Enoyl-[acyl-carrier-protein] reductase [NADH]

Details

Name
Enoyl-[acyl-carrier-protein] reductase [NADH]
Synonyms
  • 1.3.1.9
  • ENR
  • FAS-II enoyl-ACP reductase
  • NADH-dependent 2-trans-enoyl-ACP reductase
Gene Name
inhA
Organism
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Amino acid sequence
>lcl|BSEQ0051173|Enoyl-[acyl-carrier-protein] reductase [NADH]
MTGLLDGKRILVSGIITDSSIAFHIARVAQEQGAQLVLTGFDRLRLIQRITDRLPAKAPL
LELDVQNEEHLASLAGRVTEAIGAGNKLDGVVHSIGFMPQTGMGINPFFDAPYADVSKGI
HISAYSYASMAKALLPIMNPGGSIVGMDFDPSRAMPAYNWMTVAKSALESVNRFVAREAG
KYGVRSNLVAAGPIRTLAMSAIVGGALGEEAGAQIQLLEEGWDQRAPIGWNMKDATPVAK
TVCALLSDWLPATTGDIIYADGGAHTQLL
Number of residues
269
Molecular Weight
28527.55
Theoretical pI
Not Available
GO Classification
Functions
enoyl-[acyl-carrier-protein] reductase (NADH) activity / fatty acid binding / NAD+ binding
Processes
fatty acid elongation / mycolic acid biosynthetic process / response to antibiotic
Components
cell wall / plasma membrane
General Function
Enoyl-ACP reductase of the type II fatty acid syntase (FAS-II) system, which is involved in the biosynthesis of mycolic acids, a major component of mycobacterial cell walls (PubMed:25227413). Catalyzes the NADH-dependent reduction of the double bond of 2-trans-enoyl-[acyl-carrier protein], an essential step in the fatty acid elongation cycle of the FAS-II pathway (PubMed:7599116). Shows preference for long-chain fatty acyl thioester substrates (>C16), and can also use 2-trans-enoyl-CoAs as alternative substrates (PubMed:7599116). The mycobacterial FAS-II system utilizes the products of the FAS-I system as primers to extend fatty acyl chain lengths up to C56, forming the meromycolate chain that serves as the precursor for final mycolic acids (PubMed:25227413).
Specific Function
Enoyl-[acyl-carrier-protein] reductase (nadh) activity
Pfam Domain Function
Not Available
Transmembrane Regions
Not Available
Cellular Location
Not Available
Gene sequence
>lcl|BSEQ0051174|Enoyl-[acyl-carrier-protein] reductase [NADH] (inhA)
ATGACAGGACTGCTGGACGGCAAACGGATTCTGGTTAGCGGAATCATCACCGACTCGTCG
ATCGCGTTTCACATCGCACGGGTAGCCCAGGAGCAGGGCGCCCAGCTGGTGCTCACCGGG
TTCGACCGGCTGCGGCTGATTCAGCGCATCACCGACCGGCTGCCGGCAAAGGCCCCGCTG
CTCGAACTCGACGTGCAAAACGAGGAGCACCTGGCCAGCTTGGCCGGCCGGGTGACCGAG
GCGATCGGGGCGGGCAACAAGCTCGACGGGGTGGTGCATTCGATTGGGTTCATGCCGCAG
ACCGGGATGGGCATCAACCCGTTCTTCGACGCGCCCTACGCGGATGTGTCCAAGGGCATC
CACATCTCGGCGTATTCGTATGCTTCGATGGCCAAGGCGCTGCTGCCGATCATGAACCCC
GGAGGTTCCATCGTCGGCATGGACTTCGACCCGAGCCGGGCGATGCCGGCCTACAACTGG
ATGACGGTCGCCAAGAGCGCGTTGGAGTCGGTCAACAGGTTCGTGGCGCGCGAGGCCGGC
AAGTACGGTGTGCGTTCGAATCTCGTTGCCGCAGGCCCTATCCGGACGCTGGCGATGAGT
GCGATCGTCGGCGGTGCGCTCGGCGAGGAGGCCGGCGCCCAGATCCAGCTGCTCGAGGAG
GGCTGGGATCAGCGCGCTCCGATCGGCTGGAACATGAAGGATGCGACGCCGGTCGCCAAG
ACGGTGTGCGCGCTGCTGTCTGACTGGCTGCCGGCGACCACGGGTGACATCATCTACGCC
GACGGCGGCGCGCACACCCAATTGCTCTAG
Chromosome Location
Not Available
Locus
Not Available
External Identifiers
ResourceLink
UniProtKB IDP9WGR1
UniProtKB Entry NameINHA_MYCTU
General References
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  3. Quemard A, Sacchettini JC, Dessen A, Vilcheze C, Bittman R, Jacobs WR Jr, Blanchard JS: Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. Biochemistry. 1995 Jul 4;34(26):8235-41. [PubMed:7599116]
  4. Parikh S, Moynihan DP, Xiao G, Tonge PJ: Roles of tyrosine 158 and lysine 165 in the catalytic mechanism of InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis. Biochemistry. 1999 Oct 12;38(41):13623-34. [PubMed:10521269]
  5. Larsen MH, Vilcheze C, Kremer L, Besra GS, Parsons L, Salfinger M, Heifets L, Hazbon MH, Alland D, Sacchettini JC, Jacobs WR Jr: Overexpression of inhA, but not kasA, confers resistance to isoniazid and ethionamide in Mycobacterium smegmatis, M. bovis BCG and M. tuberculosis. Mol Microbiol. 2002 Oct;46(2):453-66. [PubMed:12406221]
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  17. He X, Alian A, Stroud R, Ortiz de Montellano PR: Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis. J Med Chem. 2006 Oct 19;49(21):6308-23. [PubMed:17034137]
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  20. He X, Alian A, Ortiz de Montellano PR: Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides. Bioorg Med Chem. 2007 Nov 1;15(21):6649-58. Epub 2007 Aug 15. [PubMed:17723305]
  21. Argyrou A, Vetting MW, Blanchard JS: New insight into the mechanism of action of and resistance to isoniazid: interaction of Mycobacterium tuberculosis enoyl-ACP reductase with INH-NADP. J Am Chem Soc. 2007 Aug 8;129(31):9582-3. Epub 2007 Jul 18. [PubMed:17636923]
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  34. Manjunatha UH, S Rao SP, Kondreddi RR, Noble CG, Camacho LR, Tan BH, Ng SH, Ng PS, Ma NL, Lakshminarayana SB, Herve M, Barnes SW, Yu W, Kuhen K, Blasco F, Beer D, Walker JR, Tonge PJ, Glynne R, Smith PW, Diagana TT: Direct inhibitors of InhA are active against Mycobacterium tuberculosis. Sci Transl Med. 2015 Jan 7;7(269):269ra3. doi: 10.1126/scitranslmed.3010597. [PubMed:25568071]
  35. Guardia A, Gulten G, Fernandez R, Gomez J, Wang F, Convery M, Blanco D, Martinez M, Perez-Herran E, Alonso M, Ortega F, Rullas J, Calvo D, Mata L, Young R, Sacchettini JC, Mendoza-Losana A, Remuinan M, Ballell Pages L, Castro-Pichel J: N-Benzyl-4-((heteroaryl)methyl)benzamides: A New Class of Direct NADH-Dependent 2-trans Enoyl-Acyl Carrier Protein Reductase (InhA) Inhibitors with Antitubercular Activity. ChemMedChem. 2016 Apr 5;11(7):687-701. doi: 10.1002/cmdc.201600020. Epub 2016 Mar 2. [PubMed:26934341]
  36. Martinez-Hoyos M, Perez-Herran E, Gulten G, Encinas L, Alvarez-Gomez D, Alvarez E, Ferrer-Bazaga S, Garcia-Perez A, Ortega F, Angulo-Barturen I, Rullas-Trincado J, Blanco Ruano D, Torres P, Castaneda P, Huss S, Fernandez Menendez R, Gonzalez Del Valle S, Ballell L, Barros D, Modha S, Dhar N, Signorino-Gelo F, McKinney JD, Garcia-Bustos JF, Lavandera JL, Sacchettini JC, Jimenez MS, Martin-Casabona N, Castro-Pichel J, Mendoza-Losana A: Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor. EBioMedicine. 2016 Jun;8:291-301. doi: 10.1016/j.ebiom.2016.05.006. Epub 2016 May 8. [PubMed:27428438]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB00609EthionamideapprovedyesadductDetails
DB00951Isoniazidapproved, investigationalyesadductDetails
DB02990S-(2-Acetamidoethyl) hexadecanethioateexperimentalunknownDetails
DB04289Genz-10850experimentalunknownDetails
DB07090(3S)-N-(3-CHLORO-2-METHYLPHENYL)-1-CYCLOHEXYL-5-OXOPYRROLIDINE-3-CARBOXAMIDEexperimentalunknownDetails
DB07123N-(4-METHYLBENZOYL)-4-BENZYLPIPERIDINEexperimentalunknownDetails
DB07155(3S)-1-CYCLOHEXYL-5-OXO-N-PHENYLPYRROLIDINE-3-CARBOXAMIDEexperimentalunknownDetails
DB071785-PENTYL-2-PHENOXYPHENOLexperimentalunknownDetails
DB07188(3S)-1-CYCLOHEXYL-N-(3,5-DICHLOROPHENYL)-5-OXOPYRROLIDINE-3-CARBOXAMIDEexperimentalunknownDetails
DB07192(3S)-N-(3-BROMOPHENYL)-1-CYCLOHEXYL-5-OXOPYRROLIDINE-3-CARBOXAMIDEexperimentalunknownDetails
DB07222(3S)-N-(5-CHLORO-2-METHYLPHENYL)-1-CYCLOHEXYL-5-OXOPYRROLIDINE-3-CARBOXAMIDEexperimentalunknownDetails
DB072872-(2,4-DICHLOROPHENOXY)-5-(PYRIDIN-2-YLMETHYL)PHENOLexperimentalunknownDetails
DB08604Triclosanapproved, investigationalunknownDetails
DB05154Pretomanidapprovedunknownother/unknownDetails