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Structure and function of the transketolase from Mycobacterium tuberculosis and comparison with the human enzyme
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Fullam, Elizabeth, Pojer, Florence, Bergfors, Terese, Jones, T. Alwyn and Cole, Stewart T. (2012) Structure and function of the transketolase from Mycobacterium tuberculosis and comparison with the human enzyme. Open Biology, Volume 2 (110026). Article number 110026. doi:10.1098/rsob.110026 ISSN 2046-2441.
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Official URL: http://dx.doi.org/10.1098/rsob.110026
Abstract
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 Å 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.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Subjects: | Q Science > QR Microbiology | ||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
| Library of Congress Subject Headings (LCSH): | Mycobacterium tuberculosis, Enzyme kinetics, Transketolase | ||||
| Journal or Publication Title: | Open Biology | ||||
| Publisher: | The Royal Society Publishing | ||||
| ISSN: | 2046-2441 | ||||
| Official Date: | 11 January 2012 | ||||
| Dates: |
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| Volume: | Volume 2 | ||||
| Number: | 110026 | ||||
| Article Number: | Article number 110026 | ||||
| DOI: | 10.1098/rsob.110026 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||
| Date of first compliant deposit: | 27 December 2015 | ||||
| Date of first compliant Open Access: | 27 December 2015 | ||||
| Funder: | Sixth Framework Programme (European Commission) (FP6) | ||||
| Grant number: | LHSP-CT-2005-018923 (FP6) |
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