hypothetical reaction scheme for 6-methylsalicylic acid synthesis by a multienzyme complex from Penicillium patulum.This scheme utilized malonyl-CoA, acetyl-CoA, and TPNH as reactants, and involved enzyme-bound triacetic acid as an intermediate.