title: Post-translational Acetylation of MbtA Modulates Mycobacterial Siderophore Biosynthesis.
abstract: 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.
authors: From the Department of Biochemistry and.
authors: Olivia
authors: O
authors: Vergnolle
authors: From the Department of Biochemistry and.
authors: Hua
authors: H
authors: Xu
authors: the Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461.
authors: JoAnn M
authors: JM
authors: Tufariello
authors: From the Department of Biochemistry and.
authors: Lorenza
authors: L
authors: Favrot
authors: the Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461.
authors: Adel A
authors: AA
authors: Malek
authors: the Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461.
authors: William R
authors: WR
authors: Jacobs
authors: From the Department of Biochemistry and john.blanchard@einstein.yu.edu.
authors: John S
authors: JS
authors: Blanchard
mesh_terms: D000107:Acetylation; D002384:Catalysis; D006801:Humans; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D000070837:Lysine Acetyltransferases / Q000235:genetics / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics; D010080:Oxazoles / Q000378:metabolism*; D000072417:Protein Domains; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017262:Siderophores / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D010080:Oxazoles; D017262:Siderophores; C018608:mycobactins; D000070837:Lysine Acetyltransferases; D008025:Ligases; C526815:salicyl-AMP ligase, Mycobacterium tuberculosis
keywords: MbtA; Mycobacterium tuberculosis; acetylation; enzyme structure; iron; mycobactin; post-translational modification (PTM)