The role of the iterative modules in polyketide synthase evolution

Abstract

Polyketide synthases (PKSs) assemble activated carboxylic acids to elaborate chemical compounds (1). The key synthetic step is the C-C bond-forming condensation of an acyl moiety (e.g., acetyl-coenzyme A [CoA]) with an α-carboxyacyl moiety (e.g., malonyl-CoA) on release of CO2. The emerging β-ketoacyl compound can optionally be further modified by three accessory catalytic functions. Since this reaction sequence can be repeated, with each elongation varying in accessory catalytic functions, polyketides can be rich in chemistry (Fig. 1 A ). Many polyketides are of pharmaceutical relevance, among them several top-selling small molecule drugs (2): for example, antibiotics (e.g., erythromycin and tetracycline), antineoplastics (e.g., daunorubicin), and immunosuppressants (e.g., rapamycin) (3). Fig. 1. Iterative PKS. ( A ) Concept of FAS/PKS-mediated synthesis. Processing varies, resulting in different chemistries as indicated. Domain coloring is as indicated in the legend. ( B ) Biosynthesis of the erythromycin precursor 6-DEB, MSASs, and palmitic acid. DEBS, deoxyerythronolide B synthase. ( C ) Model for the PKS evolution specifically including iterative type I PKSs. Iterative PKSs predate PKS modules that comprise assembly lines. *For clarity, one multidomain module is shown with domains in color code. ( D ) Bacterial monomodular PKS gene clusters discovered by Wang et al. (7). Example on two biosynthetic gene clusters (BGCs) indicating PKS products and BGC end products. The scheme of BGC is for illustration only and does not reflect gene organization in BGCs sgriM25 or sgriM38. PKSs are subdivided into three categories: type I PKSs are large multifunctional proteins composed of several catalytic and functional domains, type II PKSs are characterized by discrete monofunctional enzymes, and type III PKSs catalyze polyketide formation within a single active site (1). Type I PKSs are mainly responsible for the wealth of pharmacologically important activities found in this compound class. Type I PKSs further divide in iterative and modular systems. Modular type I PKSs occur as … [↵][1]1Email: grininger{at}chemie.uni-frankfurt.de. [1]: #xref-corresp-1-1