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Functional Characterization of a Vitamin B12-Dependent Methylmalonyl Pathway in Mycobacterium tuberculosis: Implications for Propionate Metabolism during Growth on Fatty Acids

  • Savvi, Suzana MRC/NHLS/WITS Molecular Mycobacteriology Research Unit and DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, School of Pathology, University of the Witwatersrand and the National Health Laboratory Service, Johannesburg, South Africa
  • Warner, Digby F. MRC/NHLS/WITS Molecular Mycobacteriology Research Unit and DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, School of Pathology, University of the Witwatersrand and the National Health Laboratory Service, Johannesburg, South Africa
  • Kana, Bavesh D. MRC/NHLS/WITS Molecular Mycobacteriology Research Unit and DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, School of Pathology, University of the Witwatersrand and the National Health Laboratory Service, Johannesburg, South Africa
  • McKinney, John D. Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
  • Mizrahi, Valerie MRC/NHLS/WITS Molecular Mycobacteriology Research Unit and DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, School of Pathology, University of the Witwatersrand and the National Health Laboratory Service, Johannesburg, South Africa
  • Dawes, Stephanie S. MRC/NHLS/WITS Molecular Mycobacteriology Research Unit and DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, School of Pathology, University of the Witwatersrand and the National Health Laboratory Service, Johannesburg, South Africa
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  • Journal of Bacteriology. - American Society for Microbiology. - 2008, vol. 190, no. 11, p. 3886-3895
Molecular Biology
Microbiology
English ABSTRACT

Mycobacterium tuberculosis is predicted to subsist on alternative carbon sources during persistence within the human host. Catabolism of odd- and branched-chain fatty acids, branched-chain amino acids, and cholesterol generates propionyl-coenzyme A (CoA) as a terminal, three-carbon (C3) product. Propionate constitutes a key precursor in lipid biosynthesis but is toxic if accumulated, potentially implicating its metabolism in M. tuberculosis pathogenesis. In addition to the well-characterized methylcitrate cycle, the M. tuberculosis genome contains a complete methylmalonyl pathway, including a mutAB-encoded methylmalonyl-CoA mutase (MCM) that requires a vitamin B12-derived cofactor for activity. Here, we demonstrate the ability of M. tuberculosis to utilize propionate as the sole carbon source in the absence of a functional methylcitrate cycle, provided that vitamin B12 is supplied exogenously. We show that this ability is dependent on mutAB and, furthermore, that an active methylmalonyl pathway allows the bypass of the glyoxylate cycle during growth on propionate in vitro. Importantly, although the glyoxylate and methylcitrate cycles supported robust growth of M. tuberculosis on the C17 fatty acid heptadecanoate, growth on valerate (C5) was significantly enhanced through vitamin B12 supplementation. Moreover, both wild-type and methylcitrate cycle mutant strains grew on B12-supplemented valerate in the presence of 3-nitropropionate, an inhibitor of the glyoxylate cycle enzyme isocitrate lyase, indicating an anaplerotic role for the methylmalonyl pathway. The demonstrated functionality of MCM reinforces the potential relevance of vitamin B12 to mycobacterial pathogenesis and suggests that vitamin B12 availability in vivo might resolve the paradoxical dispensability of the methylcitrate cycle for the growth and persistence of M. tuberculosis in mice.
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  • English
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bronze
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https://sonar.ch/global/documents/129906
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