This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The global spread of tuberculosis (TB) has been aggravated by the development of strains of the causative bacterium Mycobacterium tuberculosis (Mtb) that are resistant to the leading drugs. New TB therapies are urgently needed, but fortunately recent genome sequence, genetic and protein characterization studies have helped identify novel Mtb drug targets and key biochemical pathways for strategic intervention. In this regard, genes that code for lipid metabolism are a very important part of the bacterial genome, and 8% of the genome is involved in this activity. Of particular interest in the present context are the multiple cytochromes P450 (P450) encoded in the Mtb genome, whose biological roles are not yet understood. To date, physiological roles have been proposed for CYP125 CYP142 and CYP51 in sterol metabolism and for CYP132 in fatty acid metabolism, but none of these roles has been established. In this project, we are elucidating the function(s) of Mtb P450 enzymes, including CYP125, CYP130, CYP141, and CYP142 by comparative analyses of the global lipid profiles of normal Mtb and strains in which the individual P450 enzymes have been knocked out. This comparison will be carried out using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). The availability of knockout strains for these P450s makes possible a direct comparison of the lipidomic profiles under different growth and labeling conditions.
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