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Structure and function of the transketolase from Mycobacterium tuberculosis and comparison with the human enzyme
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
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2012 (English)In: Open Biology, ISSN 2046-2441, Vol. 2, 110026- p.Article in journal (Refereed) Published
Abstract [en]

The transketolase (TKT) enzyme in Mycobacterium tuberculosis represents a novel drug target for tuberculosis treatment and has low homology with the orthologous human enzyme. Here, we report on the structural and kinetic characterization of the transketolase from M. tuberculosis (TBTKT), a homodimer whose monomers each comprise 700 amino acids. We show that TBTKT catalyses the oxidation of donor sugars xylulose-5-phosphate and fructose-6-phosphate as well as the reduction of the acceptor sugar ribose-5-phosphate. An invariant residue of the TKT consensus sequence required for thiamine cofactor binding is mutated in TBTKT; yet its catalytic activities are unaffected, and the 2.5 angstrom resolution structure of full-length TBTKT provides an explanation for this. Key structural differences between the human and mycobacterial TKT enzymes that impact both substrate and cofactor recognition and binding were uncovered. These changes explain the kinetic differences between TBTKT and its human counterpart, and their differential inhibition by small molecules. The availability of a detailed structural model of TBTKT will enable differences between human and M. tuberculosis TKT structures to be exploited to design selective inhibitors with potential antitubercular activity.

Place, publisher, year, edition, pages
2012. Vol. 2, 110026- p.
Keyword [en]
transketolase, Mycobacterium tuberculosis, X-ray crystallography, pentose pathway, enzyme kinetics
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-180302DOI: 10.1098/rsob.110026ISI: 000307111300001OAI: oai:DiVA.org:uu-180302DiVA: diva2:549053
Available from: 2012-09-03 Created: 2012-09-03 Last updated: 2012-09-03Bibliographically approved

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Bergfors, TereseJones, T. Alwyn

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