Kinase Targets for Mycolic Acid Biosynthesis in Mycobacterium tuberculosis

Abstract

Background: Mycolic acids (MAs) are the characteristic, integral building blocks for the mycomembrane belonging to the insidious bacterial pathogen Mycobacterium tuberculosis (M.tb). These C60-C90 long α-alkyl-β-hydroxylated fatty acids provide protection to the tubercle bacilli against the outside threats, thus allowing its survival, virulence and resistance to the current antibacterial agents. In the post-genomic era, progress has been made towards understanding the crucial enzymatic machineries involved in the biosynthesis of MAs in M.tb. However, gaps still remain in the exact role of the phosphorylation and dephosphorylation of regulatory mechanisms within these systems. To date, a total of 11 serine-threonine protein kinases (STPKs) are found in M.tb. Most enzymes implicated in the MAs synthesis were found to be phosphorylated in vitro and/or in vivo. For instance, phosphorylation of KasA, KasB, mtFabH, InhA, MabA, and FadD32 downregulated their enzymatic activity, while phosphorylation of VirS increased its enzymatic activity. These observations suggest that the kinases and phosphatases system could play a role in M.tb adaptive responses and survival mechanisms in the human host. As the mycobacterial STPKs do not share a high sequence homology to the human’s, there have been some early drug discovery efforts towards developing potent and selective inhibitors. Objective: Recent updates to the kinases and phosphatases involved in the regulation of MAs biosynthesis will be presented in this mini-review, including their known small molecule inhibitors. Conclusion: Mycobacterial kinases and phosphatases involved in the MAs regulation may serve as a useful avenue for antitubercular therapy.

MtrP, a putative methyltransferase in Corynebacteria, is required for optimal membrane transport of trehalose mycolates

“…The synthetic pathways and enzymatic machineries that produce these species have been extensively studied and reviewed (4,(8)(9)(10)(11). In Mycobacteria, two independentlysynthesized fatty acids, the short alpha branch (C24-C26) and long meromycolate chain (C50-C60), produced by the single FAS-I enzyme and FAS-II complex (12,13), respectively, are modified then condensed by the cytoplasmic polyketide synthase, Pks13 (14), to form a 2alkyl 3-keto fatty acid which is then reduced by CmrA to generate the mature, hydroxylated mycolic acid (15).…”

Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents

“… 5 , 6 The MAs biosynthesis and incorporation on the mycobacterial cell wall was previously illustrated in our review article. 7 Summarised into five distinct steps, the first four steps of the process entail the biosynthesis of the MAs precursor, trehalose monomycolate (TMM), in the cytoplasm. 7 The last step involves flipping and release of the formed TMM across the inner membrane into the periplasm by the membrane transporter MmpL3.…”

“… 7 Summarised into five distinct steps, the first four steps of the process entail the biosynthesis of the MAs precursor, trehalose monomycolate (TMM), in the cytoplasm. 7 The last step involves flipping and release of the formed TMM across the inner membrane into the periplasm by the membrane transporter MmpL3. 6 Thereafter, these MAs accumulate in the M. tb cell envelope constituting the major lipid component of the outer coating of mycobacteria, rendering an extremely hydrophobic and impermeable bilayer.…”

Role of post‐translational modifications in the acquisition of drug resistance in Mycobacterium tuberculosis

“…The mycobacterial membrane is the most important organelle that protects the bacterium from unfavorable environmental conditions, immune system, and stress. The drugs that target the membrane lipid synthesis and metabolism, particularly mycolic acids, are very effective against Mtb [21,22]. MabA (beta-ketoacylacyl carrier protein reductase) and InhA (2-transenoyl-acyl carrier protein reductase) are the primary enzymes involved in the second and fourth steps, respectively, of meromycolic backbone elongation cycle during mycolic acid synthesis [54].…”