INHA_MYCTU
ID INHA_MYCTU Reviewed; 269 AA.
AC P9WGR1; 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 54.
DE RecName: Full=Enoyl-[acyl-carrier-protein] reductase [NADH] {ECO:0000303|PubMed:7599116};
DE Short=ENR {ECO:0000303|PubMed:12606558};
DE Short=Enoyl-ACP reductase {ECO:0000303|PubMed:7599116};
DE EC=1.3.1.9 {ECO:0000269|PubMed:7599116};
DE AltName: Full=FAS-II enoyl-ACP reductase {ECO:0000305};
DE AltName: Full=NADH-dependent 2-trans-enoyl-ACP reductase {ECO:0000305|PubMed:7599116};
GN Name=inhA {ECO:0000303|PubMed:8284673}; OrderedLocusNames=Rv1484;
GN ORFNames=MTCY277.05;
OS Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83332;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], DRUG TARGET, AND DRUG RESISTANCE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=8284673; DOI=10.1126/science.8284673;
RA Banerjee A., Dubnau E., Quemard A., Balasubramanian V., Um K.S., Wilson T.,
RA Collins D., de Lisle G., Jacobs W.R. Jr.;
RT "inhA, a gene encoding a target for isoniazid and ethionamide in
RT Mycobacterium tuberculosis.";
RL Science 263:227-230(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=TCVGH1;
RA Shi Z.-Y., Lee K., Hu C.-H., Liu M.-F.;
RT "The allelic profiles of multidrug-resistant Mycobacterium tuberculosis
RT isolates from Taiwan.";
RL Submitted (SEP-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=9634230; DOI=10.1038/31159;
RA Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA Barrell B.G.;
RT "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT genome sequence.";
RL Nature 393:537-544(1998).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBSTRATE
RP SPECIFICITY, REACTION MECHANISM, SUBUNIT, AND MUTAGENESIS OF SER-94.
RC STRAIN=H37Rv;
RX PubMed=7599116; DOI=10.1021/bi00026a004;
RA Quemard A., Sacchettini J.C., Dessen A., Vilcheze C., Bittman R.,
RA Jacobs W.R. Jr., Blanchard J.S.;
RT "Enzymatic characterization of the target for isoniazid in Mycobacterium
RT tuberculosis.";
RL Biochemistry 34:8235-8241(1995).
RN [5]
RP ACTIVITY REGULATION.
RX DOI=10.1021/ja962035y;
RA Basso L.A., Zheng R., Blanchard J.S.;
RT "Kinetics of inactivation of WT and C243S mutant of Mycobacterium
RT tuberculosis enoyl reductase by activated isoniazid.";
RL J. Am. Chem. Soc. 118:11301-11302(1996).
RN [6]
RP CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, REACTION MECHANISM, AND
RP MUTAGENESIS OF TYR-158 AND LYS-165.
RX PubMed=10521269; DOI=10.1021/bi990529c;
RA Parikh S., Moynihan D.P., Xiao G., Tonge P.J.;
RT "Roles of tyrosine 158 and lysine 165 in the catalytic mechanism of InhA,
RT the enoyl-ACP reductase from Mycobacterium tuberculosis.";
RL Biochemistry 38:13623-13634(1999).
RN [7]
RP DRUG TARGET, AND DRUG RESISTANCE.
RC STRAIN=H37Rv;
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).
RN [8]
RP ACTIVITY REGULATION.
RX PubMed=14623976; DOI=10.1073/pnas.2235848100;
RA Rawat R., Whitty A., Tonge P.J.;
RT "The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the
RT Mycobacterium tuberculosis enoyl reductase: adduct affinity and drug
RT resistance.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:13881-13886(2003).
RN [9]
RP IDENTIFICATION AS A DRUG TARGET [LARGE SCALE ANALYSIS].
RX PubMed=19099550; DOI=10.1186/1752-0509-2-109;
RA Raman K., Yeturu K., Chandra N.;
RT "targetTB: a target identification pipeline for Mycobacterium tuberculosis
RT through an interactome, reactome and genome-scale structural analysis.";
RL BMC Syst. Biol. 2:109-109(2008).
RN [10]
RP PHOSPHORYLATION AT THR-266, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, AND ACTIVITY REGULATION.
RC STRAIN=H37Rv;
RX PubMed=20864541; DOI=10.1074/jbc.m110.143131;
RA Khan S., Nagarajan S.N., Parikh A., Samantaray S., Singh A., Kumar D.,
RA Roy R.P., Bhatt A., Nandicoori V.K.;
RT "Phosphorylation of enoyl-acyl carrier protein reductase InhA impacts
RT mycobacterial growth and survival.";
RL J. Biol. Chem. 285:37860-37871(2010).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21969609; DOI=10.1074/mcp.m111.011627;
RA Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT mass spectrometry.";
RL Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN [12]
RP REVIEW.
RX PubMed=22283812; DOI=10.2174/156802612799984535;
RA Pan P., Tonge P.J.;
RT "Targeting InhA, the FASII enoyl-ACP reductase: SAR studies on novel
RT inhibitor scaffolds.";
RL Curr. Top. Med. Chem. 12:672-693(2012).
RN [13]
RP REVIEW, AND PATHWAY.
RX PubMed=25227413; DOI=10.1111/1574-6968.12597;
RA Duan X., Xiang X., Xie J.;
RT "Crucial components of Mycobacterium type II fatty acid biosynthesis (Fas-
RT II) and their inhibitors.";
RL FEMS Microbiol. Lett. 360:87-99(2014).
RN [14] {ECO:0007744|PDB:1ENY, ECO:0007744|PDB:1ENZ}
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF WILD-TYPE AND MUTANT ALA-94 IN
RP COMPLEX WITH NAD, MUTAGENESIS OF SER-94, AND DRUG RESISTANCE.
RX PubMed=7886450; DOI=10.1126/science.7886450;
RA Dessen A., Quemard A., Blanchard J.S., Jacobs W.R. Jr., Sacchettini J.C.;
RT "Crystal structure and function of the isoniazid target of Mycobacterium
RT tuberculosis.";
RL Science 267:1638-1641(1995).
RN [15] {ECO:0007744|PDB:1ZID}
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 3-269 IN COMPLEX WITH
RP ISONICOTINIC-ACETYL-NICOTINAMIDE-ADENINE DINUCLEOTIDE INHIBITOR (INH-NAD
RP ADDUCT), ACTIVITY REGULATION, AND MECHANISM OF ACTION OF ISONIAZID.
RX PubMed=9417034; DOI=10.1126/science.279.5347.98;
RA Rozwarski D.A., Grant G.A., Barton D.H.R., Jacobs W.R. Jr.,
RA Sacchettini J.C.;
RT "Modification of the NADH of the isoniazid target (InhA) from Mycobacterium
RT tuberculosis.";
RL Science 279:98-102(1998).
RN [16] {ECO:0007744|PDB:1BVR}
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) IN COMPLEX WITH NAD AND A C16 FATTY
RP ACYL SUBSTRATE, SUBUNIT, AND REACTION MECHANISM.
RX PubMed=10336454; DOI=10.1074/jbc.274.22.15582;
RA Rozwarski D.A., Vilcheze C., Sugantino M., Bittman R., Sacchettini J.C.;
RT "Crystal structure of the Mycobacterium tuberculosis enoyl-ACP reductase,
RT InhA, in complex with NAD+ and a C16 fatty acyl substrate.";
RL J. Biol. Chem. 274:15582-15589(1999).
RN [17] {ECO:0007744|PDB:1P44, ECO:0007744|PDB:1P45}
RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) IN COMPLEXES WITH
RP 5-{[4-(9H-FLUOREN-9-YL)PIPERAZIN-1-YL]CARBONYL}-1H-INDOLE INHIBITOR; NAD
RP AND TRICLOSAN, INHIBITOR SCREENING, AND ACTIVITY REGULATION.
RX PubMed=12606558; DOI=10.1074/jbc.m211968200;
RA Kuo M.R., Morbidoni H.R., Alland D., Sneddon S.F., Gourlie B.B.,
RA Staveski M.M., Leonard M., Gregory J.S., Janjigian A.D., Yee C.,
RA Musser J.M., Kreiswirth B., Iwamoto H., Perozzo R., Jacobs W.R. Jr.,
RA Sacchettini J.C., Fidock D.A.;
RT "Targeting tuberculosis and malaria through inhibition of enoyl reductase:
RT compound activity and structural data.";
RL J. Biol. Chem. 278:20851-20859(2003).
RN [18] {ECO:0007744|PDB:2B35, ECO:0007744|PDB:2B36, ECO:0007744|PDB:2B37}
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) IN COMPLEXES WITH NAD;
RP 5-OCTYL-2-PHENOXYPHENOL AND TRICLOSAN, AND ACTIVITY REGULATION.
RX PubMed=17163639; DOI=10.1021/cb0500042;
RA Sullivan T.J., Truglio J.J., Boyne M.E., Novichenok P., Zhang X.,
RA Stratton C.F., Li H.J., Kaur T., Amin A., Johnson F., Slayden R.A.,
RA Kisker C., Tonge P.J.;
RT "High affinity InhA inhibitors with activity against drug-resistant strains
RT of Mycobacterium tuberculosis.";
RL ACS Chem. Biol. 1:43-53(2006).
RN [19] {ECO:0007744|PDB:4TZK, ECO:0007744|PDB:4TZT, ECO:0007744|PDB:4U0J, ECO:0007744|PDB:4U0K}
RP X-RAY CRYSTALLOGRAPHY (1.62 ANGSTROMS) IN COMPLEXES WITH VARIOUS
RP PYRROLIDINE CARBOXAMIDES INHIBITORS AND NAD, INHIBITOR SCREENING, AND
RP ACTIVITY REGULATION.
RX PubMed=17034137; DOI=10.1021/jm060715y;
RA He X., Alian A., Stroud R., Ortiz de Montellano P.R.;
RT "Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl
RT carrier protein reductase from Mycobacterium tuberculosis.";
RL J. Med. Chem. 49:6308-6323(2006).
RN [20] {ECO:0007744|PDB:2AQ8, ECO:0007744|PDB:2AQH, ECO:0007744|PDB:2AQI, ECO:0007744|PDB:2AQK}
RP X-RAY CRYSTALLOGRAPHY (1.92 ANGSTROMS) OF WILD-TYPE AND MUTANTS ALA-94;
RP THR-47 AND VAL-21 IN COMPLEX WITH NAD, AND SUBUNIT.
RX PubMed=16647717; DOI=10.1016/j.jmb.2006.03.055;
RA Oliveira J.S., Pereira J.H., Canduri F., Rodrigues N.C., de Souza O.N.,
RA de Azevedo W.F. Jr., Basso L.A., Santos D.S.;
RT "Crystallographic and pre-steady-state kinetics studies on binding of NADH
RT to wild-type and isoniazid-resistant enoyl-ACP(CoA) reductase enzymes from
RT Mycobacterium tuberculosis.";
RL J. Mol. Biol. 359:646-666(2006).
RN [21] {ECO:0007744|PDB:2NV6}
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 3-269 OF MUTANT ALA-94 IN COMPLEX
RP WITH ISONICOTINIC-ACETYL-NICOTINAMIDE-ADENINE DINUCLEOTIDE INHIBITOR
RP (INH-NAD ADDUCT), DRUG TARGET, DRUG RESISTANCE, AND MUTAGENESIS OF SER-94.
RC STRAIN=H37Rv;
RX PubMed=16906155; DOI=10.1038/nm1466;
RA Vilcheze C., Wang F., Arai M., Hazbon M.H., Colangeli R., Kremer L.,
RA Weisbrod T.R., Alland D., Sacchettini J.C., Jacobs W.R. Jr.;
RT "Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves
RT the target of isoniazid.";
RL Nat. Med. 12:1027-1029(2006).
RN [22] {ECO:0007744|PDB:2NSD}
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) IN COMPLEX WITH
RP N-(4-METHYLBENZOYL)-4-BENZYLPIPERIDINE INHIBITOR AND NAD, INHIBITOR
RP SCREENING, AND ACTIVITY REGULATION.
RX PubMed=17723305; DOI=10.1016/j.bmc.2007.08.013;
RA He X., Alian A., Ortiz de Montellano P.R.;
RT "Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein
RT reductase InhA by arylamides.";
RL Bioorg. Med. Chem. 15:6649-6658(2007).
RN [23] {ECO:0007744|PDB:2PR2}
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) IN COMPLEX WITH
RP (4S)-ISONICOTINIC-ACETYL-NICOTINAMIDE-ADENINE DINUCLEOTIDE PHOSPHATE
RP INHIBITOR (INH-NADP ADDUCT).
RX PubMed=17636923; DOI=10.1021/ja073160k;
RA Argyrou A., Vetting M.W., Blanchard J.S.;
RT "New insight into the mechanism of action of and resistance to isoniazid:
RT interaction of Mycobacterium tuberculosis enoyl-ACP reductase with INH-
RT NADP.";
RL J. Am. Chem. Soc. 129:9582-9583(2007).
RN [24] {ECO:0007744|PDB:2H9I, ECO:0007744|PDB:2NTJ}
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) IN COMPLEXES WITH
RP (4S)-4-(2-PROPYLISONICOTINOYL)NICOTINAMIDE ADENINE DINUCLEOTIDE (PTH-NAD
RP ADDUCT) AND (4S)-4-(2-ETHYLISONICOTINOYL)NICOTINAMIDE ADENINE DINUCLEOTIDE
RP (ETH-NAD ADDUCT) INHIBITORS, DRUG TARGET, AND ACTIVITY REGULATION.
RX PubMed=17227913; DOI=10.1084/jem.20062100;
RA Wang F., Langley R., Gulten G., Dover L.G., Besra G.S., Jacobs W.R. Jr.,
RA Sacchettini J.C.;
RT "Mechanism of thioamide drug action against tuberculosis and leprosy.";
RL J. Exp. Med. 204:73-78(2007).
RN [25] {ECO:0007744|PDB:2IDZ, ECO:0007744|PDB:2IE0, ECO:0007744|PDB:2IEB, ECO:0007744|PDB:2IED}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF WILD-TYPE AND MUTANTS VAL-21 AND
RP ALA-94 UNCOMPLEXED AND IN COMPLEX WITH
RP ISONICOTINIC-ACETYL-NICOTINAMIDE-ADENINE DINUCLEOTIDE INHIBITOR (INH-NAD
RP ADDUCT).
RX PubMed=17588773; DOI=10.1016/j.jsb.2007.04.009;
RA Dias M.V., Vasconcelos I.B., Prado A.M., Fadel V., Basso L.A.,
RA de Azevedo W.F. Jr., Santos D.S.;
RT "Crystallographic studies on the binding of isonicotinyl-NAD adduct to
RT wild-type and isoniazid resistant 2-trans-enoyl-ACP (CoA) reductase from
RT Mycobacterium tuberculosis.";
RL J. Struct. Biol. 159:369-380(2007).
RN [26] {ECO:0007744|PDB:3FNE, ECO:0007744|PDB:3FNF, ECO:0007744|PDB:3FNG, ECO:0007744|PDB:3FNH}
RP X-RAY CRYSTALLOGRAPHY (1.97 ANGSTROMS) IN COMPLEX WITH TRICLOSAN
RP DERIVATIVES INHIBITORS AND NAD, AND ACTIVITY REGULATION.
RX PubMed=19130456; DOI=10.1002/cmdc.200800261;
RA Freundlich J.S., Wang F., Vilcheze C., Gulten G., Langley R.,
RA Schiehser G.A., Jacobus D.P., Jacobs W.R. Jr., Sacchettini J.C.;
RT "Triclosan derivatives: towards potent inhibitors of drug-sensitive and
RT drug-resistant Mycobacterium tuberculosis.";
RL ChemMedChem 4:241-248(2009).
RN [27] {ECO:0007744|PDB:2X22, ECO:0007744|PDB:2X23}
RP X-RAY CRYSTALLOGRAPHY (1.81 ANGSTROMS) IN COMPLEX WITH
RP 5-HEXYL-2-(2-METHYLPHENOXY)PHENOL INHIBITOR AND NAD, AND ACTIVITY
RP REGULATION.
RX PubMed=20200152; DOI=10.1074/jbc.m109.090373;
RA Luckner S.R., Liu N., am Ende C.W., Tonge P.J., Kisker C.;
RT "A slow, tight binding inhibitor of InhA, the enoyl-acyl carrier protein
RT reductase from Mycobacterium tuberculosis.";
RL J. Biol. Chem. 285:14330-14337(2010).
RN [28] {ECO:0007744|PDB:3OEW, ECO:0007744|PDB:3OEY, ECO:0007744|PDB:3OF2}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF WILD-TYPE AND MUTANTS ASP-266 AND
RP GLU-266 IN COMPLEX WITH NAD, PHOSPHORYLATION AT THR-266, CATALYTIC
RP ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY REGULATION, AND
RP MUTAGENESIS OF THR-266.
RC STRAIN=H37Rv;
RX PubMed=21143326; DOI=10.1111/j.1365-2958.2010.07446.x;
RA Molle V., Gulten G., Vilcheze C., Veyron-Churlet R., Zanella-Cleon I.,
RA Sacchettini J.C., Jacobs W.R. Jr., Kremer L.;
RT "Phosphorylation of InhA inhibits mycolic acid biosynthesis and growth of
RT Mycobacterium tuberculosis.";
RL Mol. Microbiol. 78:1591-1605(2010).
RN [29] {ECO:0007744|PDB:4DQU, ECO:0007744|PDB:4DRE, ECO:0007744|PDB:4DTI}
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF WILD-TYPE AND MUTANTS ALA-94 AND
RP GLY-148 IN COMPLEX WITH NADH, ACTIVITY REGULATION, CATALYTIC ACTIVITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF SER-94 AND ASP-148.
RC STRAIN=H37Rv;
RX PubMed=22987724; DOI=10.1002/emmm.201201689;
RA Hartkoorn R.C., Sala C., Neres J., Pojer F., Magnet S., Mukherjee R.,
RA Uplekar S., Boy-Rottger S., Altmann K.H., Cole S.T.;
RT "Towards a new tuberculosis drug: pyridomycin - nature's isoniazid.";
RL EMBO Mol. Med. 4:1032-1042(2012).
RN [30] {ECO:0007744|PDB:4BQP, ECO:0007744|PDB:4BQR}
RP X-RAY CRYSTALLOGRAPHY (1.89 ANGSTROMS) IN COMPLEXES WITH METHYL-THIAZOLE
RP INHIBITORS AND NAD, AND ACTIVITY REGULATION.
RX PubMed=24107081; DOI=10.1021/jm4012033;
RA Shirude P.S., Madhavapeddi P., Naik M., Murugan K., Shinde V.,
RA Nandishaiah R., Bhat J., Kumar A., Hameed S., Holdgate G., Davies G.,
RA McMiken H., Hegde N., Ambady A., Venkatraman J., Panda M., Bandodkar B.,
RA Sambandamurthy V.K., Read J.A.;
RT "Methyl-thiazoles: a novel mode of inhibition with the potential to develop
RT novel inhibitors targeting InhA in Mycobacterium tuberculosis.";
RL J. Med. Chem. 56:8533-8542(2013).
RN [31] {ECO:0007744|PDB:4OHU, ECO:0007744|PDB:4OXK, ECO:0007744|PDB:4OXN, ECO:0007744|PDB:4OXY, ECO:0007744|PDB:4OYR}
RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) IN COMPLEXES WITH VARIOUS ALKYL
RP DIPHENYL ETHER INHIBITORS AND NAD.
RX PubMed=24527857; DOI=10.1021/cb400896g;
RA Li H.J., Lai C.T., Pan P., Yu W., Liu N., Bommineni G.R., Garcia-Diaz M.,
RA Simmerling C., Tonge P.J.;
RT "A structural and energetic model for the slow-onset inhibition of the
RT Mycobacterium tuberculosis enoyl-ACP reductase InhA.";
RL ACS Chem. Biol. 9:986-993(2014).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) IN COMPLEX WITH
RP 2-(2-CYANOPHENOXY)-5-HEXYLPHENOL INHIBITOR AND NAD, AND ACTIVITY
RP REGULATION.
RX PubMed=24616444; DOI=10.1002/cmdc.201300429;
RA Pan P., Knudson S.E., Bommineni G.R., Li H.J., Lai C.T., Liu N.,
RA Garcia-Diaz M., Simmerling C., Patil S.S., Slayden R.A., Tonge P.J.;
RT "Time-dependent diaryl ether inhibitors of InhA: structure-activity
RT relationship studies of enzyme inhibition, antibacterial activity, and in
RT vivo efficacy.";
RL ChemMedChem 9:776-791(2014).
RN [33] {ECO:0007744|PDB:4BGE, ECO:0007744|PDB:4BGI, ECO:0007744|PDB:4BII}
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF WILD-TYPE AND MUTANT ALA-94 IN
RP COMPLEXES WITH NAD; PYRIDOMYCIN AND PYRIDOMYCIN ANALOG OH141 INHIBITORS,
RP AND ACTIVITY REGULATION.
RX PubMed=24292073; DOI=10.1038/nchembio.1405;
RA Hartkoorn R.C., Pojer F., Read J.A., Gingell H., Neres J., Horlacher O.P.,
RA Altmann K.H., Cole S.T.;
RT "Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl
RT reductase InhA.";
RL Nat. Chem. Biol. 10:96-98(2014).
RN [34] {ECO:0007744|PDB:4D0R, ECO:0007744|PDB:4D0S}
RP X-RAY CRYSTALLOGRAPHY (1.64 ANGSTROMS) IN COMPLEXES WITH PYRIDAZINONES AND
RP NAD.
RA Lange S.;
RT "Pyridazinones: a novel scaffold with excellent physicochemical properties
RT and safety profile for a clinically validated target of Mycobacterium
RT tuberculosis.";
RL Submitted (APR-2014) to the PDB data bank.
RN [35] {ECO:0007744|PDB:4UVD, ECO:0007744|PDB:4UVE, ECO:0007744|PDB:4UVG, ECO:0007744|PDB:4UVH, ECO:0007744|PDB:4UVI}
RP X-RAY CRYSTALLOGRAPHY (1.73 ANGSTROMS) IN COMPLEXES WITH VARIOUS PYRIMIDINE
RP ISOXAZOLES AND NAD.
RA Madhavapeddi P., Kale R.R., Cowen S.D., Ghorpade S.R., Davies G.,
RA Bellale E.V., Kale M.G., Srivastava A., Spadola L., Kawatkar A.,
RA Raichurkar A.V., Tonge M., Nandishaiah R., Guptha S., Narayan A.,
RA Gingell H., Plant D., Landge S., Menasinakai S., Prabhakar K.R., Achar V.,
RA Ambady A., Sambandamurthy V.K., Ramachandran V., Panduga V., Reddy J.,
RA Kumar C.N.N., Kaur P., Shandil R., Iyer P.S., Narayanan S., Read J.A.;
RT "Hitting the target in more than one way: novel, direct inhibitors of
RT Mycobacterium tuberculosis enoyl ACP reductase.";
RL Submitted (AUG-2014) to the PDB data bank.
RN [36] {ECO:0007744|PDB:5COQ, ECO:0007744|PDB:5CP8, ECO:0007744|PDB:5CPB}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF MUTANTS ALA-203 AND ALA-215 IN
RP COMPLEX WITH DIARYL ETHERS AND NAD.
RX PubMed=26147157; DOI=10.1021/acs.biochem.5b00284;
RA Lai C.T., Li H.J., Yu W., Shah S., Bommineni G.R., Perrone V.,
RA Garcia-Diaz M., Tonge P.J., Simmerling C.;
RT "Rational modulation of the induced-fit conformational change for slow-
RT onset inhibition in Mycobacterium tuberculosis InhA.";
RL Biochemistry 54:4683-4691(2015).
RN [37] {ECO:0007744|PDB:4TRM, ECO:0007744|PDB:4TRN, ECO:0007744|PDB:4TRO}
RP X-RAY CRYSTALLOGRAPHY (1.40 ANGSTROMS) OF THE APO FORM AND IN COMPLEXES
RP WITH NADH AND THE INH-NAD ADDUCT INHIBITOR.
RX PubMed=25891098; DOI=10.1016/j.jsb.2015.04.008;
RA Chollet A., Mourey L., Lherbet C., Delbot A., Julien S., Baltas M.,
RA Bernadou J., Pratviel G., Maveyraud L., Bernardes-Genisson V.;
RT "Crystal structure of the enoyl-ACP reductase of Mycobacterium tuberculosis
RT (InhA) in the apo-form and in complex with the active metabolite of
RT isoniazid pre-formed by a biomimetic approach.";
RL J. Struct. Biol. 190:328-337(2015).
RN [38] {ECO:0007744|PDB:4R9R, ECO:0007744|PDB:4R9S}
RP X-RAY CRYSTALLOGRAPHY (2.90 ANGSTROMS) IN COMPLEXES WITH
RP 4-HYDROXY-2-PYRIDONE INHIBITORS AND NAD, AND ACTIVITY REGULATION.
RX PubMed=25568071; DOI=10.1126/scitranslmed.3010597;
RA Manjunatha U.H., Rao S.P.S., Kondreddi R.R., Noble C.G., Camacho L.R.,
RA Tan B.H., Ng S.H., Ng P.S., Ma N.L., Lakshminarayana S.B., Herve M.,
RA Barnes S.W., Yu W., Kuhen K., Blasco F., Beer D., Walker J.R., Tonge P.J.,
RA Glynne R., Smith P.W., Diagana T.T.;
RT "Direct inhibitors of InhA are active against Mycobacterium tuberculosis.";
RL Sci. Transl. Med. 7:269ra3-269ra3(2015).
RN [39] {ECO:0007744|PDB:4QXM}
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) WITH A
RP N-BENZYL-4-((HETEROARYL)METHYL)BENZAMIDE INHIBITOR AND NAD, AND ACTIVITY
RP REGULATION.
RX PubMed=26934341; DOI=10.1002/cmdc.201600020;
RA Guardia A., Gulten G., Fernandez R., Gomez J., Wang F., Convery M.,
RA Blanco D., Martinez M., Perez-Herran E., Alonso M., Ortega F., Rullas J.,
RA Calvo D., Mata L., Young R., Sacchettini J.C., Mendoza-Losana A.,
RA Remuinan M., Ballell Pages L., Castro-Pichel J.;
RT "N-Benzyl-4-((heteroaryl)methyl)benzamides: a new class of direct NADH-
RT dependent 2-trans enoyl-acyl carrier protein reductase (InhA) inhibitors
RT with antitubercular activity.";
RL ChemMedChem 11:687-701(2016).
RN [40]
RP X-RAY CRYSTALLOGRAPHY (2.91 ANGSTROMS) IN COMPLEX WITH THE THIADIAZOLE
RP INHIBITOR GSK625 AND NAD, AND ACTIVITY REGULATION.
RX PubMed=27428438; DOI=10.1016/j.ebiom.2016.05.006;
RA Martinez-Hoyos M., Perez-Herran E., Gulten G., Encinas L.,
RA Alvarez-Gomez D., Alvarez E., Ferrer-Bazaga S., Garcia-Perez A., Ortega F.,
RA Angulo-Barturen I., Rullas-Trincado J., Blanco Ruano D., Torres P.,
RA Castaneda P., Huss S., Fernandez Menendez R., Gonzalez Del Valle S.,
RA Ballell L., Barros D., Modha S., Dhar N., Signorino-Gelo F., McKinney J.D.,
RA Garcia-Bustos J.F., Lavandera J.L., Sacchettini J.C., Jimenez M.S.,
RA Martin-Casabona N., Castro-Pichel J., Mendoza-Losana A.;
RT "Antitubercular drugs for an old target: GSK693 as a promising InhA direct
RT inhibitor.";
RL EBioMedicine 8:291-301(2016).
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 (PubMed:25227413).
CC Catalyzes the NADH-dependent reduction of the double bond of 2-trans-
CC enoyl-[acyl-carrier protein], an essential step in the fatty acid
CC elongation cycle of the FAS-II pathway (PubMed:7599116). Shows
CC preference for long-chain fatty acyl thioester substrates (>C16), and
CC can also use 2-trans-enoyl-CoAs as alternative substrates
CC (PubMed:7599116). The mycobacterial FAS-II system utilizes the products
CC of 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 (PubMed:25227413). {ECO:0000269|PubMed:7599116,
CC ECO:0000303|PubMed:25227413}.
CC -!- FUNCTION: Is the primary target of the first-line antitubercular drug
CC isoniazid (INH) and of the second-line drug ethionamide (ETH)
CC (PubMed:8284673, PubMed:12406221, PubMed:16906155, PubMed:17227913).
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 (PubMed:9417034, PubMed:16906155). Similarly, the
CC ETH-NAD adduct binds InhA (PubMed:17227913).
CC {ECO:0000269|PubMed:12406221, ECO:0000269|PubMed:16906155,
CC ECO:0000269|PubMed:17227913, ECO:0000269|PubMed:9417034,
CC ECO:0000305|PubMed:8284673}.
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:0000269|PubMed:7599116};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:10242;
CC Evidence={ECO:0000305|PubMed:7599116};
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:0000269|PubMed:10521269, ECO:0000269|PubMed:20864541,
CC ECO:0000269|PubMed:21143326, ECO:0000269|PubMed:22987724,
CC ECO:0000269|PubMed:7599116};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:18179;
CC Evidence={ECO:0000305|PubMed:7599116};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(2E)-octenoyl-[ACP] + H(+) + NADH = NAD(+) + octanoyl-[ACP];
CC Xref=Rhea:RHEA:41528, Rhea:RHEA-COMP:9635, Rhea:RHEA-COMP:9636,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945,
CC ChEBI:CHEBI:78462, ChEBI:CHEBI:78463;
CC Evidence={ECO:0000269|PubMed:7599116};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41529;
CC Evidence={ECO:0000305|PubMed:7599116};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(2E)-octenoyl-CoA + H(+) + NADH = NAD(+) + octanoyl-CoA;
CC Xref=Rhea:RHEA:63232, ChEBI:CHEBI:15378, ChEBI:CHEBI:57386,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:62242;
CC Evidence={ECO:0000269|PubMed:20864541, ECO:0000269|PubMed:22987724,
CC ECO:0000269|PubMed:7599116};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63233;
CC Evidence={ECO:0000305|PubMed:7599116};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(2E)-dodecenoyl-CoA + H(+) + NADH = dodecanoyl-CoA + NAD(+);
CC Xref=Rhea:RHEA:45408, ChEBI:CHEBI:15378, ChEBI:CHEBI:57330,
CC ChEBI:CHEBI:57375, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC Evidence={ECO:0000269|PubMed:10521269, ECO:0000269|PubMed:21143326,
CC ECO:0000269|PubMed:7599116};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45409;
CC Evidence={ECO:0000305|PubMed:7599116};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(2E)-hexadecenoyl-CoA + H(+) + NADH = hexadecanoyl-CoA +
CC NAD(+); Xref=Rhea:RHEA:46072, ChEBI:CHEBI:15378, ChEBI:CHEBI:57379,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:61526;
CC Evidence={ECO:0000269|PubMed:7599116};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46073;
CC Evidence={ECO:0000305|PubMed:7599116};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(2E)-eicosenoyl-CoA + H(+) + NADH = eicosanoyl-CoA + NAD(+);
CC Xref=Rhea:RHEA:46076, ChEBI:CHEBI:15378, ChEBI:CHEBI:57380,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:74691;
CC Evidence={ECO:0000269|PubMed:7599116};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46077;
CC Evidence={ECO:0000305|PubMed:7599116};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(2E)-tetracosenoyl-CoA + H(+) + NADH = NAD(+) + tetracosanoyl-
CC CoA; Xref=Rhea:RHEA:46080, ChEBI:CHEBI:15378, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945, ChEBI:CHEBI:65052, ChEBI:CHEBI:74693;
CC Evidence={ECO:0000269|PubMed:7599116};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46081;
CC Evidence={ECO:0000305|PubMed:7599116};
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 (PubMed:20864541, PubMed:21143326). The
CC antitubercular pro-drug isoniazid (INH) is oxidatively activated by the
CC catalase-peroxidase KatG and then covalently binds NAD to form an
CC adduct that inhibits the activity of InhA (Ref.5, PubMed:14623976,
CC PubMed:9417034). The inhibitory adduct is the isonicotinic-acyl-NADH
CC where the isonicotinic-acyl group replaces the 4S (and not the 4R)
CC hydrogen of NADH (PubMed:9417034). Similarly, the antitubercular pro-
CC drugs ethionamide (ETH) and prothionamide (PTH) are activated by the
CC flavoprotein monooxygenase EthA, and forms an adduct with NAD (ETH-NAD
CC and PTH-NAD, respectively) that is a tight-binding inhibitor of InhA
CC (PubMed:17227913). Is inhibited by triclosan and derivatives, pyrazole
CC derivative Genz-8575, indole-5-amide Genz-10850, alkyl diphenyl ethers,
CC pyrrolidine carboxamides, arylamides, pyridomycin, methyl-thiazoles, 4-
CC hydroxy-2-pyridones, and N-benzyl-4-((heteroaryl)methyl)benzamides
CC (PubMed:12606558, PubMed:17163639, PubMed:17034137, PubMed:17723305,
CC PubMed:19130456, PubMed:20200152, PubMed:22987724, PubMed:24107081,
CC PubMed:24616444, PubMed:25568071). Pyridomycin shows a unique mode of
CC InhA inhibition by simultaneously blocking parts of the NADH and the
CC lipid substrate-binding pocket of InhA (PubMed:24292073). Is also
CC inhibited by thiadiazole compounds, that have very attractive
CC antitubercular properties (PubMed:27428438).
CC {ECO:0000269|PubMed:12606558, ECO:0000269|PubMed:14623976,
CC ECO:0000269|PubMed:17034137, ECO:0000269|PubMed:17163639,
CC ECO:0000269|PubMed:17227913, ECO:0000269|PubMed:17723305,
CC ECO:0000269|PubMed:19130456, ECO:0000269|PubMed:20200152,
CC ECO:0000269|PubMed:20864541, ECO:0000269|PubMed:22987724,
CC ECO:0000269|PubMed:24107081, ECO:0000269|PubMed:24292073,
CC ECO:0000269|PubMed:24616444, ECO:0000269|PubMed:25568071,
CC ECO:0000269|PubMed:26934341, ECO:0000269|PubMed:27428438,
CC ECO:0000269|PubMed:9417034, ECO:0000269|Ref.5,
CC ECO:0000305|PubMed:21143326}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2.0 uM for 2-trans-octenoyl-ACP (at pH 6.8 and 25 degrees Celsius)
CC {ECO:0000269|PubMed:7599116};
CC KM=8.1 uM for NADH (at pH 6.8 and 25 degrees Celsius)
CC {ECO:0000269|PubMed:7599116};
CC KM=66 uM for NADH (at pH 6.8 and 25 degrees Celsius)
CC {ECO:0000269|PubMed:10521269};
CC KM=19.1 uM for NADH (at pH 6.8) {ECO:0000269|PubMed:20864541};
CC KM=13.5 uM for NADH (at pH 6.8 and 25 degrees Celsius)
CC {ECO:0000269|PubMed:22987724};
CC KM=467 uM for 2-trans-octenoyl-CoA (at pH 6.8 and 25 degrees Celsius)
CC {ECO:0000269|PubMed:7599116};
CC KM=528 uM for 2-trans-octenoyl-CoA (at pH 6.8)
CC {ECO:0000269|PubMed:20864541};
CC KM=48 uM for 2-trans-dodecenoyl-CoA (at pH 6.8 and 25 degrees
CC Celsius) {ECO:0000269|PubMed:7599116};
CC KM=27 uM for 2-trans-dodecenoyl-CoA (at pH 6.8 and 25 degrees
CC Celsius) {ECO:0000269|PubMed:10521269};
CC KM=40.9 uM for 2-trans-dodecenoyl-CoA (at pH 7.5 and 25 degrees
CC Celsius) {ECO:0000269|PubMed:21143326};
CC KM=1.5 uM for 2-trans-hexadecenoyl-CoA (at pH 6.8 and 25 degrees
CC Celsius) {ECO:0000269|PubMed:7599116};
CC Vmax=2.2 umol/min/mg enzyme for the reduction of 2-trans-octenoyl-ACP
CC (at pH 6.8 and 25 degrees Celsius) {ECO:0000269|PubMed:7599116};
CC Vmax=3.6 umol/min/mg enzyme for the reduction of 2-trans-octenoyl-CoA
CC (at pH 6.8 and 25 degrees Celsius) {ECO:0000269|PubMed:7599116};
CC Vmax=0.52 umol/min/mg enzyme for the reduction of 2-trans-octenoyl-
CC CoA (at pH 6.8 and 25 degrees Celsius) {ECO:0000269|PubMed:22987724};
CC Vmax=15.3 umol/min/mg enzyme for the reduction of 2-trans-octenoyl-
CC CoA (at pH 6.8) {ECO:0000269|PubMed:20864541};
CC Vmax=5.8 umol/min/mg enzyme for the reduction of 2-trans-dodecenoyl-
CC CoA (at pH 6.8 and 25 degrees Celsius) {ECO:0000269|PubMed:7599116};
CC Vmax=11.4 umol/min/mg enzyme for the reduction of 2-trans-dodecenoyl-
CC CoA (at pH 7.5 and 25 degrees Celsius) {ECO:0000269|PubMed:21143326};
CC Vmax=4.5 umol/min/mg enzyme for the reduction of 2-trans-
CC hexadecenoyl-CoA (at pH 6.8 and 25 degrees Celsius)
CC {ECO:0000269|PubMed:7599116};
CC Note=kcat is 320.4 min(-1) for the reduction of 2-trans-dodecenoyl-
CC CoA (at pH 7.5 and 25 degrees Celsius) (PubMed:21143326). kcat is 278
CC min(-1) for the reduction of 2-trans-dodecenoyl-CoA (at pH 6.8 and 25
CC degrees Celsius) (PubMed:10521269). {ECO:0000269|PubMed:10521269,
CC ECO:0000269|PubMed:21143326};
CC -!- PATHWAY: Lipid metabolism; mycolic acid biosynthesis.
CC {ECO:0000303|PubMed:25227413}.
CC -!- SUBUNIT: Homodimer (PubMed:7599116). Homotetramer (PubMed:10336454,
CC PubMed:16647717). {ECO:0000269|PubMed:10336454,
CC ECO:0000269|PubMed:16647717, ECO:0000269|PubMed:7599116}.
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:0000269|PubMed:20864541, ECO:0000269|PubMed:21143326}.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC {ECO:0000305|PubMed:19099550}.
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:0000269|PubMed:16906155, ECO:0000305|PubMed:7886450}.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC family. FabI subfamily. {ECO:0000305}.
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DR EMBL; U02492; AAC43210.1; -; Unassigned_DNA.
DR EMBL; AY155363; AAN75060.1; -; Genomic_DNA.
DR EMBL; AL123456; CCP44244.1; -; Genomic_DNA.
DR PIR; G70710; G70710.
DR RefSeq; NP_216000.1; NC_000962.3.
DR RefSeq; WP_003407553.1; NZ_NVQJ01000004.1.
DR PDB; 1BVR; X-ray; 2.80 A; A/B/C/D/E/F=2-269.
DR PDB; 1ENY; X-ray; 2.20 A; A=3-269.
DR PDB; 1ENZ; X-ray; 2.70 A; A=3-269.
DR PDB; 1P44; X-ray; 2.70 A; A/B/C/D/E/F=1-269.
DR PDB; 1P45; X-ray; 2.60 A; A/B=1-269.
DR PDB; 1ZID; X-ray; 2.70 A; A=3-269.
DR PDB; 2AQ8; X-ray; 1.92 A; A=1-269.
DR PDB; 2AQH; X-ray; 2.01 A; A=1-269.
DR PDB; 2AQI; X-ray; 2.20 A; A=1-269.
DR PDB; 2AQK; X-ray; 2.30 A; A=1-269.
DR PDB; 2B35; X-ray; 2.30 A; A/B/C/D/E/F=1-269.
DR PDB; 2B36; X-ray; 2.80 A; A/B/C/D/E/F=1-269.
DR PDB; 2B37; X-ray; 2.60 A; A/B/C/D/E/F=1-269.
DR PDB; 2H9I; X-ray; 2.20 A; A=2-269.
DR PDB; 2IDZ; X-ray; 2.00 A; A=2-269.
DR PDB; 2IE0; X-ray; 2.20 A; A=2-269.
DR PDB; 2IEB; X-ray; 2.20 A; A=2-269.
DR PDB; 2IED; X-ray; 2.14 A; A/B/C/D=2-269.
DR PDB; 2NSD; X-ray; 1.90 A; A/B=1-269.
DR PDB; 2NTJ; X-ray; 2.50 A; A/B=3-269.
DR PDB; 2NV6; X-ray; 1.90 A; A=3-269.
DR PDB; 2PR2; X-ray; 2.50 A; A=1-269.
DR PDB; 2X22; X-ray; 2.10 A; A/B=1-269.
DR PDB; 2X23; X-ray; 1.81 A; A/B/E/G=1-269.
DR PDB; 3FNE; X-ray; 1.98 A; A/B/C/D=1-269.
DR PDB; 3FNF; X-ray; 2.30 A; A/B/C/D=1-269.
DR PDB; 3FNG; X-ray; 1.97 A; A=1-269.
DR PDB; 3FNH; X-ray; 2.80 A; A=1-269.
DR PDB; 3OEW; X-ray; 2.20 A; A=1-269.
DR PDB; 3OEY; X-ray; 2.00 A; A=1-269.
DR PDB; 3OF2; X-ray; 2.00 A; A=1-269.
DR PDB; 4BGE; X-ray; 2.25 A; A/B/C/D/E/F=1-269.
DR PDB; 4BGI; X-ray; 2.09 A; A/B/C/D/E/F=2-269.
DR PDB; 4BII; X-ray; 1.95 A; A/B/C/D=1-269.
DR PDB; 4BQP; X-ray; 1.89 A; A/B/C/D/E/F=1-269.
DR PDB; 4BQR; X-ray; 2.05 A; A/B/C/D=1-269.
DR PDB; 4COD; X-ray; 2.40 A; B/D/F/H=1-269.
DR PDB; 4D0R; X-ray; 2.75 A; A=1-269.
DR PDB; 4D0S; X-ray; 1.64 A; A/B/C/D=1-269.
DR PDB; 4DQU; X-ray; 2.45 A; A=1-269.
DR PDB; 4DRE; X-ray; 2.40 A; A=1-269.
DR PDB; 4DTI; X-ray; 1.90 A; A=1-269.
DR PDB; 4OHU; X-ray; 1.60 A; A/B/C/D=1-269.
DR PDB; 4OIM; X-ray; 1.85 A; A=1-269.
DR PDB; 4OXK; X-ray; 1.84 A; A/B/C/D=1-269.
DR PDB; 4OXN; X-ray; 2.29 A; A/B=1-269.
DR PDB; 4OXY; X-ray; 2.35 A; A/B/C/D=1-269.
DR PDB; 4OYR; X-ray; 2.30 A; A/B/C/D=1-269.
DR PDB; 4QXM; X-ray; 2.20 A; A/C/E/G=1-269.
DR PDB; 4R9R; X-ray; 2.90 A; A/C/E/G=1-269.
DR PDB; 4R9S; X-ray; 3.20 A; A/C/E/G=1-269.
DR PDB; 4TRJ; X-ray; 1.73 A; A=1-269.
DR PDB; 4TRM; X-ray; 1.80 A; A/B/C/D/E/F=1-269.
DR PDB; 4TRN; X-ray; 1.95 A; A=1-269.
DR PDB; 4TRO; X-ray; 1.40 A; A=1-269.
DR PDB; 4TZK; X-ray; 1.62 A; A=1-269.
DR PDB; 4TZT; X-ray; 1.86 A; A=1-269.
DR PDB; 4U0J; X-ray; 1.62 A; A=1-269.
DR PDB; 4U0K; X-ray; 1.90 A; A=1-269.
DR PDB; 4UVD; X-ray; 1.82 A; A=1-269.
DR PDB; 4UVE; X-ray; 1.99 A; A=1-269.
DR PDB; 4UVG; X-ray; 1.92 A; A=1-269.
DR PDB; 4UVH; X-ray; 1.89 A; A/B/C/D=1-269.
DR PDB; 4UVI; X-ray; 1.73 A; A/B/C/D=1-269.
DR PDB; 5COQ; X-ray; 2.30 A; A/B/C/D=1-269.
DR PDB; 5CP8; X-ray; 2.40 A; A=1-269.
DR PDB; 5CPB; X-ray; 2.00 A; A/B/C/D/E/F=1-269.
DR PDB; 5CPF; X-ray; 3.41 A; A/B/C/D=1-269.
DR PDB; 5G0S; X-ray; 1.74 A; A/B/C/D=1-269.
DR PDB; 5G0T; X-ray; 1.54 A; A/B/C/D=1-269.
DR PDB; 5G0U; X-ray; 1.73 A; A/B/C/D=1-269.
DR PDB; 5G0V; X-ray; 1.79 A; A/B/C/D=1-269.
DR PDB; 5G0W; X-ray; 1.79 A; A/B/C/D=1-269.
DR PDB; 5JFO; X-ray; 2.91 A; A/B/C/D=1-269.
DR PDB; 5MTP; X-ray; 2.00 A; A/B/C/D/E/F/G/H=1-269.
DR PDB; 5MTQ; X-ray; 2.60 A; A/B/C/D/E/F/G/H=1-269.
DR PDB; 5MTR; X-ray; 2.00 A; A/B/C/D/E/F/G/H=1-269.
DR PDB; 5OIF; X-ray; 2.03 A; A/B=1-269.
DR PDB; 5OIL; X-ray; 2.76 A; A=1-269.
DR PDB; 5OIM; X-ray; 1.91 A; A=1-269.
DR PDB; 5OIN; X-ray; 2.82 A; A/B/C/D=1-269.
DR PDB; 5OIT; X-ray; 2.58 A; B/D/F/H=1-269.
DR PDB; 5UGS; X-ray; 2.80 A; A/B/C/D/E/G=1-269.
DR PDB; 5UGT; X-ray; 2.60 A; A/B/E/G=1-269.
DR PDB; 5UGU; X-ray; 1.95 A; A=1-269.
DR PDB; 6EP8; X-ray; 1.80 A; A=1-269.
DR PDB; 6GGM; X-ray; 2.73 A; P/Q=53-61.
DR PDB; 6GH1; X-ray; 2.10 A; P/Q/R/Z=53-61.
DR PDB; 6GH4; X-ray; 2.16 A; P/Q/R/Y=53-61.
DR PDB; 6GHN; X-ray; 2.54 A; P/Q=53-61.
DR PDB; 6R9W; X-ray; 1.75 A; A/B/C/D/E/F=1-269.
DR PDB; 6SQ5; X-ray; 1.84 A; A=1-269.
DR PDB; 6SQ7; X-ray; 1.76 A; A=1-269.
DR PDB; 6SQ9; X-ray; 1.75 A; A=1-269.
DR PDB; 6SQB; X-ray; 1.77 A; A=1-269.
DR PDB; 6SQD; X-ray; 1.72 A; A=1-269.
DR PDB; 6SQL; X-ray; 2.35 A; A=1-269.
DR PDB; 6ZKW; X-ray; 2.26 A; C=53-61.
DR PDB; 6ZKX; X-ray; 2.17 A; C=53-64.
DR PDB; 6ZKY; X-ray; 2.65 A; C=53-60.
DR PDB; 6ZKZ; X-ray; 2.30 A; C=53-60.
DR PDB; 7E48; X-ray; 2.50 A; A/B/C/D=1-269.
DR PDBsum; 1BVR; -.
DR PDBsum; 1ENY; -.
DR PDBsum; 1ENZ; -.
DR PDBsum; 1P44; -.
DR PDBsum; 1P45; -.
DR PDBsum; 1ZID; -.
DR PDBsum; 2AQ8; -.
DR PDBsum; 2AQH; -.
DR PDBsum; 2AQI; -.
DR PDBsum; 2AQK; -.
DR PDBsum; 2B35; -.
DR PDBsum; 2B36; -.
DR PDBsum; 2B37; -.
DR PDBsum; 2H9I; -.
DR PDBsum; 2IDZ; -.
DR PDBsum; 2IE0; -.
DR PDBsum; 2IEB; -.
DR PDBsum; 2IED; -.
DR PDBsum; 2NSD; -.
DR PDBsum; 2NTJ; -.
DR PDBsum; 2NV6; -.
DR PDBsum; 2PR2; -.
DR PDBsum; 2X22; -.
DR PDBsum; 2X23; -.
DR PDBsum; 3FNE; -.
DR PDBsum; 3FNF; -.
DR PDBsum; 3FNG; -.
DR PDBsum; 3FNH; -.
DR PDBsum; 3OEW; -.
DR PDBsum; 3OEY; -.
DR PDBsum; 3OF2; -.
DR PDBsum; 4BGE; -.
DR PDBsum; 4BGI; -.
DR PDBsum; 4BII; -.
DR PDBsum; 4BQP; -.
DR PDBsum; 4BQR; -.
DR PDBsum; 4COD; -.
DR PDBsum; 4D0R; -.
DR PDBsum; 4D0S; -.
DR PDBsum; 4DQU; -.
DR PDBsum; 4DRE; -.
DR PDBsum; 4DTI; -.
DR PDBsum; 4OHU; -.
DR PDBsum; 4OIM; -.
DR PDBsum; 4OXK; -.
DR PDBsum; 4OXN; -.
DR PDBsum; 4OXY; -.
DR PDBsum; 4OYR; -.
DR PDBsum; 4QXM; -.
DR PDBsum; 4R9R; -.
DR PDBsum; 4R9S; -.
DR PDBsum; 4TRJ; -.
DR PDBsum; 4TRM; -.
DR PDBsum; 4TRN; -.
DR PDBsum; 4TRO; -.
DR PDBsum; 4TZK; -.
DR PDBsum; 4TZT; -.
DR PDBsum; 4U0J; -.
DR PDBsum; 4U0K; -.
DR PDBsum; 4UVD; -.
DR PDBsum; 4UVE; -.
DR PDBsum; 4UVG; -.
DR PDBsum; 4UVH; -.
DR PDBsum; 4UVI; -.
DR PDBsum; 5COQ; -.
DR PDBsum; 5CP8; -.
DR PDBsum; 5CPB; -.
DR PDBsum; 5CPF; -.
DR PDBsum; 5G0S; -.
DR PDBsum; 5G0T; -.
DR PDBsum; 5G0U; -.
DR PDBsum; 5G0V; -.
DR PDBsum; 5G0W; -.
DR PDBsum; 5JFO; -.
DR PDBsum; 5MTP; -.
DR PDBsum; 5MTQ; -.
DR PDBsum; 5MTR; -.
DR PDBsum; 5OIF; -.
DR PDBsum; 5OIL; -.
DR PDBsum; 5OIM; -.
DR PDBsum; 5OIN; -.
DR PDBsum; 5OIT; -.
DR PDBsum; 5UGS; -.
DR PDBsum; 5UGT; -.
DR PDBsum; 5UGU; -.
DR PDBsum; 6EP8; -.
DR PDBsum; 6GGM; -.
DR PDBsum; 6GH1; -.
DR PDBsum; 6GH4; -.
DR PDBsum; 6GHN; -.
DR PDBsum; 6R9W; -.
DR PDBsum; 6SQ5; -.
DR PDBsum; 6SQ7; -.
DR PDBsum; 6SQ9; -.
DR PDBsum; 6SQB; -.
DR PDBsum; 6SQD; -.
DR PDBsum; 6SQL; -.
DR PDBsum; 6ZKW; -.
DR PDBsum; 6ZKX; -.
DR PDBsum; 6ZKY; -.
DR PDBsum; 6ZKZ; -.
DR PDBsum; 7E48; -.
DR AlphaFoldDB; P9WGR1; -.
DR SMR; P9WGR1; -.
DR STRING; 83332.Rv1484; -.
DR BindingDB; P9WGR1; -.
DR ChEMBL; CHEMBL1849; -.
DR DrugBank; DB07155; (3S)-1-CYCLOHEXYL-5-OXO-N-PHENYLPYRROLIDINE-3-CARBOXAMIDE.
DR DrugBank; DB07188; (3S)-1-CYCLOHEXYL-N-(3,5-DICHLOROPHENYL)-5-OXOPYRROLIDINE-3-CARBOXAMIDE.
DR DrugBank; DB07192; (3S)-N-(3-BROMOPHENYL)-1-CYCLOHEXYL-5-OXOPYRROLIDINE-3-CARBOXAMIDE.
DR DrugBank; DB07090; (3S)-N-(3-CHLORO-2-METHYLPHENYL)-1-CYCLOHEXYL-5-OXOPYRROLIDINE-3-CARBOXAMIDE.
DR DrugBank; DB07222; (3S)-N-(5-CHLORO-2-METHYLPHENYL)-1-CYCLOHEXYL-5-OXOPYRROLIDINE-3-CARBOXAMIDE.
DR DrugBank; DB07287; 2-(2,4-DICHLOROPHENOXY)-5-(PYRIDIN-2-YLMETHYL)PHENOL.
DR DrugBank; DB07178; 5-PENTYL-2-PHENOXYPHENOL.
DR DrugBank; DB00609; Ethionamide.
DR DrugBank; DB04289; Genz-10850.
DR DrugBank; DB00951; Isoniazid.
DR DrugBank; DB07123; N-(4-METHYLBENZOYL)-4-BENZYLPIPERIDINE.
DR DrugBank; DB05154; Pretomanid.
DR DrugBank; DB02990; S-(2-Acetamidoethyl) hexadecanethioate.
DR DrugBank; DB08604; Triclosan.
DR DrugCentral; P9WGR1; -.
DR SwissLipids; SLP:000000967; -.
DR iPTMnet; P9WGR1; -.
DR PaxDb; P9WGR1; -.
DR DNASU; 886523; -.
DR GeneID; 45425463; -.
DR GeneID; 886523; -.
DR KEGG; mtu:Rv1484; -.
DR TubercuList; Rv1484; -.
DR eggNOG; COG0623; Bacteria.
DR OMA; GILDMIH; -.
DR PhylomeDB; P9WGR1; -.
DR BioCyc; MetaCyc:G185E-5668-MON; -.
DR BRENDA; 1.3.1.118; 3445.
DR BRENDA; 1.3.1.9; 3445.
DR UniPathway; UPA00915; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0009274; C:peptidoglycan-based cell wall; HDA:MTBBASE.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR GO; GO:0004318; F:enoyl-[acyl-carrier-protein] reductase (NADH) activity; IDA:MTBBASE.
DR GO; GO:0016631; F:enoyl-[acyl-carrier-protein] reductase activity; IEA:UniProtKB-EC.
DR GO; GO:0005504; F:fatty acid binding; IDA:MTBBASE.
DR GO; GO:0070403; F:NAD+ binding; IDA:MTBBASE.
DR GO; GO:0050343; F:trans-2-enoyl-CoA reductase (NAD+) activity; IEA:RHEA.
DR GO; GO:0030497; P:fatty acid elongation; IMP:MTBBASE.
DR GO; GO:0071768; P:mycolic acid biosynthetic process; IDA:MTBBASE.
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 1: Evidence at protein level;
KW 3D-structure; Antibiotic resistance; Fatty acid biosynthesis;
KW Fatty acid metabolism; Lipid biosynthesis; Lipid metabolism; NAD;
KW Oxidoreductase; Phosphoprotein; Reference proteome.
FT CHAIN 1..269
FT /note="Enoyl-[acyl-carrier-protein] reductase [NADH]"
FT /id="PRO_0000054916"
FT BINDING 20..21
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:10336454,
FT ECO:0000269|PubMed:16647717, ECO:0000269|PubMed:7886450,
FT ECO:0007744|PDB:1BVR, ECO:0007744|PDB:1ENY,
FT ECO:0007744|PDB:2AQ8"
FT BINDING 64..65
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:10336454,
FT ECO:0000269|PubMed:16647717, ECO:0000269|PubMed:7886450,
FT ECO:0007744|PDB:1BVR, ECO:0007744|PDB:1ENY,
FT ECO:0007744|PDB:2AQ8"
FT BINDING 95..96
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:10336454,
FT ECO:0000269|PubMed:16647717, ECO:0000269|PubMed:7886450,
FT ECO:0007744|PDB:1BVR, ECO:0007744|PDB:1ENY,
FT ECO:0007744|PDB:2AQ8"
FT BINDING 158
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:10336454"
FT BINDING 165
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:10336454,
FT ECO:0000269|PubMed:16647717, ECO:0000269|PubMed:7886450,
FT ECO:0007744|PDB:1BVR, ECO:0007744|PDB:1ENY,
FT ECO:0007744|PDB:2AQ8"
FT BINDING 194
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:10336454,
FT ECO:0000269|PubMed:16647717, ECO:0000269|PubMed:7886450,
FT ECO:0007744|PDB:1BVR, ECO:0007744|PDB:1ENY,
FT ECO:0007744|PDB:2AQ8"
FT SITE 149
FT /note="May act as an intermediate that passes the hydride
FT ion from NADH to the substrate"
FT /evidence="ECO:0000305|PubMed:10336454"
FT SITE 158
FT /note="Transition state stabilizer"
FT /evidence="ECO:0000305|PubMed:10521269"
FT MOD_RES 266
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:20864541,
FT ECO:0000269|PubMed:21143326"
FT MUTAGEN 94
FT /note="S->A: Confers INH and ETH resistance. The mutant is
FT 17 times more resistant to inhibition by the INH-NAD
FT adduct. 5- to 6-fold decrease in affinity for NADH that
FT results from a perturbation in the hydrogen-bonding network
FT that stabilizes NADH binding. Nearly no effect on the
FT velocity of the enzyme. Has no impact on the susceptibility
FT to pyridomycin."
FT /evidence="ECO:0000269|PubMed:16906155,
FT ECO:0000269|PubMed:22987724, ECO:0000269|PubMed:7599116,
FT ECO:0000269|PubMed:7886450"
FT MUTAGEN 148
FT /note="D->G: Confers pyridomycin resistance. Has no impact
FT on the susceptibility to isoniazid and moxifloxacin. 14-
FT fold decrease in NADH affinity, while no effect on
FT catalytic activity."
FT /evidence="ECO:0000269|PubMed:22987724"
FT MUTAGEN 158
FT /note="Y->A: 1500-fold decrease in catalytic activity while
FT no effect on lipid substrate affinity."
FT /evidence="ECO:0000269|PubMed:10521269"
FT MUTAGEN 158
FT /note="Y->F: 24-fold decrease in catalytic activity while
FT no effect on lipid substrate affinity."
FT /evidence="ECO:0000269|PubMed:10521269"
FT MUTAGEN 158
FT /note="Y->S: No effect on catalytic activity."
FT /evidence="ECO:0000269|PubMed:10521269"
FT MUTAGEN 165
FT /note="K->A,M: Loss of enzyme's ability to bind NADH."
FT /evidence="ECO:0000269|PubMed:10521269"
FT MUTAGEN 165
FT /note="K->Q,R: No effect on the enzyme's catalytic ability
FT or on its ability to bind NADH."
FT /evidence="ECO:0000269|PubMed:10521269"
FT MUTAGEN 266
FT /note="T->A: No effect on catalytic activity. Loss of
FT phosphorylation. Does not alter growth of M.tuberculosis."
FT /evidence="ECO:0000269|PubMed:21143326"
FT MUTAGEN 266
FT /note="T->D,E: Severely impairs catalytic activity, as a
FT consequence of a reduced binding affinity to NADH. These
FT single point mutations are lethal to M.tuberculosis. These
FT mutants fail to complement growth and mycolic acid defects
FT of an inhA-thermosensitive M.smegmatis strain, in a similar
FT manner to what is observed following isoniazid treatment."
FT /evidence="ECO:0000269|PubMed:21143326"
FT TURN 4..7
FT /evidence="ECO:0007829|PDB:4TRO"
FT STRAND 9..13
FT /evidence="ECO:0007829|PDB:4TRO"
FT STRAND 16..20
FT /evidence="ECO:0007829|PDB:2IED"
FT HELIX 21..31
FT /evidence="ECO:0007829|PDB:4TRO"
FT STRAND 35..40
FT /evidence="ECO:0007829|PDB:4TRO"
FT HELIX 44..51
FT /evidence="ECO:0007829|PDB:4TRO"
FT STRAND 54..56
FT /evidence="ECO:0007829|PDB:4TRO"
FT STRAND 60..62
FT /evidence="ECO:0007829|PDB:4TRO"
FT HELIX 68..82
FT /evidence="ECO:0007829|PDB:4TRO"
FT STRAND 88..93
FT /evidence="ECO:0007829|PDB:4TRO"
FT HELIX 100..102
FT /evidence="ECO:0007829|PDB:4TRO"
FT STRAND 103..106
FT /evidence="ECO:0007829|PDB:5G0T"
FT HELIX 108..110
FT /evidence="ECO:0007829|PDB:4TRO"
FT HELIX 113..123
FT /evidence="ECO:0007829|PDB:4TRO"
FT HELIX 125..134
FT /evidence="ECO:0007829|PDB:4TRO"
FT HELIX 135..137
FT /evidence="ECO:0007829|PDB:4TRO"
FT STRAND 138..148
FT /evidence="ECO:0007829|PDB:4TRO"
FT STRAND 152..154
FT /evidence="ECO:0007829|PDB:5G0T"
FT TURN 156..158
FT /evidence="ECO:0007829|PDB:4TRO"
FT HELIX 159..180
FT /evidence="ECO:0007829|PDB:4TRO"
FT TURN 181..183
FT /evidence="ECO:0007829|PDB:4TRO"
FT STRAND 185..191
FT /evidence="ECO:0007829|PDB:4TRO"
FT HELIX 197..203
FT /evidence="ECO:0007829|PDB:4TRO"
FT TURN 204..207
FT /evidence="ECO:0007829|PDB:4TRO"
FT HELIX 209..225
FT /evidence="ECO:0007829|PDB:4TRO"
FT HELIX 236..246
FT /evidence="ECO:0007829|PDB:4TRO"
FT STRAND 247..249
FT /evidence="ECO:0007829|PDB:4TRO"
FT STRAND 255..261
FT /evidence="ECO:0007829|PDB:4TRO"
FT HELIX 264..266
FT /evidence="ECO:0007829|PDB:4TRO"
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
