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Enoyl-[acyl-carrier-protein] reductase [NADH] (ENR) (Enoyl-ACP reductase) (EC 1.3.1.9) (FAS-II enoyl-ACP reductase) (NADH-dependent 2-trans-enoyl-ACP reductase)

 INHA_MYCTU              Reviewed;         269 AA.
P9WGR1; F2GEM2; P0A5Y6; P46533; Q540M9;
16-APR-2014, integrated into UniProtKB/Swiss-Prot.
16-APR-2014, sequence version 1.
25-OCT-2017, entry version 30.
RecName: Full=Enoyl-[acyl-carrier-protein] reductase [NADH] {ECO:0000303|PubMed:7599116};
Short=ENR {ECO:0000303|PubMed:12606558};
Short=Enoyl-ACP reductase {ECO:0000303|PubMed:7599116};
EC=1.3.1.9 {ECO:0000269|PubMed:10521269, ECO:0000269|PubMed:20864541, ECO:0000269|PubMed:21143326, ECO:0000269|PubMed:22987724, ECO:0000269|PubMed:7599116};
AltName: Full=FAS-II enoyl-ACP reductase {ECO:0000305};
AltName: Full=NADH-dependent 2-trans-enoyl-ACP reductase {ECO:0000305|PubMed:7599116};
Name=inhA {ECO:0000303|PubMed:8284673}; OrderedLocusNames=Rv1484;
ORFNames=MTCY277.05;
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
Mycobacterium; Mycobacterium tuberculosis complex.
NCBI_TaxID=83332;
[1]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], DRUG TARGET, AND DRUG RESISTANCE.
STRAIN=ATCC 25618 / H37Rv;
PubMed=8284673; DOI=10.1126/science.8284673;
Banerjee A., Dubnau E., Quemard A., Balasubramanian V., Um K.S.,
Wilson T., Collins D., de Lisle G., Jacobs W.R. Jr.;
"inhA, a gene encoding a target for isoniazid and ethionamide in
Mycobacterium tuberculosis.";
Science 263:227-230(1994).
[2]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
STRAIN=TCVGH1;
Shi Z.-Y., Lee K., Hu C.-H., Liu M.-F.;
"The allelic profiles of multidrug-resistant Mycobacterium
tuberculosis isolates from Taiwan.";
Submitted (SEP-2002) to the EMBL/GenBank/DDBJ databases.
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
STRAIN=ATCC 25618 / H37Rv;
PubMed=9634230; DOI=10.1038/31159;
Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M.,
Harris D.E., Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III,
Tekaia F., Badcock K., Basham D., Brown D., Chillingworth T.,
Connor R., Davies R.M., Devlin K., Feltwell T., Gentles S., Hamlin N.,
Holroyd S., Hornsby T., Jagels K., Krogh A., McLean J., Moule S.,
Murphy L.D., Oliver S., Osborne J., Quail M.A., Rajandream M.A.,
Rogers J., Rutter S., Seeger K., Skelton S., Squares S., Squares R.,
Sulston J.E., Taylor K., Whitehead S., Barrell B.G.;
"Deciphering the biology of Mycobacterium tuberculosis from the
complete genome sequence.";
Nature 393:537-544(1998).
[4]
FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBSTRATE
SPECIFICITY, REACTION MECHANISM, SUBUNIT, AND MUTAGENESIS OF SER-94.
STRAIN=H37Rv;
PubMed=7599116; DOI=10.1021/bi00026a004;
Quemard A., Sacchettini J.C., Dessen A., Vilcheze C., Bittman R.,
Jacobs W.R. Jr., Blanchard J.S.;
"Enzymatic characterization of the target for isoniazid in
Mycobacterium tuberculosis.";
Biochemistry 34:8235-8241(1995).
[5]
ENZYME REGULATION.
DOI=10.1021/ja962035y;
Basso L.A., Zheng R., Blanchard J.S.;
"Kinetics of inactivation of WT and C243S mutant of Mycobacterium
tuberculosis enoyl reductase by activated isoniazid.";
J. Am. Chem. Soc. 118:11301-11302(1996).
[6]
CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, REACTION MECHANISM,
AND MUTAGENESIS OF TYR-158 AND LYS-165.
PubMed=10521269; DOI=10.1021/bi990529c;
Parikh S., Moynihan D.P., Xiao G., Tonge P.J.;
"Roles of tyrosine 158 and lysine 165 in the catalytic mechanism of
InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis.";
Biochemistry 38:13623-13634(1999).
[7]
DRUG TARGET, AND DRUG RESISTANCE.
STRAIN=H37Rv;
PubMed=12406221; DOI=10.1046/j.1365-2958.2002.03162.x;
Larsen M.H., Vilcheze C., Kremer L., Besra G.S., Parsons L.,
Salfinger M., Heifets L., Hazbon M.H., Alland D., Sacchettini J.C.,
Jacobs W.R. Jr.;
"Overexpression of inhA, but not kasA, confers resistance to isoniazid
and ethionamide in Mycobacterium smegmatis, M. bovis BCG and M.
tuberculosis.";
Mol. Microbiol. 46:453-466(2002).
[8]
ENZYME REGULATION.
PubMed=14623976; DOI=10.1073/pnas.2235848100;
Rawat R., Whitty A., Tonge P.J.;
"The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA,
the Mycobacterium tuberculosis enoyl reductase: adduct affinity and
drug resistance.";
Proc. Natl. Acad. Sci. U.S.A. 100:13881-13886(2003).
[9]
IDENTIFICATION AS A DRUG TARGET [LARGE SCALE ANALYSIS].
PubMed=19099550; DOI=10.1186/1752-0509-2-109;
Raman K., Yeturu K., Chandra N.;
"targetTB: a target identification pipeline for Mycobacterium
tuberculosis through an interactome, reactome and genome-scale
structural analysis.";
BMC Syst. Biol. 2:109-109(2008).
[10]
PHOSPHORYLATION AT THR-266, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
PROPERTIES, AND ENZYME REGULATION.
STRAIN=H37Rv;
PubMed=20864541; DOI=10.1074/jbc.M110.143131;
Khan S., Nagarajan S.N., Parikh A., Samantaray S., Singh A., Kumar D.,
Roy R.P., Bhatt A., Nandicoori V.K.;
"Phosphorylation of enoyl-acyl carrier protein reductase InhA impacts
mycobacterial growth and survival.";
J. Biol. Chem. 285:37860-37871(2010).
[11]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
STRAIN=ATCC 25618 / H37Rv;
PubMed=21969609; DOI=10.1074/mcp.M111.011627;
Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B.,
Yadav A.K., Shrivastava P., Marimuthu A., Anand S., Sundaram H.,
Kingsbury R., Harsha H.C., Nair B., Prasad T.S., Chauhan D.S.,
Katoch K., Katoch V.M., Kumar P., Chaerkady R., Ramachandran S.,
Dash D., Pandey A.;
"Proteogenomic analysis of Mycobacterium tuberculosis by high
resolution mass spectrometry.";
Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
[12]
REVIEW.
PubMed=22283812; DOI=10.2174/156802612799984535;
Pan P., Tonge P.J.;
"Targeting InhA, the FASII enoyl-ACP reductase: SAR studies on novel
inhibitor scaffolds.";
Curr. Top. Med. Chem. 12:672-693(2012).
[13]
REVIEW, AND PATHWAY.
PubMed=25227413; DOI=10.1111/1574-6968.12597;
Duan X., Xiang X., Xie J.;
"Crucial components of Mycobacterium type II fatty acid biosynthesis
(Fas-II) and their inhibitors.";
FEMS Microbiol. Lett. 360:87-99(2014).
[14] {ECO:0000244|PDB:1ENY, ECO:0000244|PDB:1ENZ}
X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF WILD-TYPE AND MUTANT ALA-94
IN COMPLEX WITH NAD, MUTAGENESIS OF SER-94, AND DRUG RESISTANCE.
PubMed=7886450; DOI=10.1126/science.7886450;
Dessen A., Quemard A., Blanchard J.S., Jacobs W.R. Jr.,
Sacchettini J.C.;
"Crystal structure and function of the isoniazid target of
Mycobacterium tuberculosis.";
Science 267:1638-1641(1995).
[15] {ECO:0000244|PDB:1ZID}
X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 3-269 IN COMPLEX WITH
ISONICOTINIC-ACETYL-NICOTINAMIDE-ADENINE DINUCLEOTIDE INHIBITOR
(INH-NAD ADDUCT), ENZYME REGULATION, AND MECHANISM OF ACTION OF
ISONIAZID.
PubMed=9417034; DOI=10.1126/science.279.5347.98;
Rozwarski D.A., Grant G.A., Barton D.H.R., Jacobs W.R. Jr.,
Sacchettini J.C.;
"Modification of the NADH of the isoniazid target (InhA) from
Mycobacterium tuberculosis.";
Science 279:98-102(1998).
[16] {ECO:0000244|PDB:1BVR}
X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) IN COMPLEX WITH NAD AND A C16
FATTY ACYL SUBSTRATE, SUBUNIT, AND REACTION MECHANISM.
PubMed=10336454; DOI=10.1074/jbc.274.22.15582;
Rozwarski D.A., Vilcheze C., Sugantino M., Bittman R.,
Sacchettini J.C.;
"Crystal structure of the Mycobacterium tuberculosis enoyl-ACP
reductase, InhA, in complex with NAD+ and a C16 fatty acyl
substrate.";
J. Biol. Chem. 274:15582-15589(1999).
[17] {ECO:0000244|PDB:1P44, ECO:0000244|PDB:1P45}
X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) IN COMPLEXES WITH
5-{[4-(9H-FLUOREN-9-YL)PIPERAZIN-1-YL]CARBONYL}-1H-INDOLE INHIBITOR;
NAD AND TRICLOSAN, INHIBITOR SCREENING, AND ENZYME REGULATION.
PubMed=12606558; DOI=10.1074/jbc.M211968200;
Kuo M.R., Morbidoni H.R., Alland D., Sneddon S.F., Gourlie B.B.,
Staveski M.M., Leonard M., Gregory J.S., Janjigian A.D., Yee C.,
Musser J.M., Kreiswirth B., Iwamoto H., Perozzo R., Jacobs W.R. Jr.,
Sacchettini J.C., Fidock D.A.;
"Targeting tuberculosis and malaria through inhibition of enoyl
reductase: compound activity and structural data.";
J. Biol. Chem. 278:20851-20859(2003).
[18] {ECO:0000244|PDB:2B35, ECO:0000244|PDB:2B36, ECO:0000244|PDB:2B37}
X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) IN COMPLEXES WITH NAD;
5-OCTYL-2-PHENOXYPHENOL AND TRICLOSAN, AND ENZYME REGULATION.
PubMed=17163639; DOI=10.1021/cb0500042;
Sullivan T.J., Truglio J.J., Boyne M.E., Novichenok P., Zhang X.,
Stratton C.F., Li H.J., Kaur T., Amin A., Johnson F., Slayden R.A.,
Kisker C., Tonge P.J.;
"High affinity InhA inhibitors with activity against drug-resistant
strains of Mycobacterium tuberculosis.";
ACS Chem. Biol. 1:43-53(2006).
[19] {ECO:0000244|PDB:4TZK, ECO:0000244|PDB:4TZT, ECO:0000244|PDB:4U0J, ECO:0000244|PDB:4U0K}
X-RAY CRYSTALLOGRAPHY (1.62 ANGSTROMS) IN COMPLEXES WITH VARIOUS
PYRROLIDINE CARBOXAMIDES INHIBITORS AND NAD, INHIBITOR SCREENING, AND
ENZYME REGULATION.
PubMed=17034137; DOI=10.1021/jm060715y;
He X., Alian A., Stroud R., Ortiz de Montellano P.R.;
"Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl
carrier protein reductase from Mycobacterium tuberculosis.";
J. Med. Chem. 49:6308-6323(2006).
[20] {ECO:0000244|PDB:2AQ8, ECO:0000244|PDB:2AQH, ECO:0000244|PDB:2AQI, ECO:0000244|PDB:2AQK}
X-RAY CRYSTALLOGRAPHY (1.92 ANGSTROMS) OF WILD-TYPE AND MUTANTS
ALA-94; THR-47 AND VAL-21 IN COMPLEX WITH NAD, AND SUBUNIT.
PubMed=16647717; DOI=10.1016/j.jmb.2006.03.055;
Oliveira J.S., Pereira J.H., Canduri F., Rodrigues N.C.,
de Souza O.N., de Azevedo W.F. Jr., Basso L.A., Santos D.S.;
"Crystallographic and pre-steady-state kinetics studies on binding of
NADH to wild-type and isoniazid-resistant enoyl-ACP(CoA) reductase
enzymes from Mycobacterium tuberculosis.";
J. Mol. Biol. 359:646-666(2006).
[21] {ECO:0000244|PDB:2NV6}
X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 3-269 OF MUTANT ALA-94 IN
COMPLEX WITH ISONICOTINIC-ACETYL-NICOTINAMIDE-ADENINE DINUCLEOTIDE
INHIBITOR (INH-NAD ADDUCT), DRUG TARGET, DRUG RESISTANCE, AND
MUTAGENESIS OF SER-94.
STRAIN=H37Rv;
PubMed=16906155; DOI=10.1038/nm1466;
Vilcheze C., Wang F., Arai M., Hazbon M.H., Colangeli R., Kremer L.,
Weisbrod T.R., Alland D., Sacchettini J.C., Jacobs W.R. Jr.;
"Transfer of a point mutation in Mycobacterium tuberculosis inhA
resolves the target of isoniazid.";
Nat. Med. 12:1027-1029(2006).
[22] {ECO:0000244|PDB:2NSD}
X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) IN COMPLEX WITH
N-(4-METHYLBENZOYL)-4-BENZYLPIPERIDINE INHIBITOR AND NAD, INHIBITOR
SCREENING, AND ENZYME REGULATION.
PubMed=17723305; DOI=10.1016/j.bmc.2007.08.013;
He X., Alian A., Ortiz de Montellano P.R.;
"Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier
protein reductase InhA by arylamides.";
Bioorg. Med. Chem. 15:6649-6658(2007).
[23] {ECO:0000244|PDB:2PR2}
X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) IN COMPLEX WITH
(4S)-ISONICOTINIC-ACETYL-NICOTINAMIDE-ADENINE DINUCLEOTIDE PHOSPHATE
INHIBITOR (INH-NADP ADDUCT).
PubMed=17636923; DOI=10.1021/ja073160k;
Argyrou A., Vetting M.W., Blanchard J.S.;
"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. 129:9582-9583(2007).
[24] {ECO:0000244|PDB:2H9I, ECO:0000244|PDB:2NTJ}
X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) IN COMPLEXES WITH
(4S)-4-(2-PROPYLISONICOTINOYL)NICOTINAMIDE ADENINE DINUCLEOTIDE
(PTH-NAD ADDUCT) AND (4S)-4-(2-ETHYLISONICOTINOYL)NICOTINAMIDE ADENINE
DINUCLEOTIDE (ETH-NAD ADDUCT) INHIBITORS, DRUG TARGET, AND ENZYME
REGULATION.
PubMed=17227913; DOI=10.1084/jem.20062100;
Wang F., Langley R., Gulten G., Dover L.G., Besra G.S.,
Jacobs W.R. Jr., Sacchettini J.C.;
"Mechanism of thioamide drug action against tuberculosis and
leprosy.";
J. Exp. Med. 204:73-78(2007).
[25] {ECO:0000244|PDB:2IDZ, ECO:0000244|PDB:2IE0, ECO:0000244|PDB:2IEB, ECO:0000244|PDB:2IED}
X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF WILD-TYPE AND MUTANTS VAL-21
AND ALA-94 UNCOMPLEXED AND IN COMPLEX WITH
ISONICOTINIC-ACETYL-NICOTINAMIDE-ADENINE DINUCLEOTIDE INHIBITOR
(INH-NAD ADDUCT).
PubMed=17588773; DOI=10.1016/j.jsb.2007.04.009;
Dias M.V., Vasconcelos I.B., Prado A.M., Fadel V., Basso L.A.,
de Azevedo W.F. Jr., Santos D.S.;
"Crystallographic studies on the binding of isonicotinyl-NAD adduct to
wild-type and isoniazid resistant 2-trans-enoyl-ACP (CoA) reductase
from Mycobacterium tuberculosis.";
J. Struct. Biol. 159:369-380(2007).
[26] {ECO:0000244|PDB:3FNE, ECO:0000244|PDB:3FNF, ECO:0000244|PDB:3FNG, ECO:0000244|PDB:3FNH}
X-RAY CRYSTALLOGRAPHY (1.97 ANGSTROMS) IN COMPLEX WITH TRICLOSAN
DERIVATIVES INHIBITORS AND NAD, AND ENZYME REGULATION.
PubMed=19130456; DOI=10.1002/cmdc.200800261;
Freundlich J.S., Wang F., Vilcheze C., Gulten G., Langley R.,
Schiehser G.A., Jacobus D.P., Jacobs W.R. Jr., Sacchettini J.C.;
"Triclosan derivatives: towards potent inhibitors of drug-sensitive
and drug-resistant Mycobacterium tuberculosis.";
ChemMedChem 4:241-248(2009).
[27] {ECO:0000244|PDB:2X22, ECO:0000244|PDB:2X23}
X-RAY CRYSTALLOGRAPHY (1.81 ANGSTROMS) IN COMPLEX WITH
5-HEXYL-2-(2-METHYLPHENOXY)PHENOL INHIBITOR AND NAD, AND ENZYME
REGULATION.
PubMed=20200152; DOI=10.1074/jbc.M109.090373;
Luckner S.R., Liu N., am Ende C.W., Tonge P.J., Kisker C.;
"A slow, tight binding inhibitor of InhA, the enoyl-acyl carrier
protein reductase from Mycobacterium tuberculosis.";
J. Biol. Chem. 285:14330-14337(2010).
[28] {ECO:0000244|PDB:3OEW, ECO:0000244|PDB:3OEY, ECO:0000244|PDB:3OF2}
X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF WILD-TPYE AND MUTANTS
ASP-266 AND GLU-266 IN COMPLEX WITH NAD, PHOSPHORYLATION AT THR-266,
CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION,
AND MUTAGENESIS OF THR-266.
STRAIN=H37Rv;
PubMed=21143326; DOI=10.1111/j.1365-2958.2010.07446.x;
Molle V., Gulten G., Vilcheze C., Veyron-Churlet R., Zanella-Cleon I.,
Sacchettini J.C., Jacobs W.R. Jr., Kremer L.;
"Phosphorylation of InhA inhibits mycolic acid biosynthesis and growth
of Mycobacterium tuberculosis.";
Mol. Microbiol. 78:1591-1605(2010).
[29] {ECO:0000244|PDB:4DQU, ECO:0000244|PDB:4DRE, ECO:0000244|PDB:4DTI}
X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF WILD-TYPE AND MUTANTS ALA-94
AND GLY-148 IN COMPLEX WITH NADH, ENZYME REGULATION, CATALYTIC
ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF SER-94 AND
ASP-148.
STRAIN=H37Rv;
PubMed=22987724; DOI=10.1002/emmm.201201689;
Hartkoorn R.C., Sala C., Neres J., Pojer F., Magnet S., Mukherjee R.,
Uplekar S., Boy-Rottger S., Altmann K.H., Cole S.T.;
"Towards a new tuberculosis drug: pyridomycin - nature's isoniazid.";
EMBO Mol. Med. 4:1032-1042(2012).
[30] {ECO:0000244|PDB:4BQP, ECO:0000244|PDB:4BQR}
X-RAY CRYSTALLOGRAPHY (1.89 ANGSTROMS) IN COMPLEXES WITH
METHYL-THIAZOLE INHIBITORS AND NAD, AND ENZYME REGULATION.
PubMed=24107081; DOI=10.1021/jm4012033;
Shirude P.S., Madhavapeddi P., Naik M., Murugan K., Shinde V.,
Nandishaiah R., Bhat J., Kumar A., Hameed S., Holdgate G., Davies G.,
McMiken H., Hegde N., Ambady A., Venkatraman J., Panda M.,
Bandodkar B., Sambandamurthy V.K., Read J.A.;
"Methyl-thiazoles: a novel mode of inhibition with the potential to
develop novel inhibitors targeting InhA in Mycobacterium
tuberculosis.";
J. Med. Chem. 56:8533-8542(2013).
[31] {ECO:0000244|PDB:4OHU, ECO:0000244|PDB:4OXK, ECO:0000244|PDB:4OXN, ECO:0000244|PDB:4OXY, ECO:0000244|PDB:4OYR}
X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) IN COMPLEXES WITH VARIOUS ALKYL
DIPHENYL ETHER INHIBITORS AND NAD.
PubMed=24527857; DOI=10.1021/cb400896g;
Li H.J., Lai C.T., Pan P., Yu W., Liu N., Bommineni G.R.,
Garcia-Diaz M., Simmerling C., Tonge P.J.;
"A structural and energetic model for the slow-onset inhibition of the
Mycobacterium tuberculosis enoyl-ACP reductase InhA.";
ACS Chem. Biol. 9:986-993(2014).
[32]
X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) IN COMPLEX WITH
2-(2-CYANOPHENOXY)-5-HEXYLPHENOL INHIBITOR AND NAD, AND ENZYME
REGULATION.
PubMed=24616444; DOI=10.1002/cmdc.201300429;
Pan P., Knudson S.E., Bommineni G.R., Li H.J., Lai C.T., Liu N.,
Garcia-Diaz M., Simmerling C., Patil S.S., Slayden R.A., Tonge P.J.;
"Time-dependent diaryl ether inhibitors of InhA: structure-activity
relationship studies of enzyme inhibition, antibacterial activity, and
in vivo efficacy.";
ChemMedChem 9:776-791(2014).
[33] {ECO:0000244|PDB:4BGE, ECO:0000244|PDB:4BGI, ECO:0000244|PDB:4BII}
X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF WILD-TYPE AND MUTANT ALA-94
IN COMPLEXES WITH NAD; PYRIDOMYCIN AND PYRIDOMYCIN ANALOG OH141
INHIBITORS, AND ENZYME REGULATION.
PubMed=24292073; DOI=10.1038/nchembio.1405;
Hartkoorn R.C., Pojer F., Read J.A., Gingell H., Neres J.,
Horlacher O.P., Altmann K.H., Cole S.T.;
"Pyridomycin bridges the NADH- and substrate-binding pockets of the
enoyl reductase InhA.";
Nat. Chem. Biol. 10:96-98(2014).
[34] {ECO:0000244|PDB:4D0R, ECO:0000244|PDB:4D0S}
X-RAY CRYSTALLOGRAPHY (1.64 ANGSTROMS) IN COMPLEXES WITH PYRIDAZINONES
AND NAD.
Lange S.;
"Pyridazinones: a novel scaffold with excellent physicochemical
properties and safety profile for a clinically validated target of
Mycobacterium tuberculosis.";
Submitted (APR-2014) to the PDB data bank.
[35] {ECO:0000244|PDB:4UVD, ECO:0000244|PDB:4UVE, ECO:0000244|PDB:4UVG, ECO:0000244|PDB:4UVH, ECO:0000244|PDB:4UVI}
X-RAY CRYSTALLOGRAPHY (1.73 ANGSTROMS) IN COMPLEXES WITH VARIOUS
PYRIMIDINE ISOXAZOLES AND NAD.
Madhavapeddi P., Kale R.R., Cowen S.D., Ghorpade S.R., Davies G.,
Bellale E.V., Kale M.G., Srivastava A., Spadola L., Kawatkar A.,
Raichurkar A.V., Tonge M., Nandishaiah R., Guptha S., Narayan A.,
Gingell H., Plant D., Landge S., Menasinakai S., Prabhakar K.R.,
Achar V., Ambady A., Sambandamurthy V.K., Ramachandran V., Panduga V.,
Reddy J., Kumar C.N.N., Kaur P., Shandil R., Iyer P.S., Narayanan S.,
Read J.A.;
"Hitting the target in more than one way: novel, direct inhibitors of
Mycobacterium tuberculosis enoyl ACP reductase.";
Submitted (AUG-2014) to the PDB data bank.
[36] {ECO:0000244|PDB:5COQ, ECO:0000244|PDB:5CP8, ECO:0000244|PDB:5CPB}
X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF MUTANTS ALA-203 AND ALA-215
IN COMPLEX WITH DIARYL ETHERS AND NAD.
PubMed=26147157; DOI=10.1021/acs.biochem.5b00284;
Lai C.T., Li H.J., Yu W., Shah S., Bommineni G.R., Perrone V.,
Garcia-Diaz M., Tonge P.J., Simmerling C.;
"Rational modulation of the induced-fit conformational change for
slow-onset inhibition in Mycobacterium tuberculosis InhA.";
Biochemistry 54:4683-4691(2015).
[37] {ECO:0000244|PDB:4TRM, ECO:0000244|PDB:4TRN, ECO:0000244|PDB:4TRO}
X-RAY CRYSTALLOGRAPHY (1.40 ANGSTROMS) OF THE APO FORM AND IN
COMPLEXES WITH NADH AND THE INH-NAD ADDUCT INHIBITOR.
PubMed=25891098; DOI=10.1016/j.jsb.2015.04.008;
Chollet A., Mourey L., Lherbet C., Delbot A., Julien S., Baltas M.,
Bernadou J., Pratviel G., Maveyraud L., Bernardes-Genisson V.;
"Crystal structure of the enoyl-ACP reductase of Mycobacterium
tuberculosis (InhA) in the apo-form and in complex with the active
metabolite of isoniazid pre-formed by a biomimetic approach.";
J. Struct. Biol. 190:328-337(2015).
[38] {ECO:0000244|PDB:4R9R, ECO:0000244|PDB:4R9S}
X-RAY CRYSTALLOGRAPHY (2.90 ANGSTROMS) IN COMPLEXES WITH
4-HYDROXY-2-PYRIDONE INHIBITORS AND NAD, AND ENZYME REGULATION.
PubMed=25568071; DOI=10.1126/scitranslmed.3010597;
Manjunatha U.H., Rao S.P.S., Kondreddi R.R., Noble C.G., Camacho L.R.,
Tan B.H., Ng S.H., Ng P.S., Ma N.L., Lakshminarayana S.B., Herve M.,
Barnes S.W., Yu W., Kuhen K., Blasco F., Beer D., Walker J.R.,
Tonge P.J., Glynne R., Smith P.W., Diagana T.T.;
"Direct inhibitors of InhA are active against Mycobacterium
tuberculosis.";
Sci. Transl. Med. 7:269ra3-269ra3(2015).
[39] {ECO:0000244|PDB:4QXM}
X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) WITH A
N-BENZYL-4-((HETEROARYL)METHYL)BENZAMIDE INHIBITOR AND NAD, AND ENZYME
REGULATION.
PubMed=26934341; DOI=10.1002/cmdc.201600020;
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 J.C.,
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 11:687-701(2016).
[40]
X-RAY CRYSTALLOGRAPHY (2.91 ANGSTROMS) IN COMPLEX WITH THE THIADIAZOLE
INHIBITOR GSK625 AND NAD, AND ENZYME REGULATION.
PubMed=27428438; DOI=10.1016/j.ebiom.2016.05.006;
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 J.D., Garcia-Bustos J.F., Lavandera J.L.,
Sacchettini J.C., Jimenez M.S., Martin-Casabona N., Castro-Pichel J.,
Mendoza-Losana A.;
"Antitubercular drugs for an old target: GSK693 as a promising InhA
direct inhibitor.";
EBioMedicine 8:291-301(2016).
-!- 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). {ECO:0000269|PubMed:7599116,
ECO:0000303|PubMed:25227413}.
-!- FUNCTION: Is the primary target of the first-line antitubercular
drug isoniazid (INH) and of the second-line drug ethionamide (ETH)
(PubMed:8284673, PubMed:12406221, PubMed:16906155,
PubMed:17227913). Overexpressed inhA confers INH and ETH
resistance to M.tuberculosis (PubMed:12406221). The mechanism of
isoniazid action against InhA is covalent attachment of the
activated form of the drug to the nicotinamide ring of NAD and
binding of the INH-NAD adduct to the active site of InhA
(PubMed:9417034, PubMed:16906155). Similarly, the ETH-NAD adduct
binds InhA (PubMed:17227913). {ECO:0000269|PubMed:12406221,
ECO:0000269|PubMed:16906155, ECO:0000269|PubMed:17227913,
ECO:0000269|PubMed:9417034, ECO:0000305|PubMed:8284673}.
-!- CATALYTIC ACTIVITY: An acyl-[acyl-carrier protein] + NAD(+) = a
trans-2,3-dehydroacyl-[acyl-carrier protein] + NADH.
{ECO:0000269|PubMed:10521269, ECO:0000269|PubMed:20864541,
ECO:0000269|PubMed:21143326, ECO:0000269|PubMed:22987724,
ECO:0000269|PubMed:7599116}.
-!- ENZYME REGULATION: InhA activity is controlled via
phosphorylation: phosphorylation on Thr-266 decreases InhA
activity (5-fold reduction) and likely negatively regulates
biosynthesis of mycolic acids and growth of the bacterium
(PubMed:20864541, PubMed:21143326). The antitubercular pro-drug
isoniazid (INH) is oxidatively activated by the catalase-
peroxidase KatG and then covalently binds NAD to form an adduct
that inhibits the activity of InhA (Ref.5, PubMed:14623976,
PubMed:9417034). The inhibitory adduct is the isonicotinic-acyl-
NADH where the isonicotinic-acyl group replaces the 4S (and not
the 4R) hydrogen of NADH (PubMed:9417034). Similarly, the
antitubercular pro-drugs ethionamide (ETH) and prothionamide (PTH)
are activated by the flavoprotein monooxygenase EthA, and forms an
adduct with NAD (ETH-NAD and PTH-NAD, respectively) that is a
tight-binding inhibitor of InhA (PubMed:17227913). Is inhibited by
triclosan and derivatives, pyrazole derivative Genz-8575, indole-
5-amide Genz-10850, alkyl diphenyl ethers, pyrrolidine
carboxamides, arylamides, pyridomycin, methyl-thiazoles, 4-
hydroxy-2-pyridones, and N-benzyl-4-((heteroaryl)methyl)benzamides
(PubMed:12606558, PubMed:17163639, PubMed:17034137,
PubMed:17723305, PubMed:19130456, PubMed:20200152,
PubMed:22987724, PubMed:24107081, PubMed:24616444,
PubMed:25568071). Pyridomycin shows a unique mode of InhA
inhibition by simultaneously blocking parts of the NADH and the
lipid substrate-binding pocket of InhA (PubMed:24292073). Is also
inhibited by thiadiazole compounds, that have very attractive
antitubercular properties (PubMed:27428438).
{ECO:0000269|PubMed:12606558, ECO:0000269|PubMed:14623976,
ECO:0000269|PubMed:17034137, ECO:0000269|PubMed:17163639,
ECO:0000269|PubMed:17227913, ECO:0000269|PubMed:17723305,
ECO:0000269|PubMed:19130456, ECO:0000269|PubMed:20200152,
ECO:0000269|PubMed:20864541, ECO:0000269|PubMed:22987724,
ECO:0000269|PubMed:24107081, ECO:0000269|PubMed:24292073,
ECO:0000269|PubMed:24616444, ECO:0000269|PubMed:25568071,
ECO:0000269|PubMed:26934341, ECO:0000269|PubMed:27428438,
ECO:0000269|PubMed:9417034, ECO:0000269|Ref.5,
ECO:0000305|PubMed:21143326}.
-!- BIOPHYSICOCHEMICAL PROPERTIES:
Kinetic parameters:
KM=2.0 uM for 2-trans-octenoyl-ACP (at pH 6.8 and 25 degrees
Celsius) {ECO:0000269|PubMed:7599116};
KM=8.1 uM for NADH (at pH 6.8 and 25 degrees Celsius)
{ECO:0000269|PubMed:7599116};
KM=66 uM for NADH (at pH 6.8 and 25 degrees Celsius)
{ECO:0000269|PubMed:10521269};
KM=19.1 uM for NADH (at pH 6.8) {ECO:0000269|PubMed:20864541};
KM=13.5 uM for NADH (at pH 6.8 and 25 degrees Celsius)
{ECO:0000269|PubMed:22987724};
KM=467 uM for 2-trans-octenoyl-CoA (at pH 6.8 and 25 degrees
Celsius) {ECO:0000269|PubMed:7599116};
KM=528 uM for 2-trans-octenoyl-CoA (at pH 6.8)
{ECO:0000269|PubMed:20864541};
KM=48 uM for 2-trans-dodecenoyl-CoA (at pH 6.8 and 25 degrees
Celsius) {ECO:0000269|PubMed:7599116};
KM=27 uM for 2-trans-dodecenoyl-CoA (at pH 6.8 and 25 degrees
Celsius) {ECO:0000269|PubMed:10521269};
KM=40.9 uM for 2-trans-dodecenoyl-CoA (at pH 7.5 and 25 degrees
Celsius) {ECO:0000269|PubMed:21143326};
KM=1.5 uM for 2-trans-hexadecenoyl-CoA (at pH 6.8 and 25 degrees
Celsius) {ECO:0000269|PubMed:7599116};
Vmax=2.2 umol/min/mg enzyme for the reduction of 2-trans-
octenoyl-ACP (at pH 6.8 and 25 degrees Celsius)
{ECO:0000269|PubMed:7599116};
Vmax=3.6 umol/min/mg enzyme for the reduction of 2-trans-
octenoyl-CoA (at pH 6.8 and 25 degrees Celsius)
{ECO:0000269|PubMed:7599116};
Vmax=0.52 umol/min/mg enzyme for the reduction of 2-trans-
octenoyl-CoA (at pH 6.8 and 25 degrees Celsius)
{ECO:0000269|PubMed:22987724};
Vmax=15.3 umol/min/mg enzyme for the reduction of 2-trans-
octenoyl-CoA (at pH 6.8) {ECO:0000269|PubMed:20864541};
Vmax=5.8 umol/min/mg enzyme for the reduction of 2-trans-
dodecenoyl-CoA (at pH 6.8 and 25 degrees Celsius)
{ECO:0000269|PubMed:7599116};
Vmax=11.4 umol/min/mg enzyme for the reduction of 2-trans-
dodecenoyl-CoA (at pH 7.5 and 25 degrees Celsius)
{ECO:0000269|PubMed:21143326};
Vmax=4.5 umol/min/mg enzyme for the reduction of 2-trans-
hexadecenoyl-CoA (at pH 6.8 and 25 degrees Celsius)
{ECO:0000269|PubMed:7599116};
Note=kcat is 320.4 min(-1) for the reduction of 2-trans-
dodecenoyl-CoA (at pH 7.5 and 25 degrees Celsius)
(PubMed:21143326). kcat is 278 min(-1) for the reduction of 2-
trans-dodecenoyl-CoA (at pH 6.8 and 25 degrees Celsius)
(PubMed:10521269). {ECO:0000269|PubMed:10521269,
ECO:0000269|PubMed:21143326};
-!- PATHWAY: Lipid metabolism; mycolic acid biosynthesis.
{ECO:0000303|PubMed:25227413}.
-!- SUBUNIT: Homodimer (PubMed:7599116). Homotetramer
(PubMed:10336454, PubMed:16647717). {ECO:0000269|PubMed:10336454,
ECO:0000269|PubMed:16647717, ECO:0000269|PubMed:7599116}.
-!- PTM: Is phosphorylated on Thr-266 in vivo. In vitro, can be
phosphorylated by multiple Ser/Thr protein kinases (STPK) such as
PknA, PknB, PknE, PknH and PknL. Phosphorylation decreases
enzymatic activity. {ECO:0000269|PubMed:20864541,
ECO:0000269|PubMed:21143326}.
-!- MISCELLANEOUS: Was identified as a high-confidence drug target.
{ECO:0000305|PubMed:19099550}.
-!- MISCELLANEOUS: Many isoniazid- and ethionamide-resistant clinical
isolates contain mutations within the inhA locus. Resistance to
isoniazid and ethionamide can be conferred by the single
substitution of alanine for serine 94; this drug resistance seems
to be directly related to a perturbation in the hydrogen-bonding
network that decreases the binding of NADH and the INH-NAD adduct.
{ECO:0000269|PubMed:16906155, ECO:0000305|PubMed:7886450}.
-!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases
(SDR) family. FabI subfamily. {ECO:0000305}.
-----------------------------------------------------------------------
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EMBL; U02492; AAC43210.1; -; Unassigned_DNA.
EMBL; AY155363; AAN75060.1; -; Genomic_DNA.
EMBL; AL123456; CCP44244.1; -; Genomic_DNA.
PIR; G70710; G70710.
RefSeq; NP_216000.1; NC_000962.3.
RefSeq; WP_003407553.1; NZ_KK339370.1.
PDB; 1BVR; X-ray; 2.80 A; A/B/C/D/E/F=2-269.
PDB; 1ENY; X-ray; 2.20 A; A=3-269.
PDB; 1ENZ; X-ray; 2.70 A; A=3-269.
PDB; 1P44; X-ray; 2.70 A; A/B/C/D/E/F=1-269.
PDB; 1P45; X-ray; 2.60 A; A/B=1-269.
PDB; 1ZID; X-ray; 2.70 A; A=3-269.
PDB; 2AQ8; X-ray; 1.92 A; A=1-269.
PDB; 2AQH; X-ray; 2.01 A; A=1-269.
PDB; 2AQI; X-ray; 2.20 A; A=1-269.
PDB; 2AQK; X-ray; 2.30 A; A=1-269.
PDB; 2B35; X-ray; 2.30 A; A/B/C/D/E/F=1-269.
PDB; 2B36; X-ray; 2.80 A; A/B/C/D/E/F=1-269.
PDB; 2B37; X-ray; 2.60 A; A/B/C/D/E/F=1-269.
PDB; 2H9I; X-ray; 2.20 A; A=2-269.
PDB; 2IDZ; X-ray; 2.00 A; A=2-269.
PDB; 2IE0; X-ray; 2.20 A; A=2-269.
PDB; 2IEB; X-ray; 2.20 A; A=2-269.
PDB; 2IED; X-ray; 2.14 A; A/B/C/D=2-269.
PDB; 2NSD; X-ray; 1.90 A; A/B=1-269.
PDB; 2NTJ; X-ray; 2.50 A; A/B=3-269.
PDB; 2NV6; X-ray; 1.90 A; A=3-269.
PDB; 2PR2; X-ray; 2.50 A; A=1-269.
PDB; 2X22; X-ray; 2.10 A; A/B=1-269.
PDB; 2X23; X-ray; 1.81 A; A/B/E/G=1-269.
PDB; 3FNE; X-ray; 1.98 A; A/B/C/D=1-269.
PDB; 3FNF; X-ray; 2.30 A; A/B/C/D=1-269.
PDB; 3FNG; X-ray; 1.97 A; A=1-269.
PDB; 3FNH; X-ray; 2.80 A; A=1-269.
PDB; 3OEW; X-ray; 2.20 A; A=1-269.
PDB; 3OEY; X-ray; 2.00 A; A=1-269.
PDB; 3OF2; X-ray; 2.00 A; A=1-269.
PDB; 4BGE; X-ray; 2.25 A; A/B/C/D/E/F=1-269.
PDB; 4BGI; X-ray; 2.09 A; A/B/C/D/E/F=2-269.
PDB; 4BII; X-ray; 1.95 A; A/B/C/D=1-269.
PDB; 4BQP; X-ray; 1.89 A; A/B/C/D/E/F=1-269.
PDB; 4BQR; X-ray; 2.05 A; A/B/C/D=1-269.
PDB; 4COD; X-ray; 2.40 A; B/D/F/H=1-269.
PDB; 4D0R; X-ray; 2.75 A; A=1-269.
PDB; 4D0S; X-ray; 1.64 A; A/B/C/D=1-269.
PDB; 4DQU; X-ray; 2.45 A; A=1-269.
PDB; 4DRE; X-ray; 2.40 A; A=1-269.
PDB; 4DTI; X-ray; 1.90 A; A=1-269.
PDB; 4OHU; X-ray; 1.60 A; A/B/C/D=1-269.
PDB; 4OIM; X-ray; 1.85 A; A=1-269.
PDB; 4OXK; X-ray; 1.84 A; A/B/C/D=1-269.
PDB; 4OXN; X-ray; 2.29 A; A/B=1-269.
PDB; 4OXY; X-ray; 2.35 A; A/B/C/D=1-269.
PDB; 4OYR; X-ray; 2.30 A; A/B/C/D=1-269.
PDB; 4QXM; X-ray; 2.20 A; A/C/E/G=1-269.
PDB; 4R9R; X-ray; 2.90 A; A/C/E/G=1-269.
PDB; 4R9S; X-ray; 3.20 A; A/C/E/G=1-269.
PDB; 4TRJ; X-ray; 1.73 A; A=1-269.
PDB; 4TRM; X-ray; 1.80 A; A/B/C/D/E/F=1-269.
PDB; 4TRN; X-ray; 1.95 A; A=1-269.
PDB; 4TRO; X-ray; 1.40 A; A=1-269.
PDB; 4TZK; X-ray; 1.62 A; A=1-269.
PDB; 4TZT; X-ray; 1.86 A; A=1-269.
PDB; 4U0J; X-ray; 1.62 A; A=1-269.
PDB; 4U0K; X-ray; 1.90 A; A=1-269.
PDB; 4UVD; X-ray; 1.82 A; A=1-269.
PDB; 4UVE; X-ray; 1.99 A; A=1-269.
PDB; 4UVG; X-ray; 1.92 A; A=1-269.
PDB; 4UVH; X-ray; 1.89 A; A/B/C/D=1-269.
PDB; 4UVI; X-ray; 1.73 A; A/B/C/D=1-269.
PDB; 5COQ; X-ray; 2.30 A; A/B/C/D=1-269.
PDB; 5CP8; X-ray; 2.40 A; A=1-269.
PDB; 5CPB; X-ray; 2.00 A; A/B/C/D/E/F=1-269.
PDB; 5CPF; X-ray; 3.41 A; A/B/C/D=1-269.
PDB; 5G0S; X-ray; 1.74 A; A/B/C/D=1-269.
PDB; 5G0T; X-ray; 1.54 A; A/B/C/D=1-269.
PDB; 5G0U; X-ray; 1.73 A; A/B/C/D=1-269.
PDB; 5G0V; X-ray; 1.79 A; A/B/C/D=1-269.
PDB; 5G0W; X-ray; 1.79 A; A/B/C/D=1-269.
PDB; 5JFO; X-ray; 2.91 A; A/B/C/D=1-269.
PDB; 5MTP; X-ray; 2.00 A; A/B/C/D/E/F/G/H=1-269.
PDB; 5MTQ; X-ray; 2.60 A; A/B/C/D/E/F/G/H=1-269.
PDB; 5MTR; X-ray; 2.00 A; A/B/C/D/E/F/G/H=1-269.
PDB; 5UGS; X-ray; 2.80 A; A/B/C/D/E/G=1-269.
PDB; 5UGT; X-ray; 2.60 A; A/B/E/G=1-269.
PDB; 5UGU; X-ray; 1.95 A; A=1-269.
PDBsum; 1BVR; -.
PDBsum; 1ENY; -.
PDBsum; 1ENZ; -.
PDBsum; 1P44; -.
PDBsum; 1P45; -.
PDBsum; 1ZID; -.
PDBsum; 2AQ8; -.
PDBsum; 2AQH; -.
PDBsum; 2AQI; -.
PDBsum; 2AQK; -.
PDBsum; 2B35; -.
PDBsum; 2B36; -.
PDBsum; 2B37; -.
PDBsum; 2H9I; -.
PDBsum; 2IDZ; -.
PDBsum; 2IE0; -.
PDBsum; 2IEB; -.
PDBsum; 2IED; -.
PDBsum; 2NSD; -.
PDBsum; 2NTJ; -.
PDBsum; 2NV6; -.
PDBsum; 2PR2; -.
PDBsum; 2X22; -.
PDBsum; 2X23; -.
PDBsum; 3FNE; -.
PDBsum; 3FNF; -.
PDBsum; 3FNG; -.
PDBsum; 3FNH; -.
PDBsum; 3OEW; -.
PDBsum; 3OEY; -.
PDBsum; 3OF2; -.
PDBsum; 4BGE; -.
PDBsum; 4BGI; -.
PDBsum; 4BII; -.
PDBsum; 4BQP; -.
PDBsum; 4BQR; -.
PDBsum; 4COD; -.
PDBsum; 4D0R; -.
PDBsum; 4D0S; -.
PDBsum; 4DQU; -.
PDBsum; 4DRE; -.
PDBsum; 4DTI; -.
PDBsum; 4OHU; -.
PDBsum; 4OIM; -.
PDBsum; 4OXK; -.
PDBsum; 4OXN; -.
PDBsum; 4OXY; -.
PDBsum; 4OYR; -.
PDBsum; 4QXM; -.
PDBsum; 4R9R; -.
PDBsum; 4R9S; -.
PDBsum; 4TRJ; -.
PDBsum; 4TRM; -.
PDBsum; 4TRN; -.
PDBsum; 4TRO; -.
PDBsum; 4TZK; -.
PDBsum; 4TZT; -.
PDBsum; 4U0J; -.
PDBsum; 4U0K; -.
PDBsum; 4UVD; -.
PDBsum; 4UVE; -.
PDBsum; 4UVG; -.
PDBsum; 4UVH; -.
PDBsum; 4UVI; -.
PDBsum; 5COQ; -.
PDBsum; 5CP8; -.
PDBsum; 5CPB; -.
PDBsum; 5CPF; -.
PDBsum; 5G0S; -.
PDBsum; 5G0T; -.
PDBsum; 5G0U; -.
PDBsum; 5G0V; -.
PDBsum; 5G0W; -.
PDBsum; 5JFO; -.
PDBsum; 5MTP; -.
PDBsum; 5MTQ; -.
PDBsum; 5MTR; -.
PDBsum; 5UGS; -.
PDBsum; 5UGT; -.
PDBsum; 5UGU; -.
ProteinModelPortal; P9WGR1; -.
SMR; P9WGR1; -.
STRING; 83332.Rv1484; -.
BindingDB; P9WGR1; -.
ChEMBL; CHEMBL1849; -.
SwissLipids; SLP:000000967; -.
iPTMnet; P9WGR1; -.
PaxDb; P9WGR1; -.
EnsemblBacteria; CCP44244; CCP44244; Rv1484.
GeneID; 886523; -.
KEGG; mtu:Rv1484; -.
TubercuList; Rv1484; -.
eggNOG; ENOG4105CSJ; Bacteria.
eggNOG; COG0623; LUCA.
KO; K11611; -.
OMA; GILDMIH; -.
PhylomeDB; P9WGR1; -.
UniPathway; UPA00915; -.
Proteomes; UP000001584; Chromosome.
GO; GO:0005618; C:cell wall; IDA:MTBBASE.
GO; GO:0005886; C:plasma membrane; IDA:MTBBASE.
GO; GO:0004318; F:enoyl-[acyl-carrier-protein] reductase (NADH) activity; IDA:MTBBASE.
GO; GO:0005504; F:fatty acid binding; IDA:MTBBASE.
GO; GO:0070403; F:NAD+ binding; IDA:MTBBASE.
GO; GO:0030497; P:fatty acid elongation; IMP:MTBBASE.
GO; GO:0071768; P:mycolic acid biosynthetic process; IDA:MTBBASE.
GO; GO:0046677; P:response to antibiotic; IEA:UniProtKB-KW.
InterPro; IPR014358; Enoyl-ACP_Rdtase_NADH.
InterPro; IPR036291; NAD(P)-bd_dom_sf.
PANTHER; PTHR43159:SF2; PTHR43159:SF2; 1.
PIRSF; PIRSF000094; Enoyl-ACP_rdct; 1.
SUPFAM; SSF51735; SSF51735; 1.
1: Evidence at protein level;
3D-structure; Antibiotic resistance; Complete proteome;
Fatty acid biosynthesis; Fatty acid metabolism; Lipid biosynthesis;
Lipid metabolism; NAD; Oxidoreductase; Phosphoprotein;
Reference proteome.
CHAIN 1 269 Enoyl-[acyl-carrier-protein] reductase
[NADH].
/FTId=PRO_0000054916.
NP_BIND 20 21 NAD. {ECO:0000244|PDB:1BVR,
ECO:0000244|PDB:1ENY,
ECO:0000244|PDB:2AQ8,
ECO:0000269|PubMed:10336454,
ECO:0000269|PubMed:16647717,
ECO:0000269|PubMed:7886450}.
NP_BIND 64 65 NAD. {ECO:0000244|PDB:1BVR,
ECO:0000244|PDB:1ENY,
ECO:0000244|PDB:2AQ8,
ECO:0000269|PubMed:10336454,
ECO:0000269|PubMed:16647717,
ECO:0000269|PubMed:7886450}.
NP_BIND 95 96 NAD. {ECO:0000244|PDB:1BVR,
ECO:0000244|PDB:1ENY,
ECO:0000244|PDB:2AQ8,
ECO:0000269|PubMed:10336454,
ECO:0000269|PubMed:16647717,
ECO:0000269|PubMed:7886450}.
BINDING 158 158 Substrate. {ECO:0000269|PubMed:10336454}.
BINDING 165 165 NAD. {ECO:0000244|PDB:1BVR,
ECO:0000244|PDB:1ENY,
ECO:0000244|PDB:2AQ8,
ECO:0000269|PubMed:10336454,
ECO:0000269|PubMed:16647717,
ECO:0000269|PubMed:7886450}.
BINDING 194 194 NAD; via amide nitrogen and carbonyl
oxygen. {ECO:0000244|PDB:1BVR,
ECO:0000244|PDB:1ENY,
ECO:0000244|PDB:2AQ8,
ECO:0000269|PubMed:10336454,
ECO:0000269|PubMed:16647717,
ECO:0000269|PubMed:7886450}.
SITE 149 149 May act as an intermediate that passes
the hydride ion from NADH to the
substrate. {ECO:0000305|PubMed:10336454}.
SITE 158 158 Transition state stabilizer.
{ECO:0000305|PubMed:10521269}.
MOD_RES 266 266 Phosphothreonine.
{ECO:0000269|PubMed:20864541,
ECO:0000269|PubMed:21143326}.
MUTAGEN 94 94 S->A: Confers INH and ETH resistance. The
mutant is 17 times more resistant to
inhibition by the INH-NAD adduct. 5- to
6-fold decrease in affinity for NADH that
results from a perturbation in the
hydrogen-bonding network that stabilizes
NADH binding. Nearly no effect on the
velocity of the enzyme. Has no impact on
the susceptibility to pyridomycin.
{ECO:0000269|PubMed:16906155,
ECO:0000269|PubMed:22987724,
ECO:0000269|PubMed:7599116,
ECO:0000269|PubMed:7886450}.
MUTAGEN 148 148 D->G: Confers pyridomycin resistance. Has
no impact on the susceptibility to
isoniazid and moxifloxacin. 14-fold
decrease in NADH affinity, while no
effect on catalytic activity.
{ECO:0000269|PubMed:22987724}.
MUTAGEN 158 158 Y->A: 1500-fold decrease in catalytic
activity while no effect on lipid
substrate affinity.
{ECO:0000269|PubMed:10521269}.
MUTAGEN 158 158 Y->F: 24-fold decrease in catalytic
activity while no effect on lipid
substrate affinity.
{ECO:0000269|PubMed:10521269}.
MUTAGEN 158 158 Y->S: No effect on catalytic activity.
{ECO:0000269|PubMed:10521269}.
MUTAGEN 165 165 K->A,M: Loss of enzyme's ability to bind
NADH. {ECO:0000269|PubMed:10521269}.
MUTAGEN 165 165 K->Q,R: No effect on the enzyme's
catalytic ability or on its ability to
bind NADH. {ECO:0000269|PubMed:10521269}.
MUTAGEN 266 266 T->A: No effect on catalytic activity.
Loss of phosphorylation. Does not alter
growth of M.tuberculosis.
{ECO:0000269|PubMed:21143326}.
MUTAGEN 266 266 T->D,E: Severely impairs catalytic
activity, as a consequence of a reduced
binding affinity to NADH. These single
point mutations are lethal to
M.tuberculosis. These mutants fail to
complement growth and mycolic acid
defects of an inhA-thermosensitive
M.smegmatis strain, in a similar manner
to what is observed following isoniazid
treatment. {ECO:0000269|PubMed:21143326}.
TURN 4 7 {ECO:0000244|PDB:4TRO}.
STRAND 9 13 {ECO:0000244|PDB:4TRO}.
STRAND 16 20 {ECO:0000244|PDB:2IED}.
HELIX 21 31 {ECO:0000244|PDB:4TRO}.
STRAND 35 40 {ECO:0000244|PDB:4TRO}.
HELIX 44 51 {ECO:0000244|PDB:4TRO}.
STRAND 54 56 {ECO:0000244|PDB:4TRO}.
STRAND 60 62 {ECO:0000244|PDB:4TRO}.
HELIX 68 82 {ECO:0000244|PDB:4TRO}.
STRAND 88 93 {ECO:0000244|PDB:4TRO}.
HELIX 100 102 {ECO:0000244|PDB:4TRO}.
STRAND 103 106 {ECO:0000244|PDB:5G0T}.
HELIX 108 110 {ECO:0000244|PDB:4TRO}.
HELIX 113 123 {ECO:0000244|PDB:4TRO}.
HELIX 125 134 {ECO:0000244|PDB:4TRO}.
HELIX 135 137 {ECO:0000244|PDB:4TRO}.
STRAND 138 148 {ECO:0000244|PDB:4TRO}.
STRAND 152 154 {ECO:0000244|PDB:5G0T}.
TURN 156 158 {ECO:0000244|PDB:4TRO}.
HELIX 159 180 {ECO:0000244|PDB:4TRO}.
TURN 181 183 {ECO:0000244|PDB:4TRO}.
STRAND 185 191 {ECO:0000244|PDB:4TRO}.
HELIX 197 203 {ECO:0000244|PDB:4TRO}.
TURN 204 207 {ECO:0000244|PDB:4TRO}.
HELIX 209 225 {ECO:0000244|PDB:4TRO}.
HELIX 236 246 {ECO:0000244|PDB:4TRO}.
STRAND 247 249 {ECO:0000244|PDB:4TRO}.
STRAND 255 261 {ECO:0000244|PDB:4TRO}.
HELIX 264 266 {ECO:0000244|PDB:4TRO}.
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


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