Abstract
Recent data indicate that the metabolism of Mycobacterium tuberculosis (Mtb) inside its host cell is heavily dependent on cholesterol and fatty acids. Mtb exhibits a unique capacity to co-metabolize different carbon sources and the products from these substrates are compartmentalized metabolically. Isocitrate lies at one of the key nodes of carbon metabolism and can feed into either the glyoxylate shunt (via isocitrate lyase) or the TCA cycle (via isocitrate dehydrogenase (ICDH) activity) and we sought to better understand the regulation at this junction. An isocitrate lyase-deficient mutant of Mtb (Δicl1) exhibited a delayed growth phenotype in stearic acid (C18 fatty acid) media and we isolated rescue mutants that had lost this growth delay. We found that mutations in the gene rv2170 promoted Mtb replication under these conditions and rescued the growth delay in a Δicl1 background. The Mtb Rv2170 protein shows lysine acetyltransferase activity, which is capable of post-translationally modifying lysine residues of the ICDH protein leading to a reduction in its enzymatic activity. Our data show that contrary to most bacteria that regulate ICDH activity through phosphorylation, Mtb is capable of regulating ICDH activity by acetylation. This mechanism of regulation is similar to that utilized for mammalian mitochondrial ICDH.
Highlights
Recent data indicate that the metabolism of Mycobacterium tuberculosis (Mtb) inside its host cell is heavily dependent on cholesterol and fatty acids
The environmental heterogeneity within the granuloma likely presents certain challenges to Mtb through the variation in oxygen tension and the availability of nutrients, which appear limited in diversity if not always in abundance. To adapt to these environments, Mtb efficiently reprograms its metabolism[6], most notably towards the effective utilization of host-derived fatty acids and cholesterol[7, 8] as the primary carbon source(s) exploited in vivo. Most bacteria regulate their metabolism through carbon catabolite repression (CCR)[9], which results in diauxic growth as preferred carbon sources are individually and sequentially depleted from the medium
In Mtb, isocitrate lyase (ICL1, Rv0467), the first enzyme in the glyoxylate shunt is required for growth on fatty acid as sole carbon source[23]
Summary
Recent data indicate that the metabolism of Mycobacterium tuberculosis (Mtb) inside its host cell is heavily dependent on cholesterol and fatty acids. In E. coli, ICDH activity and the flow of carbon from isocitrate into the TCA cycle is modulated by post-translational modification through phosphorylation of ICDH by AceK14. In this current study we probed the regulation of ICL1 and ICDH1 activities and took an advantage of a growth defect phenotype in an Mtb Δicl[1] mutant when grown on fatty acids as a sole carbon source.
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