The chemistry and biology of fatty acid, polyketide, and nonribosomal peptide biosynthesis

Abstract

Polyketide synthases, fatty acid synthases, and non-ribosomal peptide synthetases are a structurally and mechanistically related class of enzymes that catalyze the synthesis of biopolymers in the absence of a nucleic acid or other template. These enzymes utilize the common mechanistic feature of activating monomers for condensation via covalently-bound thioesters of phosphopantetheine prosthetic groups. The information for the sequence and length of the resulting polymer appears to be encoded entirely within the responsible proteins. Polyketide and fatty acid biosyntheses begin with condensation of the coenzyme A thioester of a short-chain carboxylic acid “starter unit” such as acetate or propionate with the coenzyme A thioester of a dicarboxylic acid “extender unit” such as malonate or methyl malonate. The driving force for the condensation is provided by the decarboxylation of the extender unit. In the case of fatty acid synthesis, the resulting β-carbonyl is completely reduced to a methylene; however, during the synthesis of complex polyketides, the β-carbonyl may be left untouched or variably reduced to alcohol, olefinic, or methylene functionalities depending on the position that the extender unit will occupy in the final product. This cycle is repeated, and the number of elongation cycles is a characteristic of the enzyme catalyst. In polyketide biosynthesis, the full-length polyketide chain cyclizes in a specific manner, and is tailored by the action of additional enzymes in the pathway. Several architectural paradigms are known for polyketide and fatty acid synthases. While the bacterial enzymes are composed of several monofunctional polypeptides which are used during each cycle of chain elongation, fatty acid and polyketide synthases in higher organisms are multifunctional proteins with an individual set of active sites dedicated to each cycle of condensation and ketoreduction. Peptide synthetases also exhibit a one-to-one correspondence between the enzyme sequence and the structure of the product. Together, these systems represent a unique mechanism for the synthesis of biopolymers in which the template and the catalyst are the same molecule.