Natural Products in Chemical Biology

8

POLYKETIDE POLYETHERS

ALISON M. HILL

School of Biosciences, University of Exeter, Stocker Road, Exeter, United Kingdom

This review covers the biosynthesis of terrestrial and marine polyethers and discusses their biologic properties and the molecular genetics and enzymology of the proteins responsible for their formation. The biosynthesis of monensin, nanchangmycin, nonactin, and the marine polyether ladders are discussed in detail. Novel enzymes found only in type I polyketide polyether gene clusters that are responsible for the epoxidation and cyclization of polyene biosynthetic intermediates are described. The macrotetrolide biosynthetic gene cluster, which is an ACP-less type II polyketide synthase that functions noniteratively is reviewed.

The first polyether antibiotic to be isolated was nigericin 1 in 1951. By 1983, more than 70 terrestrial polyether antibiotics had been reported and Cane et al. (1) had proposed a unified stereochemical model to account for their biosynthesis, including the polyene–polyepoxide model of polyether formation. It took almost 20 years for the first polyether gene cluster to be reported (2). In contrast, the first marine polyethers were reported in 1981, and a model to explain the biosynthesis of marine polyether ladder compounds was proposed in 2006.

8.1 BIOLOGICAL BACKGROUND

Interest in these compounds (Fig. 8.1) derives from their ability to transport ions across biologic membranes, and some terrestrial polyethers have been used widely in ...