Erratum for the Research Article “Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition” by E. Ballinger, J. Mosior, T. Hartman, K. Burns-Huang, B. Gold, R. Morris, L. Goullieux, I. Blanc, J. Vaubourgeix, S. Lagrange, L. Fraisse, S. Sans, C. Couturier, E. Bacqué, K. Rhee, S. M. Scarry, J. Aubé, G. Yang, O. Ouerfelli, D. Schnappinger, T. R. Ioerger, C. A. Engelhart, J. A. McConnell, K. McAulay, A. Fay, C. Roubert, J. Sacchettini, C. Nathan

Science ◽  
2019 ◽  
Vol 364 (6446) ◽  
pp. eaay3546
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Enzyme Inhibition ◽  
Coenzyme A ◽  
Research Article

scholarly journals Biochemical and Structural Characterization of an Essential Acyl Coenzyme A Carboxylase from Mycobacterium tuberculosis

2006 ◽  
Vol 188 (2) ◽  
pp. 477-486 ◽  
Author(s):  
Gabriela Gago ◽  
Daniel Kurth ◽  
Lautaro Diacovich ◽  
Shiou-Chuan Tsai ◽  
Hugo Gramajo
Keyword(s):  
Fatty Acids ◽  
Mycobacterium Tuberculosis ◽  
Coenzyme A ◽  
Physiological Role ◽  
Kinetic Properties ◽  
Aliphatic Chain ◽  
Heterologous Protein Expression ◽  
Main Role ◽  
Enzyme Complex ◽  
Protein Expression And Purification

ABSTRACT Pathogenic mycobacteria contain a variety of unique fatty acids that have methyl branches at an even-numbered position at the carboxyl end and a long n-aliphatic chain. One such group of acids, called mycocerosic acids, is found uniquely in the cell wall of pathogenic mycobacteria, and their biosynthesis is essential for growth and pathogenesis. Therefore, the biosynthetic pathway of the unique precursor of such lipids, methylmalonyl coenzyme A (CoA), represents an attractive target for developing new antituberculous drugs. Heterologous protein expression and purification of the individual subunits allowed the successful reconstitution of an essential acyl-CoA carboxylase from Mycobacterium tuberculosis, whose main role appears to be the synthesis of methylmalonyl-CoA. The enzyme complex was reconstituted from the α biotinylated subunit AccA3, the carboxyltransferase β subunit AccD5, and the ε subunit AccE5 (Rv3281). The kinetic properties of this enzyme showed a clear substrate preference for propionyl-CoA compared with acetyl-CoA (specificity constant fivefold higher), indicating that the main physiological role of this enzyme complex is to generate methylmalonyl-CoA for the biosynthesis of branched-chain fatty acids. The α and β subunits are capable of forming a stable α6-β6 subcomplex but with very low specific activity. The addition of the ε subunit, which binds tightly to the α-β subcomplex, is essential for gaining maximal enzyme activity.

scholarly journals Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition

Science ◽  
2019 ◽  
Vol 363 (6426) ◽  
pp. eaau8959 ◽  
Author(s):  
Elaine Ballinger ◽  
John Mosior ◽  
Travis Hartman ◽  
Kristin Burns-Huang ◽  
Ben Gold ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Coenzyme A ◽  
Loss Of Function ◽  
Phosphopantetheinyl Transferase ◽  
Carrier Proteins ◽  
Regulatory Pathway ◽  
Acyl Carrier Proteins ◽  
Antimycobacterial Agents ◽  
Further Development ◽  
Cocrystal Structure

Mycobacterium tuberculosis (Mtb) is the leading infectious cause of death in humans. Synthesis of lipids critical for Mtb’s cell wall and virulence depends on phosphopantetheinyl transferase (PptT), an enzyme that transfers 4′-phosphopantetheine (Ppt) from coenzyme A (CoA) to diverse acyl carrier proteins. We identified a compound that kills Mtb by binding and partially inhibiting PptT. Killing of Mtb by the compound is potentiated by another enzyme encoded in the same operon, Ppt hydrolase (PptH), that undoes the PptT reaction. Thus, loss-of-function mutants of PptH displayed antimicrobial resistance. Our PptT-inhibitor cocrystal structure may aid further development of antimycobacterial agents against this long-sought target. The opposing reactions of PptT and PptH uncover a regulatory pathway in CoA physiology.

scholarly journals Long-Chain Fatty Acyl Coenzyme A Ligase FadD2 Mediates Intrinsic Pyrazinamide Resistance in Mycobacterium tuberculosis

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Brandon C. Rosen ◽  
Nicholas A. Dillon ◽  
Nicholas D. Peterson ◽  
Yusuke Minato ◽  
Anthony D. Baughn
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Coenzyme A ◽  
Fatty Acyl ◽  
Wild Type ◽  
Intrinsic Resistance ◽  
First Line ◽  
Minimum Concentration ◽  
Content Type ◽  
Acyl Coenzyme A ◽  
Long Chain

ABSTRACT Pyrazinamide (PZA) is a first-line tuberculosis (TB) drug that has been in clinical use for 60 years yet still has an unresolved mechanism of action. Based upon the observation that the minimum concentration of PZA required to inhibit the growth of Mycobacterium tuberculosis is approximately 1,000-fold higher than that of other first-line drugs, we hypothesized that M. tuberculosis expresses factors that mediate intrinsic resistance to PZA. To identify genes associated with intrinsic PZA resistance, a library of transposon-mutagenized Mycobacterium bovis BCG strains was screened for strains showing hypersusceptibility to the active form of PZA, pyrazinoic acid (POA). Disruption of the long-chain fatty acyl coenzyme A (CoA) ligase FadD2 enhanced POA susceptibility by 16-fold on agar medium, and the wild-type level of susceptibility was restored upon expression of fadD2 from an integrating mycobacterial vector. Consistent with the recent observation that POA perturbs mycobacterial CoA metabolism, the fadD2 mutant strain was more vulnerable to POA-mediated CoA depletion than the wild-type strain. Ectopic expression of the M. tuberculosis pyrazinamidase PncA, necessary for conversion of PZA to POA, in the fadD2 transposon insertion mutant conferred at least a 16-fold increase in PZA susceptibility under active growth conditions in liquid culture at neutral pH. Importantly, deletion of fadD2 in M. tuberculosis strain H37Rv also resulted in enhanced susceptibility to POA. These results indicate that FadD2 is associated with intrinsic PZA and POA resistance and provide a proof of concept for the target-based potentiation of PZA activity in M. tuberculosis.

scholarly journals Validation of CoaBC as a Bactericidal Target in the Coenzyme A Pathway of Mycobacterium tuberculosis

2016 ◽  
Vol 2 (12) ◽  
pp. 958-968 ◽  
Author(s):  
Joanna C. Evans ◽  
Carolina Trujillo ◽  
Zhe Wang ◽  
Hyungjin Eoh ◽  
Sabine Ehrt ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Coenzyme A
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