Post-translational acetylation of MbtA modulates mycobacterial siderophore biosynthesis

Olivia Vergnolle, Hua Xu, Jo Ann M Tufariello, Lorenza Favrot, Adel A. Malek, William R. Jacobs, John S. Blanchard

Research output: Contribution to journalArticle

9 Citations (Scopus)

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, posttranslationally 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.

Original languageEnglish (US)
Pages (from-to)22315-22326
Number of pages12
JournalJournal of Biological Chemistry
Volume291
Issue number42
DOIs
StatePublished - Oct 14 2016

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Siderophores
Acetylation
Biosynthesis
Mycobacterium tuberculosis
Acyl Carrier Protein
Acetyltransferases
Lysine
Iron
Iron Chelating Agents
Mycobacterium smegmatis
Proteins
Salicylic Acid
Genes
Enzymes
Enzyme inhibition
Human Body
NAD
Ligation
Phenotype
Chemical activation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Post-translational acetylation of MbtA modulates mycobacterial siderophore biosynthesis. / Vergnolle, Olivia; Xu, Hua; Tufariello, Jo Ann M; Favrot, Lorenza; Malek, Adel A.; Jacobs, William R.; Blanchard, John S.

In: Journal of Biological Chemistry, Vol. 291, No. 42, 14.10.2016, p. 22315-22326.

Research output: Contribution to journalArticle

Vergnolle, Olivia ; Xu, Hua ; Tufariello, Jo Ann M ; Favrot, Lorenza ; Malek, Adel A. ; Jacobs, William R. ; Blanchard, John S. / Post-translational acetylation of MbtA modulates mycobacterial siderophore biosynthesis. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 42. pp. 22315-22326.
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