title: The mabA gene from the inhA operon of Mycobacterium tuberculosis encodes a 3-ketoacyl reductase that fails to confer isoniazid resistance.
abstract: A target of the anti-tuberculosis drugs isoniazid (INH) and ethionamide (ETH) has been shown to be an enoyl reductase, encoded by the inhA gene. The mabA (mycolic acid biosynthesis A) gene is located immediately upstream of inhA in Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium smegmatis. The MabA protein from M. tuberculosis was expressed in Escherichia coli and shown to have 3-ketoacyl reductase activity, consistent with a role in mycolic acid biosynthesis. In M. smegmatis, inhA and mabA are independently transcribed, but in M. tuberculosis and M. bovis BCG, mabA and inhA constitute a single operon. Several INH-ETH-resistant M. tuberculosis clinical isolates contain point mutations in the ribosome-binding site of mabA in the mabA-inhA operon. However, genetic dissection of this operon reveals that the INH-ETH-resistance phenotype is encoded only by inhA, and not by mabA.
authors.affiliation: Department of Microbiology and Immunologyl, Howard Hughes Medical Institute, and Department of Biochemistry.
authors.forename: Asesh
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Albert Einstein College of MedicineBronx, NY 10461USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Sugantino
authors.affiliation: Albert Einstein College of MedicineBronx, NY 10461USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
authors.affiliation: Department of Microbiology and Immunologyl, Howard Hughes Medical Institute, and Department of Biochemistry.
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
mesh_terms: D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase; D000429:Alcohol Oxidoreductases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000995:Antitubercular Agents / Q000494:pharmacology; D001426:Bacterial Proteins; D001483:Base Sequence; D003001:Cloning, Molecular; D017124:Conserved Sequence; D004352:Drug Resistance, Microbial / Q000235:genetics; D005000:Ethionamide / Q000494:pharmacology; D005822:Genetic Vectors; D007538:Isoniazid / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D009876:Operon / Q000235:genetics; D010088:Oxidoreductases / Q000235:genetics*; D010641:Phenotype; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D010088:Oxidoreductases; D000429:Alcohol Oxidoreductases; D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase; C085257:InhA protein, Mycobacterium; D005000:Ethionamide; D007538:Isoniazid