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Research article - Peer-reviewed, 2008

Structural, biochemical, and in vivo investigations of the threonine synthase from Mycobacterium tuberculosis

Covarrubias, Adrian Suarez; Hogbom, Martin; Bergfors, Terese; Carrol, Paul; Mannerstedt, Karin; Oscarson, Stefan; Parish, Tanya; Jones, T. Alwyn; Mowbray, Sherry L.


Threonine biosynthesis is a general feature of prokaryotes, eukaryotic microorganisms, and higher plants. Since mammals lack the appropriate synthetic machinery, instead obtaining the amino acid through their diet, the pathway is a potential focus for the development of novel antibiotics, antifungal agents, and herbicides. Threonine synthase (TS), a pyridoxal-5-phosphate-dependent enzyme, catalyzes the final step in the pathway, in which L-homoserine phosphate and water are converted into threonine and inorganic phosphate. In the present publication, we report structural and functional studies of Mycobacterium tuberculosis TS, the product of the rv1295 (thrC) gene. The structure gives new insights into the catalytic mechanism of TSs in general, specifically by suggesting the direct involvement of the phosphate moiety of the cofactor, rather than the inorganic phosphate product, in transferring a proton from C4' to C-gamma in the formation of the alpha beta-unsaturated aldimine. It further provides a basis for understanding why this enzyme has a higher pH optimum than has been reported elsewhere for TSs and gives rise to the prediction that the equivalent enzyme from Thermus thermophilus will exhibit similar behavior. A deletion of the relevant gene generated a strain of M. tuberculosis that requires threonine for growth; such auxotrophic strains are frequently attenuated in vivo, indicating that TS is a potential drug target in this organism. (C) 2008 Elsevier Ltd. All rights reserved.


threonine biosynthesis; tuberculosis; enzyme mechanism; X-ray structure; drug target

Published in

Journal of Molecular Biology
2008, volume: 381, number: 3, pages: 622-633

Authors' information

Covarrubias, Adrian Suárez
Uppsala University
Högbom, Martin
Uppsala University
Bergfors, Terese
Uppsala University
Carroll, Paul
Blizard Institute of Cell and Molecular Science
Mannerstedt, Karin
Stockholm University
Oscarson, Stefan
Stockholm University
Parish, Tanya
Blizard Institute of Cell and Molecular Science
Jones, T. Alwyn
Uppsala University
Mowbray, Sherry
Swedish University of Agricultural Sciences, Department of Molecular Biology

Sustainable Development Goals

SDG3 Good health and well-being

UKÄ Subject classification

Food Science

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