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Fine Tuning of Antibiotic Activity by a Tailoring Hydroxylase in a Trans-AT Polyketide Synthase Pathway

Lookup NU author(s): Professor Paul RaceORCiD


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© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. The addition or removal of hydroxy groups modulates the activity of many pharmacologically active biomolecules. It can be integral to the basic biosynthetic factory or result from associated tailoring steps. For the anti-MRSA antibiotic mupirocin, removal of a C8-hydroxy group late in the biosynthetic pathway gives the active pseudomonic acid A. An extra hydroxylation, at C4, occurs in the related but more potent antibiotic thiomarinol A. We report here in vivo and in vitro studies that show that the putative non-haem-iron(II)/α-ketoglutaratedependent dioxygenase TmuB, from the thiomarinol cluster, 4-hydroxylates various pseudomonic acids whereas C8-OH, and other substituents around the tetrahydropyran ring, block enzyme action but not substrate binding. Molecular modelling suggested a basis for selectivity, but mutation studies had a limited ability to rationally modify TmuB substrate specificity. 4-Hydroxylation had opposite effects on the potency of mupirocin and thiomarinol. Thus, TmuB can be added to the toolbox of polyketide tailoring technologies for the in vivo generation of new antibiotics in the future.

Publication metadata

Author(s): Mohammad HH, Connolly JA, Song Z, Hothersall J, Race PR, Willis CL, Simpson TJ, Winn PJ, Thomas CM

Publication type: Article

Publication status: Published

Journal: ChemBioChem

Year: 2018

Volume: 19

Issue: 8

Pages: 836-841

Print publication date: 16/04/2018

Online publication date: 24/01/2018

Acceptance date: 24/01/2018

ISSN (print): 1439-4227

ISSN (electronic): 1439-7633

Publisher: Wiley-VCH Verlag


DOI: 10.1002/cbic.201800036

PubMed id: 29363252


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