Mechanism and Regulation of Mycobactin Fatty Acyl-AMP Ligase FadD33

Vergnolle, Olivia; Xu, Hua; Blanchard, John S.

doi:10.1074/jbc.m113.495549

Cited by 38 publications

(42 citation statements)

References 39 publications

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“…In M. tuberculosis , this situation is relevant after engulfment by human macrophages, where the organism maintains its metabolic equilibrium using host fatty acids and cholesterol (19). There are other fatty acyl synthetases that are similarly regulated in M. tuberculosis , including the fatty acyl synthetase implicated in mycobactin biosynthesis (20). Mycobacterium tuberculosis thus has evolved posttranslational modification, specifically enzyme acetylation, to adapt its metabolic activity to the various environments that it encounters and survives.…”

Section: Resultsmentioning

confidence: 99%

Acetylation of acetyl-CoA synthetase from Mycobacterium tuberculosis leads to specific inactivation of the adenylation reaction

Noy

Blanchard

2014

Archives of Biochemistry and Biophysics

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Acetyl-CoA synthetase (ACS) catalyzes the formation of AcCoA from acetate, ATP and Coenzyme A, allowing the organism to grow on acetate as the sole carbon source. ACS was the first enzyme in Mycobacterium tuberculosis shown to be regulated by posttranslational acetylation by the cAMP-dependent protein acetyltransferase. This modification results in the inactivation of the enzyme and can be reversed in the presence of NAD+ and a mycobacterial sirtuin-like deacetylase. In this study we characterize the kinetic mechanism of MtACS, where the overall reaction can be divided into two half-reactions: the acetyl-adenylate forming reaction and the thiol-ligation reaction. We also provide evidence for the existence of the acetyl-adenylate intermediate via 31P-NMR spectroscopy. Furthermore, we dissect the regulatory role of K617 acetylation and show that acetylation inhibits only the first, adenylation half-reaction while leaving the second half reaction unchanged. Finally, we demonstrate that the chemical mechanism of the enzyme relies on a conformational change which is controlled by the protonation state of aspartate 525. Together with our earlier results, this suggests a degree of regulation of enzyme activity that is appropriate for the role of the enzyme in central carbon metabolism.

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Section: Resultsmentioning

confidence: 99%

Acetylation of acetyl-CoA synthetase from Mycobacterium tuberculosis leads to specific inactivation of the adenylation reaction

Noy

Blanchard

2014

Archives of Biochemistry and Biophysics

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“…Mutation of the biochemical machinery responsible for mycobactin biosynthesis inhibits M. tuberculosis growth whilst preventing the establishment of infection . Inhibitors for several enzymes in the mycobactin biosynthetic pathway have been investigated; however, of these targets, MbtA, which catalyses the condensation reaction between salicylate and an aroyl acyl carrier protein via a salicyl‐AMP intermediate ( 387 ), has been the most extensively and successfully exploited and has no mammalian homologues. Ferreras et al.…”

Section: Tuberculosismentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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“…Activated M. tuberculosis Pat acetylates and inhibits the activity of multiple downstream enzymes such as ACS, fatty acyl-CoA ligase FadD13, and fatty acyl-AMP ligase FadD33, which regulate fatty acid metabolism and siderophore biosynthesis, respectively. 140,145,146 …”

Section: Proteinsmentioning

confidence: 99%

Bacterial GCN5-Related N-Acetyltransferases: From Resistance to Regulation

2016

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The GCN5-related N-acetyltransferases family (GNAT) is an important family of proteins that includes more than 100000 members among eukaryotes and prokaryotes. Acetylation appears as a major regulatory post-translational modification and is as widespread as phosphorylation. N-Acetyltransferases transfer an acetyl group from acetyl-CoA to a large array of substrates, from small molecules such as aminoglycoside antibiotics to macromolecules. Acetylation of proteins can occur at two different positions, either at the amino-terminal end (αN-acetylation) or at the ε-amino group (εN-acetylation) of an internal lysine residue. GNAT members have been classified into different groups on the basis of their substrate specificity, and in spite of a very low primary sequence identity, GNAT proteins display a common and conserved fold. This Current Topic reviews the different classes of bacterial GNAT proteins, their functions, their structural characteristics, and their mechanism of action.

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Mechanism and Regulation of Mycobactin Fatty Acyl-AMP Ligase FadD33

Cited by 38 publications

References 39 publications

Acetylation of acetyl-CoA synthetase from Mycobacterium tuberculosis leads to specific inactivation of the adenylation reaction

Acetylation of acetyl-CoA synthetase from Mycobacterium tuberculosis leads to specific inactivation of the adenylation reaction

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Bacterial GCN5-Related N-Acetyltransferases: From Resistance to Regulation

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