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Abstract
Polyketides belong to the most valuable natural products, including diverse bioactive compounds, such as antibiotics, anticancer drugs, antifungal agents, immunosuppressants and others. Their structures are assembled by polyketide synthases (PKSs). Modular PKSs are composed of modules, which involve sets of domains catalysing the stepwise polyketide biosynthesis. The acyltransferase (AT) domains and their “partners”, the acyl carrier proteins (ACPs), thereby play an essential role. The AT loads the building blocks onto the “substrate acceptor”, the ACP. Thus, the AT dictates which building blocks are incorporated into the polyketide structure. The precursor- and occasionally the ACP-specificity of the ATs differ across the polyketide pathways and therefore, the ATs contribute to the structural diversity within this group of complex natural products. Those features make the AT enzymes one of the most promising tools for manipulation of polyketide assembly lines and generation of new polyketide compounds. However, the AT-based PKS engineering is still not straightforward and thus, rational design of functional PKSs requires detailed understanding of the complex machineries. This review summarizes the attempts of PKS engineering by exploiting the AT attributes for the modification of polyketide structures. The article includes 253 references and covers the most relevant literature published until May 2018.
Highlights
Polyketides are a large class of structurally complex compounds with interesting and valuable activities
The goal of this review is to present an overview on the AT-targeted polyketide synthases (PKSs) engineering attempts and the recently gained knowledge, which renews the hope for programmable PKS modification and the production of new polyketide derivatives
The structure of a polyketide scaffold, synthesized by a modular PKS assembly line reflects the order of the catalytic domains within the PKS-modules, which usually corresponds to the chromosomal order of the underlying genes
Summary
Polyketides are a large class of structurally complex compounds with interesting and valuable activities. After the ACP-loading step, the KS domain of the PKS catalyses the decarboxylative Claisen-like condensation of the newly loaded unit and the already existing polyketide chain Additional optional domains, such as the ketoreductase (KR), dehydratase (DH), enoylreductase (ER) and methyltransferase (MT) process the generated β-ketoacyl thioester intermediate. Those include the length of the polyketide chain, oxidation state and stereochemistry of the β-keto groups, mechanism of termination and chain release, as well as post-PKS tailoring steps [2] Most of those variations result from the features of the PKS system (type of the PKS, PKS module and domain composition) and modification enzymes. The synopsis includes an introduction into the PKS assembly lines and its AT-domains, a brief summary of the biosynthesis of polyketide precursors, mechanistic and structural insights into PKSs and a more detailed description of the AT-based engineering strategies applied to modular type I PKSs and their future perspectives
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