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Issue 3, 2015
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Uncovering the structures of modular polyketide synthases

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Covering: up to 2014

The modular polyketide synthases (PKSs) are multienzyme proteins responsible for the assembly of diverse secondary metabolites of high economic and therapeutic importance. These molecular ‘assembly lines’ consist of repeated functional units called ‘modules’ organized into gigantic polypeptides. For several decades, concerted efforts have been made to understand in detail the structure and function of PKSs in order to facilitate genetic engineering of the systems towards the production of polyketide analogues for evaluation as drug leads. Despite this intense activity, it has not yet been possible to solve the crystal structure of a single module, let alone a multimodular subunit. Nonetheless, on the basis of analysis of the structures of modular fragments and the study of the related multienzyme of animal fatty acid synthase (FAS), several models of modular PKS architecture have been proposed. This year, however, the situation has changed – three modular structures have been characterized, not by X-ray crystallography, but by the complementary methods of single-particle cryo-electron microscopy and small-angle X-ray scattering. This review aims to compare the cryo-EM structures and SAXS-derived structural models, and to interpret them in the context of previously obtained data and existing architectural proposals. The consequences for genetic engineering of the systems will also be discussed, as well as unresolved questions and future directions.

Graphical abstract: Uncovering the structures of modular polyketide synthases

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Publication details

The article was received on 22 Jul 2014 and first published on 14 Oct 2014

Article type: Review Article
DOI: 10.1039/C4NP00098F
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Citation: Nat. Prod. Rep., 2015,32, 436-453
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    Uncovering the structures of modular polyketide synthases

    K. J. Weissman, Nat. Prod. Rep., 2015, 32, 436
    DOI: 10.1039/C4NP00098F

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