Abstract
Polyketides are a diverse class of medically important natural products whose biosynthesis is catalysed by polyketide synthases (PKSs), in a fashion highly analogous to fatty acid biosynthesis. In modular PKSs, the polyketide chain is assembled by the successive condensation of activated carboxylic acid-derived units, where chain extension occurs with the intermediates remaining covalently bound to the enzyme, with the growing polyketide tethered to an acyl carrier domain (ACP). Carboxylated acyl-CoA precursors serve as activated donors that are selected by the acyltransferase domain (AT) providing extender units that are added to the growing chain by condensation catalysed by the ketosynthase domain (KS). The action of ketoreductase (KR), dehydratase (DH), and enoylreductase (ER) activities can result in unreduced, partially reduced, or fully reduced centres within the polyketide chain depending on which of these enzymes are present and active. The PKS-catalysed assembly process generates stereochemical diversity, because carbon–carbon double bonds may have either cis- or trans- geometry, and because of the chirality of centres bearing hydroxyl groups (where they are retained) and branching methyl groups (the latter arising from use of propionate extender units). This review shall cover the studies that have determined the stereochemistry in many of the reactions involved in polyketide biosynthesis by modular PKSs.
Highlights
Polyketides are a diverse class of medically important natural products whose biosynthesis is catalysed by polyketide synthases (PKSs), in a fashion highly analogous to fatty acid biosynthesis
The “assembly-line” PKS enzymes that biosynthesize complex polyketides are known as modular PKSs and contain catalytic domains that are usually covalently linked with the domains organized into “modules” in which the enzyme activities are specific to a given step in chain elongation
In what is described as the “co-linearity rule,” the organization of modules in modular PKSs and the catalytic activities present in each module determines the structure of the polyketide chain
Summary
Polyketides are among the most important microbial natural products used in medicine Members of this diverse family of compounds are used as a wide variety of therapeutics, including antibiotics such as erythromycin, anticancer epothilones, immunosuppressant rapamycin, and cholesterol-lowering lovastatin, to name only a few [1,2,3,4]. In what is described as the “co-linearity rule,” the organization of modules in modular PKSs and the catalytic activities present in each module determines the structure of the polyketide chain (with potential post-PKS tailoring or decoration of the chain occurring after polyketide biosynthesis) It is the modularity of these biosynthetic enzymes and the countless ways in which the “assembly-line” can be configured in modular PKSs of different organisms that gives rise to the vast structural and functional diversity of complex polyketides [5,6]
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