Polyketide and non-ribosomal peptide synthases: Falling together by coming apart

Microorganisms have invented many devious ways to thwart their foes and survive in adverse environments. Non-motile microbes, especially ones that inhabit soil and marine environments, are noted for an ability to produce a wide range of chemicals (1). These are usually called “secondary metabolites,” because of their seeming dispensability for the organism's ontogeny. It is obvious from the complex structures of such metabolites that their production involves unusual biochemistry as well as complex genetics devoted to the property of self-defense, intercellular communication, and other aspects of microbial life.

The polyketide synthases (PKSs) and non-ribosomal peptide synthases (NRPSs) (2) constitute a class of multifunctional proteins that govern complex enzymology with fascinating mechanisms and great commercial appeal, because the enzymes create a multitude of secondary metabolites, many of which have become important drugs. These enzymes represent some of the largest proteins known, and, as a consequence of their multifunctional character, a single protein can catalyze dozens of discrete biochemical reactions. For example, the rapamycin PKS (3) and cyclosporin NRPS (4) catalyze 51 and 40 steps in assembly of their respective products. Before the revelation about the leinamycin PKS (5) featured in this issue, type I modular PKSs (6, 7) were known to have the following characteristics. Integral to all of them is the ability to recognize simple fatty acid CoA esters and transfer them, by the acyltransferase (AT) domain, onto an acyl carrier protein (ACP) domain; and to join two thioester intermediates, one bound to the ACP and the other to the ketosynthase (KS) domain, coincident with decarboxylation of the ACP-bound substrate, to form an enzyme-bound β-ketothioester. If the product of these reactions is not released from the PKS, usually by the action of a thioesterase (TE) domain situated at the C terminus of a module, it can undergo a series …