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Mycobacterium tuberculosis , the pathogen that causes tuberculosis, presumably utilizes fatty acids as a major carbon source during infection within the host. Metabolism of even-chain-length fatty acids yields acetyl-CoA, whereas metabolism of odd-chain-length fatty acids additionally yields propionyl-CoA. Utilization of these compounds by tubercle bacilli requires functional glyoxylate and methylcitrate cycles, respectively. Enzymes involved in both pathways are essential for  M. tuberculosis  viability and persistence during growth on fatty acids. However, little is known about regulatory factors responsible for adjusting the expression of genes encoding these enzymes to particular growth conditions. Here, we characterized the novel role of PrpR as a transcription factor that is directly involved in regulating genes encoding the key enzymes of methylcitrate (methylcitrate dehydratase [PrpD] and methylcitrate synthase [PrpC]) and glyoxylate (isocitrate lyase [Icl1]) cycles. Using cell-free systems and intact cells, we demonstrated an interaction of PrpR protein with  prpDC  and  icl1  promoter regions and identified a consensus sequence recognized by PrpR. Moreover, we showed that an  M. tuberculosis prpR -deletion strain exhibits impaired growth  in vitro  on propionate as the sole carbon source. Real-time quantitative reverse transcription-polymerase chain reaction confirmed that PrpR acts as a transcriptional activator of  prpDC  and  icl1  genes when propionate is the main carbon source. Similar results were also obtained for a non-pathogenic  Mycobacterium smegmatis  strain. Additionally, we found that  ramB , a  prpR  paralog that controls the glyoxylate cycle, is negatively regulated by PrpR. Our data demonstrate that PrpR is essential for the utilization of odd-chain-length fatty acids by tubercle bacilli. Since PrpR also acts as a  ramB  repressor, our findings suggest that it plays a key role in regulating expression of enzymes involved in both glyoxylate and methylcitrate pathways.

A Novel Role of the PrpR as a Transcription Factor Involved in the Regulation of Methylcitrate Pathway in Mycobacterium tuberculosis