Fine tuning of antibiotic activity by a tailoring hydroxylase in a trans-AT polyketide synthase pathway

Research output: Contribution to journalArticlepeer-review

Standard

Fine tuning of antibiotic activity by a tailoring hydroxylase in a trans-AT polyketide synthase pathway. / Mohammad, Hadi; Connolly, Jack; Song, Zhongshu; Hothersall, Joanne; Race, Paul R; Willis, Christine L; Simpson, Thomas J; Winn, Peter; Thomas, Christopher.

In: ChemBioChem, 24.01.2018.

Research output: Contribution to journalArticlepeer-review

Harvard

APA

Vancouver

Author

Mohammad, Hadi ; Connolly, Jack ; Song, Zhongshu ; Hothersall, Joanne ; Race, Paul R ; Willis, Christine L ; Simpson, Thomas J ; Winn, Peter ; Thomas, Christopher. / Fine tuning of antibiotic activity by a tailoring hydroxylase in a trans-AT polyketide synthase pathway. In: ChemBioChem. 2018.

Bibtex

@article{1cf6d8fd59634546b26cf33594cf1431,
title = "Fine tuning of antibiotic activity by a tailoring hydroxylase in a trans-AT polyketide synthase pathway",
abstract = "Addition or removal of hydroxyl 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 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.",
author = "Hadi Mohammad and Jack Connolly and Zhongshu Song and Joanne Hothersall and Race, {Paul R} and Willis, {Christine L} and Simpson, {Thomas J} and Peter Winn and Christopher Thomas",
year = "2018",
month = jan,
day = "24",
doi = "10.1002/cbic.201800036",
language = "English",
journal = "ChemBioChem",
issn = "1439-4227",
publisher = "Wiley-VCH Verlag",

}

RIS

TY - JOUR

T1 - Fine tuning of antibiotic activity by a tailoring hydroxylase in a trans-AT polyketide synthase pathway

AU - Mohammad, Hadi

AU - Connolly, Jack

AU - Song, Zhongshu

AU - Hothersall, Joanne

AU - Race, Paul R

AU - Willis, Christine L

AU - Simpson, Thomas J

AU - Winn, Peter

AU - Thomas, Christopher

PY - 2018/1/24

Y1 - 2018/1/24

N2 - Addition or removal of hydroxyl 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 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.

AB - Addition or removal of hydroxyl 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 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.

U2 - 10.1002/cbic.201800036

DO - 10.1002/cbic.201800036

M3 - Article

JO - ChemBioChem

JF - ChemBioChem

SN - 1439-4227

M1 - cbic.201800036

ER -