Complete Reconstitution of a Highly Reducing Iterative Polyketide Synthase

Abstract

Dissecting Megaenzyme Mechanisms Filamentous fungi contain a class of multidomain enzymes, the highly-reducing iterative polyketide synthases (HR-IPKSs), which produce important natural products such as the cholesterol-lowering drug lovastatin. To produce their complex products, these megasynthases use multiple catalytic domains repeatedly in different combinations, but mechanistic details remain unclear. Ma et al. (p. 589 ) now report in vitro reconstitution of the complete catalytic function of lovastatin nonaketide synthase (LovB), the megasynthase that works together with a partner enzyme LovC to complete nearly 40 chemical steps required to construct the core of lovastatin. Analyses of the dependency of enzyme function on cofactors and on the partner enzyme elucidate the programming rules for this system.