Rv1484 (inhA)

Current annotations:
- TBCAP: (community-based annotations - see table at bottom of page)
- TBDB: enoyl-[acyl-carrier-protein] reductase [NADH]
- REFSEQ: enoyl-(acyl carrier protein) reductase
- PATRIC: Enoyl-[acyl-carrier-protein] reductase [NADH] (EC 1.3.1.9)
- TUBERCULIST: NADH-dependent enoyl-[acyl-carrier-protein] reductase InhA (NADH-dependent enoyl-ACP reductase)
- NCBI: NADH-dependent enoyl-[acyl-carrier-protein] reductase InhA (NADH-dependent enoyl-ACP reductase)
- updated information (H37Rv4):
  - gene name: inhA
  - function: aka 'fabI'
  - reference:
Type: Not Target
Start: 1674202
End: 1675011
Operon:

Trans-membrane region:
Role: I.H.1 - Synthesis of fatty and mycolic acids
GO terms:
- GO:0071768 - mycolic acid biosynthetic process (Uniprot)
- GO:0070403 - NAD+ binding (Uniprot)
- GO:0055114 - oxidation-reduction process (Uniprot)
- GO:0046677 - response to antibiotic (Uniprot)
- GO:0030497 - fatty acid elongation (Uniprot)
- GO:0016491 - oxidoreductase activity (Uniprot)
- GO:0006633 - fatty acid biosynthetic process (Uniprot)
- GO:0006631 - fatty acid metabolic process (Uniprot)
- GO:0006629 - lipid metabolic process (Uniprot)
- GO:0005886 - plasma membrane (Uniprot)
- GO:0005618 - cell wall (Uniprot)
- GO:0005504 - fatty acid binding (Uniprot)
- GO:0004318 - enoyl-[acyl-carrier-protein] reductase (NADH) activity (Uniprot)
Reaction(s) (based on iSM810 metabolic model):
Gene Expression Profile (Transcriptional Responses to Drugs; Boshoff et al, 2004)
Gene Modules extracted from cluster analysis of 249 transcriptomic datasets using ICA
Orthologs among selected mycobacteria
Protein structure: 3of2, 2pr2, 2nsd, 2ieb, 2b35, 2ied, 2nv6, 3oew, 2h9i, 2x23, 2x22, 4dqu, 1bvr, 2h7p, 2h7l, 2h7m, 2h7n, 2h7i, 2aq8, 2b36, 2b37, 2ie0, 2ntj, 4dti, 2idz, 4dre, 1p44, 1p45, 3fng, 3fnf, 1enz, 1eny, 3fne, 1zid, 3fnh, 2aqk, 2aqi, 2aqh, 3oey
Search for Homologs in PDB

Top 10 Homologs in PDB (as of Nov 2020):

PDB	aa ident	species	PDB title
6SQL	100%	Mycobacterium tuberculosis H37Rv	Crystal structure of M. tuberculosis InhA in complex with NAD+ and N-(3-(aminomethyl)phenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide
6SQD	100%	Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)	Crystal structure of M. tuberculosis InhA in complex with NAD+ and 2-pyrazol-1-ylbenzoic acid
6SQB	100%	Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)	Crystal structure of M. tuberculosis InhA in complex with NAD+ and 3-(3-chlorophenyl)propanoic acid
6SQ9	100%	Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)	Crystal structure of M. tuberculosis InhA in complex with NAD+ and 3-hydroxynaphthalene-2-carboxylic acid
6SQ7	100%	Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)	Crystal structure of M. tuberculosis InhA in complex with NAD+ and 2-(4-chloro-3-nitrobenzoyl)benzoic acid
6SQ5	100%	Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)	Crystal structure of M. tuberculosis InhA in complex with NAD+ and 3-[3-(trifluoromethyl)phenyl]prop-2-enoic acid
6R9W	100%	Mycobacterium tuberculosis H37Rv	Crystal structure of InhA in complex with AP-124 inhibitor
5W07	100%	Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh)	CRYSTAL STRUCTURE OF THE INHA FROM MYCOBACTERIUM TUBERCULOSIS IN COMPLEX WITH AN12855, EBSI 4333.
5VRN	100%	Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh)	CRYSTAL STRUCTURE OF THE INHA FROM MYCOBACTERIUM TUBERCULOSIS IN COMPLEX WITH AN12855, EBSI 4333.
5VRM	100%	Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh)	CRYSTAL STRUCTURE OF THE INHA FROM MYCOBACTERIUM TUBERCULOSIS IN COMPLEX WITH AN12855, EBSI 4333.

Links to additional information on inhA:
- TBDB (updated)
- Phyre2 structure prediction, model: final.casp.pdb (from Mao et al, 2013)
- UniProt
- AlphaFold model
- Vulnerability = -9.913 (from Jeremy Rock's lab)
- Mycobrowser
- PATRIC
- KEGG - nucleotide and amino acid sequences of gene
- BioCyc
- Systems Biology

Amino Acid Sequence

MTGLLDGKRILVSGIITDSSIAFHIARVAQEQGAQLVLTGFDRLRLIQRITDRLPAKAPLLELDVQNEEHLASLAGRVTEAIGAGNKLDGVVHSIGFMPQ
TGMGINPFFDAPYADVSKGIHISAYSYASMAKALLPIMNPGGSIVGMDFDPSRAMPAYNWMTVAKSALESVNRFVAREAGKYGVRSNLVAAGPIRTLAMS
AIVGGALGEEAGAQIQLLEEGWDQRAPIGWNMKDATPVAKTVCALLSDWLPATTGDIIYADGGAHTQLL

(Nucleotide sequence available on KEGG)

Additional Information

aka FabI

Analysis of Positive Selection in Clinical Isolates new

Analysis of dN/dS (omega) in two collections of Mtb clinical isolates using GenomegaMap (Window model) (see description of methods)
- Moldova: 2,057 clinical isolates
- global set: 5,195 clinical isolates from 15 other countries
In the omega plots, the black line shows the mean estimate of omega (dN/dS) at each codon, and the blue lines are the bounds for the 95% credible interval (95%CI, from MCMC sampling).
A gene is under significant positive selection if the lower-bound of the 95%CI of omega (lower blue line) exceeds 1.0 at any codon.

	Moldova (2,057)	global set (5,195)
under significant positive selection?	NO	NO
omega peak height (95%CI lower bound)	2.33 (0.38)	1.51 (0.5)
codons under selection
omega plots
genetic variants*	link	link
statistics at each codon	link	link

* example format for variants: "D27 (GAC): D27H (CAC,11)" means "Asp27 (native codon GAC) mutated to His (codon CAC) in 11 isolates"

ESSENTIALITY

MtbTnDB - interactive tool for exploring a database of published TnSeq datasets for Mtb

TnSeqCorr - genes with correlated TnSeq profiles across ~100 conditions

Rv1484/inhA, gene len: 809 bp, num TA sites: 10

condition	dataset	call	medium	method	notes
in-vitro	DeJesus 2017 mBio	essential	7H9	HMM	fully saturated, 14 TnSeq libraries combined
in-vitro	Sassetti 2003 Mol Micro	non-essential	7H9	TRASH	essential if hybridization ratio<0.2
in-vivo (mice)	Sassetti 2003 PNAS	non-essential	BL6 mice	TRASH	essential if hybridization ratio<0.4, min over 4 timepoints (1-8 weeks)
in-vitro (glycerol)	Griffin 2011 PPath	essential	M9 minimal+glycerol	Gumbel	2 replicates; Padj<0.05
in-vitro (cholesterol)	Griffin 2011 PPath	essential	M9 minimal+cholesterol	Gumbel	3 replicates; Padj<0.05
differentially essential in cholesterol	Griffin 2011 PPath	NO (LFC=0.0)	cholesterol vs glycerol	resampling-SR	YES if Padj<0.05, else not significant; LFC<0 means less insertions/more essential in cholesterol
in-vitro	Smith 2022 eLife	essential	7H9	HMM	6 replicates (raw data in Subramaniam 2017, PMID 31752678)
in-vivo (mice)	Smith 2022 eLife	essential	BL6 mice	HMM	6 replicates (raw data in Subramaniam 2017, PMID 31752678)
differentially essential in mice	Smith 2022 eLife	NO (LFC=0.0)	in-vivo vs in-vitro	ZINB	YES if Padj<0.05, else not significant; LFC<0 means less insertions/more essential in mice
in-vitro (minimal)	Minato 2019 mSys	essential	minimal medium	HMM
in-vitro (YM rich medium)	Minato 2019 mSys	essential	YM rich medium	HMM	7H9 supplemented with ~20 metabolites (amino acids, cofactors)
differentially essential in YM rich medium	Minato 2019 mSys	NO (LFC=0.0)	YM rich vs minimal medium	resampling

TnSeq Data No data currently available.

No TnSeq data currently available for this Target.

RNASeq Data No data currently available.

No RNA-Seq data currently available for this Target.

Metabolomic Profiles No data currently available.

No Metabolomic data currently available for this Target.

Proteomic Data No data currently available.

No Proteomic data currently available for this Target.

Regulatory Relationships from Systems Biology

BioCyc

Gene interactions based on ChIPSeq and Transcription Factor Over-Expression (TFOE) (Systems Biology)

NOTE: Green edges represent the connected genes being classified as differentially essential as a result of the middle gene being knocked out. These interactions are inferred based on RNASeq.

Interactions based on ChIPSeq data

Binds To:
- No bindings to other targets were found.
Bound By:
- Rv0818 (-)

Interactions based on ChIPSeq data (Minch et al. 2014)

Binds To:
- No bindings to other targets were found.
Bound By:
- Rv0967 (csoR) (Direct binding)
- Rv1255c (-) (Direct binding)
- Rv1353c (-) (Upstream of operon)

Interactions based on TFOE data (Rustad et al. 2014)

Upregulates:
- Does not upregulate other genes.
Upregulated by:
- Not upregulated by other genes.
Downregulates:
- Does not downregulate other genes.
Downregulated by:
- Rv0818 (-)

Property	Value	Creator	Evidence	PMID	Comment
Term	TBRXN:FAS140 fatty acid synthase (n-C14:0) - IDA	njamshidi	IDA	10840036	mtFABH (Rv0533c) - link between FAS I and FAS II - highest affinity for C12:0, see PMID: 10840036 (since FA synthesis is lumped, does not extend immediately to FAS II). KH. Choi, L. Kremer et al. Identification and substrate specificity of beta -ketoacyl (acyl carrier protein) synthase III (mtFabH) from Mycobacterium tuberculosis. J. Biol. Chem. 2000
Citation	Identification and substrate specificity of beta -ketoacyl (acyl carrier protein) synthase III (mtFabH) from Mycobacterium tuberculosis. KH. Choi, L. Kremer et al. J. Biol. Chem. 2000	njamshidi	IDA	10840036	mtFABH (Rv0533c) - link between FAS I and FAS II - highest affinity for C12:0, see PMID: 10840036 (since FA synthesis is lumped, does not extend immediately to FAS II).
Term	EC:2.3.1.85 Fatty-acid synthase. - IDA	njamshidi	IDA	10840036	mtFABH (Rv0533c) - link between FAS I and FAS II - highest affinity for C12:0, see PMID: 10840036 (since FA synthesis is lumped, does not extend immediately to FAS II). KH. Choi, L. Kremer et al. Identification and substrate specificity of beta -ketoacyl (acyl carrier protein) synthase III (mtFabH) from Mycobacterium tuberculosis. J. Biol. Chem. 2000
Interaction	Inhibition Rv0197	aparna.vchalam	IPI		Affinity purification (Physical interaction) authors,L. Cabusora,E. Sutton,A. Fulmer,CV. Forst Differential network expression during drug and stress response. Bioinformatics 2005
Interaction	Inhibition Rv0197	aparna.vchalam	IPI		Affinity purification (Physical interaction) ME. Boyne, TJ. Sullivan et al. Targeting fatty acid biosynthesis for the development of novel chemotherapeutics against Mycobacterium tuberculosis: evaluation of A-ring-modified diphenyl ethers as high-affinity InhA inhibitors. Antimicrob. Agents Chemother. 2007
Name	2-trans-Enoyl-ACP reductase	mjackson	IDA		FAS-II
Citation	Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis. K. Takayama, C. Wang et al. Clin. Microbiol. Rev. 2005	jjmcfadden		15653820	Inferred from direct assay
Term	EC:2.1.1.- Transferases. Transferring one-carbon groups. Methyltransferases. - NR	jjmcfadden	NR		Inferred from direct assay K. Takayama, C. Wang et al. Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis. Clin. Microbiol. Rev. 2005
Term	EC:2.3.1.41 Beta-ketoacyl-acyl-carrier-protein synthase I. - NR	jjmcfadden	NR		Inferred from direct assay K. Takayama, C. Wang et al. Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis. Clin. Microbiol. Rev. 2005
Citation	Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. A. Qumard, JC. Sacchettini et al. Biochemistry 1995	extern:JZUCKER		7599116	Reaction blocked in mutant
Term	EC:1.3.1.10 Enoyl-[acyl-carrier-protein] reductase (NADPH, B-specific). - NR	extern:JZUCKER	NR		Reaction blocked in mutant A. Qumard, JC. Sacchettini et al. Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. Biochemistry 1995
Term	EC:1.3.1.9 Enoyl-[acyl-carrier-protein] reductase (NADH). - NR	extern:JZUCKER	NR		Reaction blocked in mutant A. Qumard, JC. Sacchettini et al. Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. Biochemistry 1995

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