Fine Tuning of Antibiotic Activity by a Tailoring Hydroxylase in a Trans-AT Polyketide Synthase Pathway
| Autor: | Joanne Hothersall, Zhongshu Song, Jack A. Connolly, Thomas J. Simpson, Peter J. Winn, Hadi H. Mohammad, Paul R. Race, Christine L. Willis, Christopher M. Thomas |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Stereochemistry
BrisSynBio 010402 general chemistry medicine.disease_cause Hydroxylation 01 natural sciences Biochemistry antibiotics Mixed Function Oxygenases Substrate Specificity hydroxylation Polyketide chemistry.chemical_compound In vivo Dioxygenase Polyketide synthase medicine Molecular Biology Synthetic biology mupirocin Mutation biology 010405 organic chemistry Chemistry Organic Chemistry Bristol BioDesign Institute Substrate (chemistry) In vitro 0104 chemical sciences Anti-Bacterial Agents biology.protein Molecular Medicine thiomarinol Polyketide Synthases polyketides |
| Zdroj: | Mohammad, H H, Connolly, J A, Song, Z, Hothersall, J, Race, P R, Willis, C L, Simpson, T J, Winn, P J & Thomas, C M 2018, ' Fine Tuning of Antibiotic Activity by a Tailoring Hydroxylase in a Trans-AT Polyketide Synthase Pathway ', ChemBioChem, vol. 19, no. 8, pp. 836-841 . https://doi.org/10.1002/cbic.201800036 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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