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Publication - Dr Paul Race

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

    Citation

    Mohammad, HH, Connolly, JA, Song, Z, Hothersall, J, Race, PR, Willis, CL, Simpson, TJ, Winn, PJ & Thomas, CM, 2018, ‘Fine Tuning of Antibiotic Activity by a Tailoring Hydroxylase in a Trans-AT Polyketide Synthase Pathway’. ChemBioChem, vol 19., pp. 836-841

    Abstract

    Hydroxylation modulates the activity of many pharmacological biomolecules. It can be integral to the basic biosynthetic factory or result from tailoring steps. For anti-MRSA antibiotic mupirocin, removal of C8-hydroxyl late in biosynthesis gives the active pseudomonic acid A. An extra hydroxylation, at C4, occurs in the related antibiotic thiomarinol A. We report here that putative non-heme-iron(II)/α-ketoglutarate-dependent dioxygenase TmuB, from the thiomarinol cluster, 4-hydroxylates various pseudomonic acids while C8-OH, and other substituents around the pyran ring, block enzyme action but not substrate binding. Molecular modelling suggested a basis for selectivity but mutational studies showed 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 in vivo generation of new antibiotics in the future.

    Full details in the University publications repository