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Protein

Enoyl-[acyl-carrier-protein] reductase [NADH]

Gene

inhA

Organism
Mycobacterium smegmatis (strain ATCC 700084 / mc(2)155)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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).By similarity2 Publications
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).By similarity2 Publications

Catalytic activityi

An acyl-[acyl-carrier protein] + NAD+ = a trans-2,3-dehydroacyl-[acyl-carrier protein] + NADH.1 Publication

Enzyme regulationi

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).By similarity2 Publications

Pathwayi: mycolic acid biosynthesis

This protein is involved in the pathway mycolic acid biosynthesis, which is part of Lipid metabolism.2 Publications
View all proteins of this organism that are known to be involved in the pathway mycolic acid biosynthesis and in Lipid metabolism.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei149May act as an intermediate that passes the hydride ion from NADH to the substrateBy similarity1
Binding sitei158SubstrateBy similarity1
Sitei158Transition state stabilizerBy similarity1
Binding sitei165NADBy similarity1
Binding sitei194NAD; via amide nitrogen and carbonyl oxygenBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi20 – 21NADBy similarity2
Nucleotide bindingi64 – 65NADBy similarity2
Nucleotide bindingi95 – 96NADBy similarity2

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Oxidoreductase

Keywords - Biological processi

Antibiotic resistance, Fatty acid biosynthesis, Fatty acid metabolism, Lipid biosynthesis, Lipid metabolism

Keywords - Ligandi

NAD

Enzyme and pathway databases

UniPathwayiUPA00915.

Names & Taxonomyi

Protein namesi
Recommended name:
Enoyl-[acyl-carrier-protein] reductase [NADH]1 Publication (EC:1.3.1.91 Publication)
Short name:
ENRBy similarity
Short name:
Enoyl-ACP reductase1 Publication
Alternative name(s):
FAS-II enoyl-ACP reductase1 Publication
NADH-dependent 2-trans-enoyl-ACP reductase1 Publication
Gene namesi
Name:inhA1 Publication
Ordered Locus Names:MSMEG_3151, MSMEI_3070
OrganismiMycobacterium smegmatis (strain ATCC 700084 / mc(2)155)
Taxonomic identifieri246196 [NCBI]
Taxonomic lineageiBacteriaActinobacteriaCorynebacterialesMycobacteriaceaeMycobacterium
Proteomesi
  • UP000006158 Componenti: Chromosome
  • UP000000757 Componenti: Chromosome

Subcellular locationi

  • Secretedcell wall 1 Publication

Keywords - Cellular componenti

Cell wall, Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi238V → F: Thermosensitive mutant that shows high resistance to INH and ETH. Displays total loss of catalytic activity at 42 degrees Celsius. Thermal inactivation of InhA in M.smegmatis results in the inhibition of mycolic acid biosynthesis, a decrease in hexadecanoic acid (C(16:0)) and a concomitant increase of tetracosanoic acid (C(24:0)) in a manner equivalent to that seen in INH-treated cells. Moreover, the InhA-inactivated cells, like INH-treated cells, undergo a drastic morphological change, leading to cell lysis. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000549131 – 269Enoyl-[acyl-carrier-protein] reductase [NADH]Add BLAST269

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei266PhosphothreonineBy similarity1

Post-translational modificationi

Is phosphorylated in vivo (PubMed:20864541). Phosphorylation on Thr-266 decreases enzymatic activity (By similarity).By similarity1 Publication

Keywords - PTMi

Phosphoprotein

Interactioni

Subunit structurei

Homodimer. Homotetramer.By similarity

Protein-protein interaction databases

STRINGi246196.MSMEG_3151.

Structurei

3D structure databases

ProteinModelPortaliP42829.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Phylogenomic databases

eggNOGiENOG4105CSJ. Bacteria.
COG0623. LUCA.
KOiK11611.
OMAiIFGVANE.
OrthoDBiPOG091H06HU.

Family and domain databases

Gene3Di3.40.50.720. 1 hit.
InterProiIPR014358. Enoyl-ACP_Rdtase_NADH.
IPR016040. NAD(P)-bd_dom.
IPR002347. SDR_fam.
[Graphical view]
PANTHERiPTHR24322. PTHR24322. 1 hit.
PTHR24322:SF317. PTHR24322:SF317. 1 hit.
PIRSFiPIRSF000094. Enoyl-ACP_rdct. 1 hit.
SUPFAMiSSF51735. SSF51735. 1 hit.

Sequencei

Sequence statusi: Complete.

P42829-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MTGLLEGKRI LVTGIITDSS IAFHIAKVAQ EAGAELVLTG FDRLKLVKRI
60 70 80 90 100
ADRLPKPAPL LELDVQNEEH LSTLADRITA EIGEGNKIDG VVHSIGFMPQ
110 120 130 140 150
SGMGINPFFD APYEDVSKGI HISAYSYASL AKAVLPIMNP GGGIVGMDFD
160 170 180 190 200
PTRAMPAYNW MTVAKSALES VNRFVAREAG KVGVRSNLVA AGPIRTLAMS
210 220 230 240 250
AIVGGALGDE AGQQMQLLEE GWDQRAPLGW NMKDPTPVAK TVCALLSDWL
260
PATTGTVIYA DGGASTQLL
Length:269
Mass (Da):28,527
Last modified:November 1, 1995 - v1
Checksum:iAD3BD962D2B78FC6
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural varianti94S → A in strain: mc(2)651; INH- and ETH-resistant. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U02530 Unassigned DNA. Translation: AAC43211.1.
CP000480 Genomic DNA. Translation: ABK73247.1.
CP001663 Genomic DNA. Translation: AFP39534.1.
RefSeqiWP_003894540.1. NZ_CP009494.1.
YP_887466.1. NC_008596.1.

Genome annotation databases

EnsemblBacteriaiABK73247; ABK73247; MSMEG_3151.
AFP39534; AFP39534; MSMEI_3070.
GeneIDi4537137.
KEGGimsb:LJ00_15670.
msg:MSMEI_3070.
msm:MSMEG_3151.
PATRICi18078728. VBIMycSme59918_3112.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U02530 Unassigned DNA. Translation: AAC43211.1.
CP000480 Genomic DNA. Translation: ABK73247.1.
CP001663 Genomic DNA. Translation: AFP39534.1.
RefSeqiWP_003894540.1. NZ_CP009494.1.
YP_887466.1. NC_008596.1.

3D structure databases

ProteinModelPortaliP42829.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi246196.MSMEG_3151.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsemblBacteriaiABK73247; ABK73247; MSMEG_3151.
AFP39534; AFP39534; MSMEI_3070.
GeneIDi4537137.
KEGGimsb:LJ00_15670.
msg:MSMEI_3070.
msm:MSMEG_3151.
PATRICi18078728. VBIMycSme59918_3112.

Phylogenomic databases

eggNOGiENOG4105CSJ. Bacteria.
COG0623. LUCA.
KOiK11611.
OMAiIFGVANE.
OrthoDBiPOG091H06HU.

Enzyme and pathway databases

UniPathwayiUPA00915.

Family and domain databases

Gene3Di3.40.50.720. 1 hit.
InterProiIPR014358. Enoyl-ACP_Rdtase_NADH.
IPR016040. NAD(P)-bd_dom.
IPR002347. SDR_fam.
[Graphical view]
PANTHERiPTHR24322. PTHR24322. 1 hit.
PTHR24322:SF317. PTHR24322:SF317. 1 hit.
PIRSFiPIRSF000094. Enoyl-ACP_rdct. 1 hit.
SUPFAMiSSF51735. SSF51735. 1 hit.
ProtoNetiSearch...

Entry informationi

Entry nameiINHA_MYCS2
AccessioniPrimary (citable) accession number: P42829
Secondary accession number(s): A0QX28, I7GAK9
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: November 1, 1995
Last modified: November 30, 2016
This is version 113 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programProkaryotic Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.