The Mycobacterium tuberculosis ino1 gene is essential for growth and virulence


Movahedzadeh, F; Smith, DA; Norman, RA; Dinadayala, P; Murray-Rust, J; Russell, DG; Kendall, SL; Rison, SCG; McAlister, MSB; Bancroft, GJ; McDonald, NQ; Daffe, M; Av-Gay, Y; Stoker, NG; (2004) The Mycobacterium tuberculosis ino1 gene is essential for growth and virulence. Molecular microbiology, 51 (4). pp. 1003-1014. ISSN 0950-382X DOI: https://doi.org/10.1046/j.1365-2958.2003.03900.x

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Abstract

Inositol is utilized by Mycobacterium tuberculosis in the production of its major thiol and of essential cell wall lipoglycans. We have constructed a mutant lacking the gene encoding inositol-1-phosphate synthase (ino1), which catalyses the first committed step in inositol synthesis. This mutant is only viable in the presence of extremely high levels of inositol. Mutant bacteria cultured in inositol-free medium for four weeks showed a reduction in levels of mycothiol, but phosphatidylinositol mannoside, lipomannan and lipoarabinomannan levels were not altered. The ino1 mutant was attenuated in resting macrophages and in SCID mice. We used site-directed mutagenesis to alter four putative active site residues; all four alterations resulted in a loss of activity, and we demonstrated that a D310N mutation caused loss of the active site Zn2+ ion and a conformational change in the NAD(+) cofactor.

Item Type: Article
Keywords: Complete genome sequence, mycobacterium-bovis bcg, inositol-1-, phosphate synthase, granuloma-formation, auxotrophic mutant, crystal-structure, tuberculosis, expression, phosphatidylinositol, identification
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Research Centre: TB Centre
PubMed ID: 14763976
Web of Science ID: 188768300009
URI: http://researchonline.lshtm.ac.uk/id/eprint/14862

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