Abstract
Polyketides are a diverse group of natural products that form the basis of many important drugs. The engineering of the polyketide synthase (PKS) enzymes responsible for the formation of these compounds has long been considered to have great potential for producing new bioactive molecules. Recent advances in this field have contributed to the understanding of this powerful and complex enzymatic machinery, particularly with regard to domain activity and engineering, unique building block formation and incorporation, and programming rules and limitations. New developments in tools for in vitro biochemical analysis, full-length megasynthase structural studies, and in vivo heterologous expression will continue to improve our fundamental understanding of polyketide synthesis as well as our ability to engineer the production of polyketides.
Highlights
Polyketide compounds are a large family of natural products with great structural diversity and complexity
Polyketides are formed by a family of enzymes known as polyketide synthases (PKSs), which often operate in an assembly line-like fashion to join together acyl coenzyme A (CoA) building blocks[1]
For the relatively simple class of non-reducing iterative type I PKSs (NR-PKSs) that are involved in aromatic polyketide synthesis, the starter unit acyl carrier protein (ACP) transacylase (SAT) domain has been the focus of several recent studies including domain swapping to generate new aromatic polyketides[23] and structural analysis to identify the basis for acyl unit selection[24], since unnatural starter units are often properly processed by the rest of the catalytic domains of non-reducing polyketide synthase (NR-PKS) (Figure 1B)[25]
Summary
Polyketide compounds are a large family of natural products with great structural diversity and complexity. The core catalytic domains of type I and II PKSs include the ketosynthase (KS) domain, which is responsible for catalyzing decarboxylative Claisen condensations for chain extension; the acyltransferase (AT) domain, which is responsible for building block selection and loading; and the acyl carrier protein (ACP) domain, on which the polyketide chain is elongated (Figure 1A).
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