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Molecular basis for extender unit specificity of mycobacterial polyketide synthases

Abstract : Mycobacterium tuberculosis is the causative agent of the tuberculosis disease, which claims more human lives each year than any other bacterial pathogen. M. tuberculosis and other mycobacterial pathogens have developed a range of unique features that enhance their virulence and promote their survival in the human host. Among these features lies the particular cell envelope with high lipid content, which plays a substantial role in mycobacterial pathogenicity. Several envelope components of M. tuberculosis and other mycobacteria, e.g. mycolic acids, phthiocerol dimycocerosates and phenolic glycolipids, belong to the ‘family’ of polyketides, secondary metabolites synthesized by fascinating versatile enzymes – polyketide synthases. These megasynthases consist of multiple catalytic domains, among which the acyltransferase domain plays a key role in selecting and transferring the substrates required for polyketide extension. Here, we present three new crystal structures of acyltransferase domains of mycobacterial polyketide synthases and, for one of them, provide evidence for the identification of residues determining extender unit specificity. Unravelling the molecular basis for such specificity is of high importance considering the role played by extender units for the final structure of key mycobacterial components. This work provides major advances for the use of mycobacterial polyketide synthases as potential therapeutic targets and, more generally, contributes to the prediction and bioengineering of polyketide synthases with desired specificity.
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https://hal-cnrs.archives-ouvertes.fr/hal-03018677
Contributor : Lionel Mourey Connect in order to contact the contributor
Submitted on : Monday, November 23, 2020 - 9:08:33 AM
Last modification on : Wednesday, October 27, 2021 - 5:55:48 AM
Long-term archiving on: : Wednesday, February 24, 2021 - 6:23:08 PM

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Anna Grabowska, Yoann Brison, Laurent Maveyraud, Sabine Gavalda, Alexandre Faille, et al.. Molecular basis for extender unit specificity of mycobacterial polyketide synthases. ACS Chemical Biology, American Chemical Society, In press. ⟨hal-03018677⟩

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