INHA_MYCTO
ID INHA_MYCTO Reviewed; 269 AA.
AC P9WGR0; F2GEM2; P0A5Y6; P46533; Q540M9;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 50.
DE RecName: Full=Enoyl-[acyl-carrier-protein] reductase [NADH] {ECO:0000250|UniProtKB:P9WGR1};
DE Short=ENR {ECO:0000250|UniProtKB:P9WGR1};
DE Short=Enoyl-ACP reductase {ECO:0000250|UniProtKB:P9WGR1};
DE EC=1.3.1.9 {ECO:0000250|UniProtKB:P9WGR1};
DE AltName: Full=FAS-II enoyl-ACP reductase {ECO:0000250|UniProtKB:P9WGR1};
DE AltName: Full=NADH-dependent 2-trans-enoyl-ACP reductase {ECO:0000250|UniProtKB:P9WGR1};
GN Name=inhA {ECO:0000312|EMBL:AAK45796.1}; OrderedLocusNames=MT1531;
OS Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83331;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=CDC 1551 / Oshkosh;
RX PubMed=12218036; DOI=10.1128/jb.184.19.5479-5490.2002;
RA Fleischmann R.D., Alland D., Eisen J.A., Carpenter L., White O.,
RA Peterson J.D., DeBoy R.T., Dodson R.J., Gwinn M.L., Haft D.H., Hickey E.K.,
RA Kolonay J.F., Nelson W.C., Umayam L.A., Ermolaeva M.D., Salzberg S.L.,
RA Delcher A., Utterback T.R., Weidman J.F., Khouri H.M., Gill J., Mikula A.,
RA Bishai W., Jacobs W.R. Jr., Venter J.C., Fraser C.M.;
RT "Whole-genome comparison of Mycobacterium tuberculosis clinical and
RT laboratory strains.";
RL J. Bacteriol. 184:5479-5490(2002).
RN [2]
RP DRUG TARGET, AND DRUG RESISTANCE.
RC STRAIN=CDC 1551 / Oshkosh;
RX PubMed=12406221; DOI=10.1046/j.1365-2958.2002.03162.x;
RA Larsen M.H., Vilcheze C., Kremer L., Besra G.S., Parsons L., Salfinger M.,
RA Heifets L., Hazbon M.H., Alland D., Sacchettini J.C., Jacobs W.R. Jr.;
RT "Overexpression of inhA, but not kasA, confers resistance to isoniazid and
RT ethionamide in Mycobacterium smegmatis, M. bovis BCG and M. tuberculosis.";
RL Mol. Microbiol. 46:453-466(2002).
CC -!- FUNCTION: Enoyl-ACP reductase of the type II fatty acid syntase (FAS-
CC II) system, which is involved in the biosynthesis of mycolic acids, a
CC major component of mycobacterial cell walls. Catalyzes the NADH-
CC dependent reduction of the double bond of 2-trans-enoyl-[acyl-carrier
CC protein], an essential step in the fatty acid elongation cycle of the
CC FAS-II pathway. Shows preference for long-chain fatty acyl thioester
CC substrates (>C16), and can also use 2-trans-enoyl-CoAs as alternative
CC substrates. The mycobacterial FAS-II system utilizes the products of
CC the FAS-I system as primers to extend fatty acyl chain lengths up to
CC C56, forming the meromycolate chain that serves as the precursor for
CC final mycolic acids. {ECO:0000250|UniProtKB:P9WGR1}.
CC -!- FUNCTION: Is the primary target of the first-line antitubercular drug
CC isoniazid (INH) and of the second-line drug ethionamide (ETH).
CC Overexpressed inhA confers INH and ETH resistance to M.tuberculosis
CC (PubMed:12406221). The mechanism of isoniazid action against InhA is
CC covalent attachment of the activated form of the drug to the
CC nicotinamide ring of NAD and binding of the INH-NAD adduct to the
CC active site of InhA. Similarly, the ETH-NAD adduct binds InhA (By
CC similarity). {ECO:0000250|UniProtKB:P9WGR1,
CC ECO:0000269|PubMed:12406221}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 2,3-saturated acyl-[ACP] + NAD(+) = a (2E)-enoyl-[ACP] +
CC H(+) + NADH; Xref=Rhea:RHEA:10240, Rhea:RHEA-COMP:9925, Rhea:RHEA-
CC COMP:9926, ChEBI:CHEBI:15378, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945,
CC ChEBI:CHEBI:78784, ChEBI:CHEBI:78785; EC=1.3.1.9;
CC Evidence={ECO:0000250|UniProtKB:P9WGR1};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:10242;
CC Evidence={ECO:0000250|UniProtKB:P9WGR1};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 2,3-saturated acyl-CoA + NAD(+) = a (2E)-enoyl-CoA + H(+) +
CC NADH; Xref=Rhea:RHEA:18177, ChEBI:CHEBI:15378, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945, ChEBI:CHEBI:58856, ChEBI:CHEBI:65111;
CC Evidence={ECO:0000250|UniProtKB:P9WGR1};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:18179;
CC Evidence={ECO:0000250|UniProtKB:P9WGR1};
CC -!- ACTIVITY REGULATION: InhA activity is controlled via phosphorylation:
CC phosphorylation on Thr-266 decreases InhA activity (5-fold reduction)
CC and likely negatively regulates biosynthesis of mycolic acids and
CC growth of the bacterium. The antitubercular pro-drug isoniazid (INH) is
CC oxidatively activated by the catalase-peroxidase KatG and then
CC covalently binds NAD to form an adduct that inhibits the activity of
CC InhA. The inhibitory adduct is the isonicotinic-acyl-NADH where the
CC isonicotinic-acyl group replaces the 4S (and not the 4R) hydrogen of
CC NADH. Similarly, the antitubercular pro-drugs ethionamide (ETH) and
CC prothionamide (PTH) are activated by the flavoprotein monooxygenase
CC EthA, and forms an adduct with NAD (ETH-NAD and PTH-NAD, respectively)
CC that is a tight-binding inhibitor of InhA. Is inhibited by triclosan
CC and derivatives, pyrazole derivative Genz-8575, indole-5-amide Genz-
CC 10850, alkyl diphenyl/diaryl ethers, pyrrolidine carboxamides,
CC arylamides, pyridomycin, methyl-thiazoles, 4-hydroxy-2-pyridones, and
CC N-benzyl-4-((heteroaryl)methyl)benzamides. Pyridomycin shows a unique
CC mode of InhA inhibition by simultaneously blocking parts of the NADH
CC and the lipid substrate-binding pocket of InhA. Is also inhibited by
CC thiadiazole compounds, that have very attractive antitubercular
CC properties. {ECO:0000250|UniProtKB:P9WGR1}.
CC -!- PATHWAY: Lipid metabolism; mycolic acid biosynthesis.
CC {ECO:0000250|UniProtKB:P9WGR1}.
CC -!- SUBUNIT: Homodimer. Homotetramer. {ECO:0000250|UniProtKB:P9WGR1}.
CC -!- PTM: Is phosphorylated on Thr-266 in vivo. In vitro, can be
CC phosphorylated by multiple Ser/Thr protein kinases (STPK) such as PknA,
CC PknB, PknE, PknH and PknL. Phosphorylation decreases enzymatic
CC activity. {ECO:0000250|UniProtKB:P9WGR1}.
CC -!- MISCELLANEOUS: Many isoniazid- and ethionamide-resistant clinical
CC isolates contain mutations within the inhA locus. Resistance to
CC isoniazid and ethionamide can be conferred by the single substitution
CC of alanine for serine 94; this drug resistance seems to be directly
CC related to a perturbation in the hydrogen-bonding network that
CC decreases the binding of NADH and the INH-NAD adduct.
CC {ECO:0000250|UniProtKB:P9WGR1}.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC family. FabI subfamily. {ECO:0000305}.
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DR EMBL; AE000516; AAK45796.1; -; Genomic_DNA.
DR PIR; G70710; G70710.
DR RefSeq; WP_003407553.1; NZ_KK341227.1.
DR AlphaFoldDB; P9WGR0; -.
DR SMR; P9WGR0; -.
DR EnsemblBacteria; AAK45796; AAK45796; MT1531.
DR GeneID; 45425463; -.
DR KEGG; mtc:MT1531; -.
DR PATRIC; fig|83331.31.peg.1646; -.
DR HOGENOM; CLU_010194_10_1_11; -.
DR UniPathway; UPA00915; -.
DR Proteomes; UP000001020; Chromosome.
DR GO; GO:0004318; F:enoyl-[acyl-carrier-protein] reductase (NADH) activity; IEA:UniProtKB-EC.
DR GO; GO:0016631; F:enoyl-[acyl-carrier-protein] reductase activity; IEA:UniProtKB-EC.
DR GO; GO:0050343; F:trans-2-enoyl-CoA reductase (NAD+) activity; IEA:RHEA.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0046677; P:response to antibiotic; IEA:UniProtKB-KW.
DR CDD; cd05372; ENR_SDR; 1.
DR InterPro; IPR014358; Enoyl-ACP_Rdtase_NADH.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR PANTHER; PTHR43159; PTHR43159; 1.
DR PIRSF; PIRSF000094; Enoyl-ACP_rdct; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
PE 3: Inferred from homology;
KW Antibiotic resistance; Fatty acid biosynthesis; Fatty acid metabolism;
KW Lipid biosynthesis; Lipid metabolism; NAD; Oxidoreductase; Phosphoprotein.
FT CHAIN 1..269
FT /note="Enoyl-[acyl-carrier-protein] reductase [NADH]"
FT /id="PRO_0000428318"
FT BINDING 20..21
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P9WGR1"
FT BINDING 64..65
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P9WGR1"
FT BINDING 95..96
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P9WGR1"
FT BINDING 158
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WGR1"
FT BINDING 165
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P9WGR1"
FT BINDING 194
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P9WGR1"
FT SITE 149
FT /note="May act as an intermediate that passes the hydride
FT ion from NADH to the substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WGR1"
FT SITE 158
FT /note="Transition state stabilizer"
FT /evidence="ECO:0000250|UniProtKB:P9WGR1"
FT MOD_RES 266
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P9WGR1"
SQ SEQUENCE 269 AA; 28528 MW; F161D6D6A631CA08 CRC64;
MTGLLDGKRI LVSGIITDSS IAFHIARVAQ EQGAQLVLTG FDRLRLIQRI TDRLPAKAPL
LELDVQNEEH LASLAGRVTE AIGAGNKLDG VVHSIGFMPQ TGMGINPFFD APYADVSKGI
HISAYSYASM AKALLPIMNP GGSIVGMDFD PSRAMPAYNW MTVAKSALES VNRFVAREAG
KYGVRSNLVA AGPIRTLAMS AIVGGALGEE AGAQIQLLEE GWDQRAPIGW NMKDATPVAK
TVCALLSDWL PATTGDIIYA DGGAHTQLL
