INHA_MYCS2
ID INHA_MYCS2 Reviewed; 269 AA.
AC P42829; A0QX28; I7GAK9;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 1.
DT 03-AUG-2022, entry version 143.
DE RecName: Full=Enoyl-[acyl-carrier-protein] reductase [NADH] {ECO:0000303|PubMed:10869086};
DE Short=ENR {ECO:0000250|UniProtKB:P9WGR1};
DE Short=Enoyl-ACP reductase {ECO:0000303|PubMed:10869086};
DE EC=1.3.1.9 {ECO:0000305|PubMed:10869086};
DE AltName: Full=FAS-II enoyl-ACP reductase {ECO:0000303|PubMed:10869086};
DE AltName: Full=NADH-dependent 2-trans-enoyl-ACP reductase {ECO:0000305|PubMed:10869086};
GN Name=inhA {ECO:0000303|PubMed:8284673};
GN OrderedLocusNames=MSMEG_3151, MSMEI_3070;
OS Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155) (Mycobacterium
OS smegmatis).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycolicibacterium.
OX NCBI_TaxID=246196;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], CHARACTERIZATION OF VARIANT SER-94, AND
RP DRUG RESISTANCE.
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 [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 700084 / mc(2)155;
RA Fleischmann R.D., Dodson R.J., Haft D.H., Merkel J.S., Nelson W.C.,
RA Fraser C.M.;
RL Submitted (OCT-2006) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 700084 / mc(2)155;
RX PubMed=17295914; DOI=10.1186/gb-2007-8-2-r20;
RA Deshayes C., Perrodou E., Gallien S., Euphrasie D., Schaeffer C.,
RA Van-Dorsselaer A., Poch O., Lecompte O., Reyrat J.-M.;
RT "Interrupted coding sequences in Mycobacterium smegmatis: authentic
RT mutations or sequencing errors?";
RL Genome Biol. 8:R20.1-R20.9(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 700084 / mc(2)155;
RX PubMed=18955433; DOI=10.1101/gr.081901.108;
RA Gallien S., Perrodou E., Carapito C., Deshayes C., Reyrat J.-M.,
RA Van Dorsselaer A., Poch O., Schaeffer C., Lecompte O.;
RT "Ortho-proteogenomics: multiple proteomes investigation through orthology
RT and a new MS-based protocol.";
RL Genome Res. 19:128-135(2009).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, DRUG TARGET, PATHWAY, AND MUTAGENESIS OF
RP VAL-238.
RC STRAIN=ATCC 700084 / mc(2)155;
RX PubMed=10869086; DOI=10.1128/jb.182.14.4059-4067.2000;
RA Vilcheze C., Morbidoni H.R., Weisbrod T.R., Iwamoto H., Kuo M.,
RA Sacchettini J.C., Jacobs W.R. Jr.;
RT "Inactivation of the inhA-encoded fatty acid synthase II (FASII) enoyl-acyl
RT carrier protein reductase induces accumulation of the FASI end products and
RT cell lysis of Mycobacterium smegmatis.";
RL J. Bacteriol. 182:4059-4067(2000).
RN [6]
RP FUNCTION IN THE FAS-II SYSTEM, ACTIVITY REGULATION, PATHWAY, AND
RP SUBCELLULAR LOCATION.
RC STRAIN=ATCC 700084 / mc(2)155;
RX PubMed=10708367; DOI=10.1099/00221287-146-2-289;
RA Marrakchi H., Laneelle G., Quemard A.;
RT "InhA, a target of the antituberculous drug isoniazid, is involved in a
RT mycobacterial fatty acid elongation system, FAS-II.";
RL Microbiology 146:289-296(2000).
RN [7]
RP DRUG TARGET, AND DRUG RESISTANCE.
RC STRAIN=ATCC 700084 / mc(2)155;
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 PHOSPHORYLATION AT THR-266, 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).
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:10708367).
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:10869086,
CC PubMed:10708367). Shows preference for long-chain fatty acyl thioester
CC substrates (>C16), and can also use 2-trans-enoyl-CoAs as alternative
CC substrates (By similarity). The mycobacterial FAS-II system utilizes
CC the products of the FAS-I system as primers to extend fatty acyl chain
CC lengths up to C56, forming the meromycolate chain that serves as the
CC precursor for final mycolic acids (PubMed:10869086, PubMed:10708367).
CC {ECO:0000250|UniProtKB:P9WGR1, ECO:0000269|PubMed:10708367,
CC ECO:0000269|PubMed:10869086}.
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:12406221, PubMed:10869086). Overexpressed inhA confers INH and
CC ETH resistance to M.smegmatis (PubMed:12406221). The mechanism of
CC isoniazid action against InhA is covalent attachment of the activated
CC form of the drug to the nicotinamide ring of NAD and binding of the
CC INH-NAD adduct to the active site of InhA (By similarity). Similarly,
CC the ETH-NAD adduct binds InhA (By similarity).
CC {ECO:0000250|UniProtKB:P9WGR1, ECO:0000269|PubMed:10869086,
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:0000305|PubMed:10869086};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:10242;
CC Evidence={ECO:0000305|PubMed:10869086};
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:10869086};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:18179;
CC Evidence={ECO:0000305|PubMed:10869086};
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:10869086};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63233;
CC Evidence={ECO:0000305|PubMed:10869086};
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:10869086};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45409;
CC Evidence={ECO:0000305|PubMed:10869086};
CC -!- ACTIVITY REGULATION: InhA activity is controlled via phosphorylation:
CC phosphorylation on Thr-266 decreases InhA activity and likely
CC negatively regulates biosynthesis of mycolic acids and growth of the
CC bacterium (PubMed:20864541) (By similarity). InhA activity is likely
CC inhibited by activated isoniazid, hexadecynoyl-CoA and octadecynoyl-
CC CoA, which also block the biosynthesis of mycolic acids
CC (PubMed:10708367). 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 (By similarity). The inhibitory adduct is the isonicotinic-acyl-
CC NADH where the isonicotinic-acyl group replaces the 4S (and not the 4R)
CC hydrogen of NADH (By similarity). 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 (By similarity). {ECO:0000250|UniProtKB:P9WGR1,
CC ECO:0000305|PubMed:10708367, ECO:0000305|PubMed:20864541}.
CC -!- PATHWAY: Lipid metabolism; mycolic acid biosynthesis.
CC {ECO:0000269|PubMed:10708367, ECO:0000269|PubMed:10869086}.
CC -!- SUBUNIT: Homodimer. Homotetramer. {ECO:0000250|UniProtKB:P9WGR1}.
CC -!- SUBCELLULAR LOCATION: Secreted, cell wall
CC {ECO:0000269|PubMed:10708367}.
CC -!- PTM: Is phosphorylated in vivo (PubMed:20864541). Phosphorylation on
CC Thr-266 decreases enzymatic activity (By similarity).
CC {ECO:0000250|UniProtKB:P9WGR1, ECO:0000269|PubMed:20864541}.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC family. FabI subfamily. {ECO:0000305}.
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DR EMBL; U02530; AAC43211.1; -; Unassigned_DNA.
DR EMBL; CP000480; ABK73247.1; -; Genomic_DNA.
DR EMBL; CP001663; AFP39534.1; -; Genomic_DNA.
DR RefSeq; WP_003894540.1; NZ_SIJM01000002.1.
DR RefSeq; YP_887466.1; NC_008596.1.
DR AlphaFoldDB; P42829; -.
DR SMR; P42829; -.
DR STRING; 246196.MSMEI_3070; -.
DR PRIDE; P42829; -.
DR EnsemblBacteria; ABK73247; ABK73247; MSMEG_3151.
DR EnsemblBacteria; AFP39534; AFP39534; MSMEI_3070.
DR GeneID; 66734552; -.
DR KEGG; msg:MSMEI_3070; -.
DR KEGG; msm:MSMEG_3151; -.
DR PATRIC; fig|246196.19.peg.3112; -.
DR eggNOG; COG0623; Bacteria.
DR OMA; GILDMIH; -.
DR OrthoDB; 762291at2; -.
DR BRENDA; 1.3.1.118; 3512.
DR BRENDA; 1.3.1.9; 3512.
DR UniPathway; UPA00915; -.
DR Proteomes; UP000000757; Chromosome.
DR Proteomes; UP000006158; Chromosome.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-KW.
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 1: Evidence at protein level;
KW Antibiotic resistance; Cell wall; Fatty acid biosynthesis;
KW Fatty acid metabolism; Lipid biosynthesis; Lipid metabolism; NAD;
KW Oxidoreductase; Phosphoprotein; Reference proteome; Secreted.
FT CHAIN 1..269
FT /note="Enoyl-[acyl-carrier-protein] reductase [NADH]"
FT /id="PRO_0000054913"
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"
FT VARIANT 94
FT /note="S -> A (in strain: mc(2)651; INH- and ETH-
FT resistant)"
FT /evidence="ECO:0000269|PubMed:8284673"
FT MUTAGEN 238
FT /note="V->F: Thermosensitive mutant that shows high
FT resistance to INH and ETH. Displays total loss of catalytic
FT activity at 42 degrees Celsius. Thermal inactivation of
FT InhA in M.smegmatis results in the inhibition of mycolic
FT acid biosynthesis, a decrease in hexadecanoic acid
FT (C(16:0)) and a concomitant increase of tetracosanoic acid
FT (C(24:0)) in a manner equivalent to that seen in INH-
FT treated cells. Moreover, the InhA-inactivated cells, like
FT INH-treated cells, undergo a drastic morphological change,
FT leading to cell lysis."
FT /evidence="ECO:0000269|PubMed:10869086"
SQ SEQUENCE 269 AA; 28527 MW; AD3BD962D2B78FC6 CRC64;
MTGLLEGKRI LVTGIITDSS IAFHIAKVAQ EAGAELVLTG FDRLKLVKRI ADRLPKPAPL
LELDVQNEEH LSTLADRITA EIGEGNKIDG VVHSIGFMPQ SGMGINPFFD APYEDVSKGI
HISAYSYASL AKAVLPIMNP GGGIVGMDFD PTRAMPAYNW MTVAKSALES VNRFVAREAG
KVGVRSNLVA AGPIRTLAMS AIVGGALGDE AGQQMQLLEE GWDQRAPLGW NMKDPTPVAK
TVCALLSDWL PATTGTVIYA DGGASTQLL
