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Structural analysis of mycobacterial branched-chain aminotransferase: implications for inhibitor design
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
2010 (English)In: Acta Crystallographica Section D: Biological Crystallography, ISSN 0907-4449, E-ISSN 1399-0047, Vol. 66, 549-557 p.Article in journal (Refereed) Published
Abstract [en]

The branched-chain aminotransferase (BCAT) of Mycobacterium tuberculosis has been characterized as being essential to the survival of the bacterium. The enzyme is pyridoxal 5'-phosphate-dependent and belongs to the aminotransferase IIIa subfamily, to which the human BCATs also belong. The overall sequence similarity is high within the subfamily and the sequence identity among the active-site residues is high. In order to identify structurally unique features of M. tuberculosis BCAT, X-ray structural and functional analyses of the closely related BCAT from M. smegmatis were carried out. The crystal structures include the apo form at 2.2 angstrom resolution and a 1.9 angstrom structure of the holo form cocrystallized with the inhibitor O-benzylhydroxylamine (Obe). The analyses highlighted the active-site residues Tyr209 and Gly243 as being structurally unique characteristics of the mycobacterial BCATs relative to the human BCATs. The inhibitory activities of Obe and ammonium sulfate were verified in an inhibition assay. Modelling of the inhibitor Obe in the substrate pocket indicated potential for the design of a mycobacterial-specific inhibitor.

Place, publisher, year, edition, pages
2010. Vol. 66, 549-557 p.
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-136327DOI: 10.1107/S0907444910004877ISI: 000277186800006OAI: oai:DiVA.org:uu-136327DiVA: diva2:376888
Available from: 2010-12-13 Created: 2010-12-11 Last updated: 2017-12-11Bibliographically approved

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