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inhA  -  enoyl-ACP reductase

Mycobacterium tuberculosis CDC1551

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Disease relevance of inhA

  • One of these, the acyclic 4S isomer of isoniazid-NAD, targets the inhA-encoded enoyl-ACP reductase, an enzyme essential for mycolic acid biosynthesis in Mycobacterium tuberculosis [1].
  • In this work, multicopy plasmids expressing either inhA or kasA genes were transformed into M. smegmatis, M. bovis BCG and three different M. tuberculosis strains [2].
  • To overcome problems with unstable expression of an M. tuberculosis inhA-encoded enoyl reductase mutant protein and lack of expression of two mabA-encoded ketoacyl reductase mutants, a sub-population of E. coli BL21(DE3) host cells was selected from a small-opaque colony [3].

High impact information on inhA


Chemical compound and disease context of inhA


Biological context of inhA

  • The nucleotide sequences of the katG and inhA genes and the mabA-inhA promoter region were also determined [9].
  • At least one mutation was found in the katG and inhA regulatory region in 83% (30/36) of the multidrug-resistant isolates, and mutations at katG codon 315 were identified in 78% (28/36) [10].
  • Mycobacteria containing inhA plasmids uniformly exhibited 20-fold or greater increased resistance to INH and 10-fold or greater increased resistance to ETH [2].
  • The inhA region from 2 clinical isolates whose resistance has been attributed to changes in the upstream promoter region has been cloned and was not sufficient to impart INH resistance to the level of the parent strain on sensitive M. tuberculosis [11].
  • Mutations in known genetic markers of isoniazid resistance were detected in 25 of 42 isoniazid-resistant isolates: 20 strains had katG gene alterations and 5 had perturbations in the inhA operon [12].

Anatomical context of inhA

  • A library of clones, containing small fragments of M. tuberculosis DNA cloned upstream of inhA in a plasmid vector, was electroporated into M. tuberculosis, and the resulting culture was used to infect the human monocytic THP-1 cell line [13].
  • Sixteen of 19 isolates with alterations on the 3' end of the ribosome binding site upstream of mabA in inhA locus simultaneously harbored Ser315Thr mutations in KatG [14].

Associations of inhA with chemical compounds

  • Sequencing of consecutive isolates identified by the National Tuberculosis Program showed 89% of isoniazid-resistant isolates could be detected by targeting just 2 codons, katG 315 and -15C-->T in the inhA promoter, while rifampin resistance will be more complex to detect, with many different mutation and insertion events in rpoB [15].
  • 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 [16].

Other interactions of inhA

  • Despite this complexity, a preponderance of evidence implicates inhA, which codes for an enoyl-acyl carrier protein reductase of the fatty acid synthase II (FASII), as the primary target of INH [17].

Analytical, diagnostic and therapeutic context of inhA


  1. Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid. Argyrou, A., Vetting, M.W., Aladegbami, B., Blanchard, J.S. Nat. Struct. Mol. Biol. (2006) [Pubmed]
  2. Overexpression of inhA, but not kasA, confers resistance to isoniazid and ethionamide in Mycobacterium smegmatis, M. bovis BCG and M. tuberculosis. Larsen, M.H., Vilchèze, C., Kremer, L., Besra, G.S., Parsons, L., Salfinger, M., Heifets, L., Hazbon, M.H., Alland, D., Sacchettini, J.C., Jacobs, W.R. Mol. Microbiol. (2002) [Pubmed]
  3. Selection of an Escherichia coli host that expresses mutant forms of Mycobacterium tuberculosis 2-trans enoyl-ACP(CoA) reductase and 3-ketoacyl-ACP(CoA) reductase enzymes. Poletto, S.S., da Fonseca, I.O., de Carvalho, L.P., Basso, L.A., Santos, D.S. Protein Expr. Purif. (2004) [Pubmed]
  4. Effect of inhA and katG on isoniazid resistance and virulence of Mycobacterium bovis. Wilson, T.M., de Lisle, G.W., Collins, D.M. Mol. Microbiol. (1995) [Pubmed]
  5. Population genetics study of isoniazid resistance mutations and evolution of multidrug-resistant Mycobacterium tuberculosis. Hazbón, M.H., Brimacombe, M., Bobadilla del Valle, M., Cavatore, M., Guerrero, M.I., Varma-Basil, M., Billman-Jacobe, H., Lavender, C., Fyfe, J., García-García, L., León, C.I., Bose, M., Chaves, F., Murray, M., Eisenach, K.D., Sifuentes-Osornio, J., Cave, M.D., Ponce de León, A., Alland, D. Antimicrob. Agents Chemother. (2006) [Pubmed]
  6. Molecular characterization of isoniazid-resistant Mycobacterium tuberculosis isolates collected in Australia. Lavender, C., Globan, M., Sievers, A., Billman-Jacobe, H., Fyfe, J. Antimicrob. Agents Chemother. (2005) [Pubmed]
  7. ethA, inhA, and katG loci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates. Morlock, G.P., Metchock, B., Sikes, D., Crawford, J.T., Cooksey, R.C. Antimicrob. Agents Chemother. (2003) [Pubmed]
  8. Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. Quémard, A., Sacchettini, J.C., Dessen, A., Vilcheze, C., Bittman, R., Jacobs, W.R., Blanchard, J.S. Biochemistry (1995) [Pubmed]
  9. Performance of the Genotype MTBDR Line Probe Assay for Detection of Resistance to Rifampin and Isoniazid in Strains of Mycobacterium tuberculosis with Low- and High-Level Resistance. Brossier, F., Veziris, N., Truffot-Pernot, C., Jarlier, V., Sougakoff, W. J. Clin. Microbiol. (2006) [Pubmed]
  10. Genotypic Analysis of Multidrug-Resistant Mycobacterium tuberculosis Isolates Recovered From Central China. Zhang, S.L., Qi, H., Qiu, D.L., Li, D.X., Zhang, J., Du, C.M., Wang, G.B., Yang, Z.R., Sun, Q. Biochem. Genet. (2007) [Pubmed]
  11. Biochemical and genetic data suggest that InhA is not the primary target for activated isoniazid in Mycobacterium tuberculosis. Mdluli, K., Sherman, D.R., Hickey, M.J., Kreiswirth, B.N., Morris, S., Stover, C.K., Barry, C.E. J. Infect. Dis. (1996) [Pubmed]
  12. Molecular mechanisms of multiple drug resistance in clinical isolates of Mycobacterium tuberculosis. Morris, S., Bai, G.H., Suffys, P., Portillo-Gomez, L., Fairchok, M., Rouse, D. J. Infect. Dis. (1995) [Pubmed]
  13. Mycobacterium tuberculosis genes induced during infection of human macrophages. Dubnau, E., Fontán, P., Manganelli, R., Soares-Appel, S., Smith, I. Infect. Immun. (2002) [Pubmed]
  14. Genomic mutations in the katG, inhA and aphC genes are useful for the prediction of isoniazid resistance in Mycobacterium tuberculosis isolates from Kwazulu Natal, South Africa. Kiepiela, P., Bishop, K.S., Smith, A.N., Roux, L., York, D.F. Tuber. Lung Dis. (2000) [Pubmed]
  15. Mutations prevalent among rifampin- and isoniazid-resistant Mycobacterium tuberculosis isolates from a hospital in Vietnam. Caws, M., Duy, P.M., Tho, D.Q., Lan, N.T., Hoa, D.V., Farrar, J. J. Clin. Microbiol. (2006) [Pubmed]
  16. The mabA gene from the inhA operon of Mycobacterium tuberculosis encodes a 3-ketoacyl reductase that fails to confer isoniazid resistance. Banerjee, A., Sugantino, M., Sacchettini, J.C., Jacobs, W.R. Microbiology (Reading, Engl.) (1998) [Pubmed]
  17. Inactivation of the inhA-encoded fatty acid synthase II (FASII) enoyl-acyl carrier protein reductase induces accumulation of the FASI end products and cell lysis of Mycobacterium smegmatis. Vilchèze, C., Morbidoni, H.R., Weisbrod, T.R., Iwamoto, H., Kuo, M., Sacchettini, J.C., Jacobs, W.R. J. Bacteriol. (2000) [Pubmed]
  18. katG mutations in isoniazid-resistant Mycobacterium tuberculosis isolates recovered from Finnish patients. Marttila, H.J., Soini, H., Huovinen, P., Viljanen, M.K. Antimicrob. Agents Chemother. (1996) [Pubmed]
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