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Fine Tuning of Antibiotic Activity by a Tailoring Hydroxylase in a Trans‐AT Polyketide Synthase Pathway
Author(s) -
Mohammad Hadi H.,
Connolly Jack A.,
Song Zhongshu,
Hothersall Joanne,
Race Paul R.,
Willis Christine L.,
Simpson Thomas J.,
Winn Peter J.,
Thomas Christopher M.
Publication year - 2018
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800036
Subject(s) - hydroxylation , mupirocin , stereochemistry , chemistry , polyketide , polyketide synthase , enzyme , tetrahydropyran , nonribosomal peptide , in vivo , biochemistry , biosynthesis , combinatorial chemistry , biology , bacteria , ring (chemistry) , methicillin resistant staphylococcus aureus , microbiology and biotechnology , genetics , staphylococcus aureus , organic chemistry
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.