Recent advances in the biosynthesis of unusual polyketide synthase substrates

Abstract

Covering: 2003 to July 2015 for polyketide synthase starter units and 2012 to September 2015 for polyketide synthase extender units This highlight provides an overview of recent advances in understanding the diversity of polyketide synthase (PKS) substrate building blocks. Substrates functioning as starter units and extender units contribute significantly to the chemical complexity and structural diversity exhibited by this class of natural products. This article complements and extends upon the current comprehensive reviews that have been published on these two topics (Moore and Hertweck, Nat. Prod. Rep., 2002, 19, 70; Chan et. al., Nat. Prod. Rep., 2009, 1, 90; Wilson and Moore, Nat. Prod. Rep., 2012, 29, 72).

Strategies to diversify natural products for drug discovery

“…). One challenge could be to reliably and consistently incorporate diverse substrates into natural product biosynthetic pathway …”

“…One challenge could be to reliably and consistently incorporate diverse substrates into natural product biosynthetic pathway. 238 If the biosynthetic enzymes in wild organisms are sufficiently flexible as far as substrates are concerned, the exogenous addition of designed and synthesized molecules to the cultures of organisms leads to natural product analogue generation. Unexpected incorporation patterns may be observed.…”

Involvement of β‐Alkylation Machinery and Two Sets of Ketosynthase‐Chain‐Length Factors in the Biosynthesis of Fogacin Polyketides in Actinoplanes missouriensis

“…Alkylation of a polyketide chain is an important strategy to generate polyketide diversity. Two systems are known for the α alkylation of a polyketide chain: incorporation of alkylmalonyl‐CoA and methylation of the α‐carbon by using S ‐adenosylmethionine (SAM) . The former is the most commonly observed strategy for polyketide alkylation, and various alkyl groups, such as methyl, ethyl, and methoxy, can be introduced into a polyketide chain with alkylmalonyl‐CoA.…”

Thioester reduction and aldehyde transamination are universal steps in actinobacterial polyketide alkaloid biosynthesis

“…1 Remarkable molecular machines known as type I modular polyketide synthases (PKSs) are responsible for the biosynthesis of the overwhelming majority of these natural products. 2 Modular PKSs employ several distinct strategies for the creation of structural diversity, including the utilization of a variety of starter and extender units for assembly of the polyketide chain, 3 diverse mechanisms for release of the fully-assembled chain from the PKS, 4 and a wide range of on- and post-PKS tailoring reactions. Among these, the mechanism of chain release is arguably of prime importance in defining which structural class a metabolite belongs to.…”