Oleoyl Coenzyme A Regulates Interaction of Transcriptional Regulator RaaS (Rv1219c) with DNA in Mycobacteria

Abstract

Background: RaaS mediates mycobacterial survival in nonpermissive growth conditions by controlling expression of ATP-dependent efflux pumps.Results: Oleoyl-CoA regulates binding of the RaaS transcription factor to DNA and thus expression of the RaaS regulon and RaaS-mediated persistence.Conclusion: The activity of bacterial efflux is regulated by metabolites that are produced during active growth.Significance: Dysregulation of efflux pumps results in killing of persisting mycobacteria with low metabolic activity.

A Mycobacterium tuberculosis Effector Targets Mitochondrion, Controls Energy Metabolism, and Limits Cytochrome c Exit

“…The last four amino acid residues ( 140 WACN 143 ) composed a strictly conserved motif in all Rv1813c homologous proteins that includes one of the conserved cysteines. The fold-recognition and modeling server @TOME2 previously used in many studies for protein function identification even at low sequence identity ( 17 ) failed to identify any close or distant Rv1813c structural homologs.…”

AMycobacterium tuberculosiseffector targets mitochondrion, controls energy metabolism and limits cytochrome c exit

“…The last four amino acid residues ( 140 WACN 143 ) composed a strictly conserved motif in all Rv1813c homologous proteins that includes one of the conserved cysteines. Fold-recognition and modelling server @TOME2 previously used in many studies for protein function identification even at low sequence identity (Turapov et al, 2014) failed to identify any close or distant Rv1813c structural homologues.…”

Mycobacterium tuberculosis response to cholesterol is integrated with environmental pH and potassium levels via a lipid metabolism regulator

“…Rv1219c is a transcription factor that acts as an autorepressor, repressing expression of the ABC transporter system encoded by rv1217c-rv1218c that reside in the same operon, and has been studied primarily in the context of drug resistance [ 27 , 50 , 51 ]. Intriguingly, long chain fatty acid CoA derivatives have been reported to bind in a large cavity in the C-terminal ligand-binding domain of Rv1219c, affecting its ability to bind target DNA [ 27 ]. Whether cholesterol may also bind to this ligand-binding domain of Rv1219c, and how Mce3R may work with Rv1219c in coordinating Mtb cholesterol metabolism with environmental pH, are thus also exciting questions for follow-up studies.…”

“…Specifically, a Δmce3R mutant fails to synergistically upregulate genes in the cholesterol regulon in the simultaneous presence of acidic pH, and in the K + regulon in the simultaneous presence of cholesterol, even while response to each signal individually is unaffected ( -rv1218c) were specifically downregulated in the cholesterol/acidic pH dual condition, but not in acidic pH or cholesterol alone, upon mce3R deletion. Rv1219c is a transcription factor that acts as an autorepressor, repressing expression of the ABC transporter system encoded by rv1217c-rv1218c that reside in the same operon, and has been studied primarily in the context of drug resistance [27,50,51]. Intriguingly, long chain fatty acid CoA derivatives have been reported to bind in a large cavity in the C-terminal ligand-binding domain of Rv1219c, affecting its ability to bind target DNA [27].…”

“…As noted above, these seven transcription factors are known or predicted to be involved in lipid metabolism. Specifically, mce1R, mce2R, rv1219c, and rv1816 have previously been shown to be involved in fatty acid metabolism [23][24][25][26][27], kstR is a key regulator of cholesterol β-oxidation [28,29], and rv1129c is involved in propionyl-CoA metabolism [30]. mce3R is predicted to be involved in lipid metabolism due to the homology of the Mce3 complex that it regulates to the other Mce complexes [31][32][33][34], and the role of genes such as fadE17 and fadE18 that lie within the Mce3R regulon [35].…”