Post-translational Acetylation of MbtA Modulates Mycobacterial Siderophore BiosynthesisThis work was supported by National Institutes of Health Grants AI60899 (to J. S. B.) and AI26170, AI098925, and P01AI63537 (to W. R. J.). This research used resources of the Advanced Photon Source, a U.S. Department of Energy Office of Science User Facility operated for the Department of Energy Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357. Use of the Lilly Research Laborat

• Published in: The Journal of biological chemistry 2016-10, Vol.291 (42), p.22315-22326
• Main Authors: Vergnolle, Olivia, Xu, Hua, Tufariello, JoAnn M., Favrot, Lorenza, Malek, Adel A., Jacobs, William R., Blanchard, John S.
• Format: Article
• Language: English
• Subjects: acetylation; enzyme structure; iron; MbtA; Mycobacterium tuberculosis; mycobactin; post-translational modification (PTM)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.744532

Iron is an essential element for life, but its soluble form is scarce in the environment and is rarer in the human body. Mtb (Mycobacterium tuberculosis) produces two aryl-capped siderophores, mycobactin (MBT) and carboxymycobactin (cMBT), to chelate intracellular iron. The adenylating enzyme MbtA catalyzes the first step of mycobactin biosynthesis in two half-reactions: activation of the salicylic acid as an acyl-adenylate and ligation onto the acyl carrier protein (ACP) domain of MbtB to form covalently salicylated MbtB-ACP. We report the first apo-MbtA structure from Mycobacterium smegmatis at 2.3 Å. We demonstrate here that MbtA activity can be reversibly, post-translationally regulated by acetylation. Indeed the mycobacterial Pat (protein lysine acetyltransferase), Rv0998, specifically acetylates MbtA on lysine 546, in a cAMP-dependent manner, leading to enzyme inhibition. MbtA acetylation can be reversed by the NAD+-dependent DAc (deacetyltransferase), Rv1151c. Deletion of Pat and DAc genes in Mtb revealed distinct phenotypes for strains lacking one or the other gene at low pH and limiting iron conditions. This study establishes a direct connection between the reversible acetylation system Pat/DAc and the ability of Mtb to adapt in limited iron conditions, which is critical for mycobacterial infection.