| IED ID | IndEnz0018000544 |
| Enzyme Type ID | peroxidase000544 |
| Protein Name |
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 |
| Gene Name | inhA MSMEG_3151 MSMEI_3070 |
| Organism | Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155) (Mycobacterium smegmatis) |
| Taxonomic Lineage | cellular organisms Bacteria Terrabacteria group Actinobacteria Actinomycetia (high G+C Gram-positive bacteria) Corynebacteriales Mycobacteriaceae Mycolicibacterium Mycolicibacterium smegmatis (Mycobacterium smegmatis) Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155) (Mycobacterium smegmatis) |
| Enzyme Sequence | MTGLLEGKRILVTGIITDSSIAFHIAKVAQEAGAELVLTGFDRLKLVKRIADRLPKPAPLLELDVQNEEHLSTLADRITAEIGEGNKIDGVVHSIGFMPQSGMGINPFFDAPYEDVSKGIHISAYSYASLAKAVLPIMNPGGGIVGMDFDPTRAMPAYNWMTVAKSALESVNRFVAREAGKVGVRSNLVAAGPIRTLAMSAIVGGALGDEAGQQMQLLEEGWDQRAPLGWNMKDPTPVAKTVCALLSDWLPATTGTVIYADGGASTQLL |
| Enzyme Length | 269 |
| Uniprot Accession Number | P42829 |
| Absorption | |
| Active Site | |
| Activity Regulation | ACTIVITY REGULATION: InhA activity is controlled via phosphorylation: phosphorylation on Thr-266 decreases InhA activity and likely negatively regulates biosynthesis of mycolic acids and growth of the bacterium (PubMed:20864541) (By similarity). InhA activity is likely inhibited by activated isoniazid, hexadecynoyl-CoA and octadecynoyl-CoA, which also block the biosynthesis of mycolic acids (PubMed:10708367). 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 (By similarity). The inhibitory adduct is the isonicotinic-acyl-NADH where the isonicotinic-acyl group replaces the 4S (and not the 4R) hydrogen of NADH (By similarity). 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 (By similarity). {ECO:0000250|UniProtKB:P9WGR1, ECO:0000305|PubMed:10708367, ECO:0000305|PubMed:20864541}. |
| Binding Site | BINDING 158; /note=Substrate; /evidence=ECO:0000250|UniProtKB:P9WGR1; BINDING 165; /note=NAD; /evidence=ECO:0000250|UniProtKB:P9WGR1; BINDING 194; /note=NAD; via amide nitrogen and carbonyl oxygen; /evidence=ECO:0000250|UniProtKB:P9WGR1 |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=a 2,3-saturated acyl-[ACP] + NAD(+) = a (2E)-enoyl-[ACP] + H(+) + NADH; Xref=Rhea:RHEA:10240, Rhea:RHEA-COMP:9925, Rhea:RHEA-COMP:9926, ChEBI:CHEBI:15378, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:78784, ChEBI:CHEBI:78785; EC=1.3.1.9; Evidence={ECO:0000305|PubMed:10869086};PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:10242; Evidence={ECO:0000305|PubMed:10869086}; CATALYTIC ACTIVITY: Reaction=a 2,3-saturated acyl-CoA + NAD(+) = a (2E)-enoyl-CoA + H(+) + NADH; Xref=Rhea:RHEA:18177, ChEBI:CHEBI:15378, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:58856, ChEBI:CHEBI:65111; Evidence={ECO:0000269|PubMed:10869086};PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:18179; Evidence={ECO:0000305|PubMed:10869086}; CATALYTIC ACTIVITY: Reaction=(2E)-octenoyl-CoA + H(+) + NADH = NAD(+) + octanoyl-CoA; Xref=Rhea:RHEA:63232, ChEBI:CHEBI:15378, ChEBI:CHEBI:57386, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:62242; Evidence={ECO:0000269|PubMed:10869086};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63233; Evidence={ECO:0000305|PubMed:10869086}; CATALYTIC ACTIVITY: Reaction=(2E)-dodecenoyl-CoA + H(+) + NADH = dodecanoyl-CoA + NAD(+); Xref=Rhea:RHEA:45408, ChEBI:CHEBI:15378, ChEBI:CHEBI:57330, ChEBI:CHEBI:57375, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; Evidence={ECO:0000269|PubMed:10869086};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45409; Evidence={ECO:0000305|PubMed:10869086}; |
| DNA Binding | |
| EC Number | 1.3.1.9 |
| Enzyme Function | 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:10708367). 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:10869086, PubMed:10708367). Shows preference for long-chain fatty acyl thioester substrates (>C16), and can also use 2-trans-enoyl-CoAs as alternative substrates (By similarity). 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:10869086, PubMed:10708367). {ECO:0000250|UniProtKB:P9WGR1, ECO:0000269|PubMed:10708367, ECO:0000269|PubMed:10869086}.; FUNCTION: Is the primary target of the first-line antitubercular drug isoniazid (INH) and of the second-line drug ethionamide (ETH) (PubMed:12406221, PubMed:10869086). Overexpressed inhA confers INH and ETH resistance to M.smegmatis (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 (By similarity). Similarly, the ETH-NAD adduct binds InhA (By similarity). {ECO:0000250|UniProtKB:P9WGR1, ECO:0000269|PubMed:10869086, ECO:0000269|PubMed:12406221}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | PATHWAY: Lipid metabolism; mycolic acid biosynthesis. {ECO:0000269|PubMed:10708367, ECO:0000269|PubMed:10869086}. |
| nucleotide Binding | NP_BIND 20..21; /note=NAD; /evidence=ECO:0000250|UniProtKB:P9WGR1; NP_BIND 64..65; /note=NAD; /evidence=ECO:0000250|UniProtKB:P9WGR1; NP_BIND 95..96; /note=NAD; /evidence=ECO:0000250|UniProtKB:P9WGR1 |
| Features | Binding site (3); Chain (1); Modified residue (1); Mutagenesis (1); Natural variant (1); Nucleotide binding (3); Site (2) |
| Keywords | Antibiotic resistance;Cell wall;Fatty acid biosynthesis;Fatty acid metabolism;Lipid biosynthesis;Lipid metabolism;NAD;Oxidoreductase;Phosphoprotein;Reference proteome;Secreted |
| Interact With | |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Secreted, cell wall {ECO:0000269|PubMed:10708367}. |
| Modified Residue | MOD_RES 266; /note=Phosphothreonine; /evidence=ECO:0000250|UniProtKB:P9WGR1 |
| Post Translational Modification | PTM: Is phosphorylated in vivo (PubMed:20864541). Phosphorylation on Thr-266 decreases enzymatic activity (By similarity). {ECO:0000250|UniProtKB:P9WGR1, ECO:0000269|PubMed:20864541}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | - |
| Motif | |
| Gene Encoded By | |
| Mass | 28,527 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | RHEA:10240; RHEA:10242; RHEA:18177; RHEA:18179; RHEA:63232; RHEA:63233; RHEA:45408; RHEA:45409 |
| Cross Reference Brenda | 1.3.1.118;1.3.1.9; |