Rv3826 (fadD23)

Current annotations:
- TBCAP: (community-based annotations - see table at bottom of page)
- TBDB: fatty acid CoA ligase FadD23
- REFSEQ: acyl-CoA synthetase
- PATRIC: Long-chain-fatty-acid--CoA ligase (EC 6.2.1.3)
- TUBERCULIST: Probable fatty-acid-AMP ligase FadD23 (fatty-acid-AMP synthetase) (fatty-acid-AMP synthase)
- NCBI: Probable fatty-acid-AMP ligase FadD23 (fatty-acid-AMP synthetase) (fatty-acid-AMP synthase)
- updated information (H37Rv4):
  - gene name: fadD23
  - function: sulfolipid-1 synthesis
  - reference: Yan 2023; PMID: 36896429
Type: Not Target
Start: 4299812
End: 4301566
Operon:

Trans-membrane region:
Role: I.A.3 - Fatty acids
GO terms:
- GO:0102391 - decanoate-CoA ligase activity (Uniprot)
- GO:0071766 - Actinobacterium-type cell wall biogenesis (Uniprot)
- GO:0070566 - adenylyltransferase activity (Uniprot)
- GO:0046506 - sulfolipid biosynthetic process (Uniprot)
- GO:0016874 - ligase activity (Uniprot)
- GO:0016021 - integral component of membrane (Uniprot)
- GO:0016020 - membrane (Uniprot)
- GO:0008152 - metabolic process (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:0005524 - ATP binding (Uniprot)
- GO:0004467 - long-chain fatty acid-CoA ligase activity (Uniprot)
- GO:0003824 - catalytic activity (Uniprot)
- GO:0001676 - long-chain fatty acid metabolic process (Uniprot)
- GO:0000166 - nucleotide binding (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:
Search for Homologs in PDB

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

PDB	aa ident	species	PDB title
3E53	64%	Mycobacterium tuberculosis	Crystal structure of N-terminal domain of a Fatty Acyl AMP Ligase FAAL28 from Mycobacterium tuberculosis
3T5A	64%	Mycobacterium tuberculosis	Crystal structure of N-terminal domain of FAAL28 G330W mutant from Mycobacterium tuberculosis
5D6N	37%	Mycobacterium smegmatis (strain ATCC 700084 / mc(2)155)	Crystal structure of a mycobacterial protein
5ICR	36%	Mycobacterium smegmatis (strain ATCC 700084 / mc(2)155)	2.25 Angstrom Resolution Crystal Structure of Fatty-Acid-CoA Ligase (FadD32) from Mycobacterium smegmatis in complex with Inhibitor 5'-O-[(11-phenoxyundecanoyl)sulfamoyl]adenosine.
5EY9	36%	Mycobacterium marinum	Structure of FadD32 from Mycobacterium marinum complexed to AMPC12
5EY8	36%	Mycobacterium smegmatis	Structure of FadD32 from Mycobacterium smegmatis complexed to AMPC20
5D6J	36%	Mycobacterium smegmatis (strain ATCC 700084 / mc(2)155)	Crystal structure of a mycobacterial protein
5HM3	36%	Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)	2.25 Angstrom Resolution Crystal Structure of Long-chain-fatty-acid-AMP Ligase FadD32 from Mycobacterium tuberculosis in complex with Inhibitor 5'-O-[(11-phenoxyundecanoyl)sulfamoyl]adenosine

Links to additional information on fadD23:
- Mycobrowser
- PATRIC
- TBDB (updated)
- Phyre2 structure prediction, model: final.casp.pdb (from Mao et al, 2013)
- UniProt
- AlphaFold model
- Vulnerability = 2.117 (from Jeremy Rock's lab)
- KEGG - nucleotide and amino acid sequences of gene
- BioCyc
- Systems Biology

Amino Acid Sequence

MVSLSIPSMLRQCVNLHPDGTAFTYIDYERDSEGISESLTWSQVYRRTLNVAAEVRRHAAIGDRAVILAPQGLDYIVAFLGALQAGLIAVPLSAPLGGAS
DERVDAVVRDAKPNVVLTTSAIMGDVVPRVTPPPGIASPPTVAVDQLDLDSPIRSNIVDDSLQTTAYLQYTSGSTRTPAGVMITYKNILANFQQMISAYF
ADTGAVPPLDLFIMSWLPFYHDMGLVLGVCAPIIVGCGAVLTSPVAFLQRPARWLQLMAREGQAFSAAPNFAFELTAAKAIDDDLAGLDLGRIKTILCGS
ERVHPATLKRFVDRFSRFNLREFAIRPAYGLAEATVYVATSQAGQPPEIRYFEPHELSAGQAKPCATGAGTALVSYPLPQSPIVRIVDPNTNTECPPGTI
GEIWVHGDNVAGGYWEKPDETERTFGGALVAPSAGTPVGPWLRTGDSGFVSEDKFFIIGRIKDLLIVYGRNHSPDDIEATIQEITRGRCAAIAVPSNGVE
KLVAIVELNNRGNLDTERLSFVTREVTSAISTSHGLSVSDLVLVAPGSIPITTSGKVRRAECVKLYRHNEFTRLDAKPLQASDL

(Nucleotide sequence available on KEGG)

Additional Information

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)	1.66 (0.52)	1.61 (0.73)
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

Rv3826/fadD23, gene len: 1754 bp, num TA sites: 51

condition	dataset	call	medium	method	notes
in-vitro	DeJesus 2017 mBio	non-essential	7H9	HMM	fully saturated, 14 TnSeq libraries combined
in-vitro	Sassetti 2003 Mol Micro	no data	7H9	TRASH	essential if hybridization ratio<0.2
in-vivo (mice)	Sassetti 2003 PNAS	no data	BL6 mice	TRASH	essential if hybridization ratio<0.4, min over 4 timepoints (1-8 weeks)
in-vitro (glycerol)	Griffin 2011 PPath	non-essential	M9 minimal+glycerol	Gumbel	2 replicates; Padj<0.05
in-vitro (cholesterol)	Griffin 2011 PPath	non-essential	M9 minimal+cholesterol	Gumbel	3 replicates; Padj<0.05
differentially essential in cholesterol	Griffin 2011 PPath	NO (LFC=-0.64)	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	non-essential	7H9	HMM	6 replicates (raw data in Subramaniam 2017, PMID 31752678)
in-vivo (mice)	Smith 2022 eLife	non-essential	BL6 mice	HMM	6 replicates (raw data in Subramaniam 2017, PMID 31752678)
differentially essential in mice	Smith 2022 eLife	NO (LFC=0.202)	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	non-essential	minimal medium	HMM
in-vitro (YM rich medium)	Minato 2019 mSys	non-essential	YM rich medium	HMM	7H9 supplemented with ~20 metabolites (amino acids, vitamins)
differentially essential in YM rich medium	Minato 2019 mSys	NO (LFC=1.1)	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:

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

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

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:

Property	Value	Creator	Evidence	PMID	Comment
Citation	Selection of transposon mutants of Mycobacterium tuberculosis with increased macrophage infectivity identifies fadD23 to be involved in sulfolipid production and association with macrophages. J. Lynett & RW. Stokes Microbiology (Reading, Engl.) 2007	ashwinigbhat	IEP	17768256	Co-expression (Functional linkage)
Interaction	Transcription Rv1221	ashwinigbhat	IEP		Co-expression (Functional linkage) J. Lynett & RW. Stokes Selection of transposon mutants of Mycobacterium tuberculosis with increased macrophage infectivity identifies fadD23 to be involved in sulfolipid production and association with macrophages. Microbiology (Reading, Engl.) 2007
Citation	[Prevention and therapy of disorders of pulmonary microcirculation]. authors,KT. Schricker Klin Anasthesiol Intensivther 1979	ashwinigbhat	IEP	94119	Co-expression (Functional linkage)
Interaction	Transcription Rv1221	ashwinigbhat	IEP		Co-expression (Functional linkage) authors,KT. Schricker [Prevention and therapy of disorders of pulmonary microcirculation]. Klin Anasthesiol Intensivther 1979
Interaction	PhysicalInteraction Rv3827c	priti.priety	IMP		Affinity purification (Physical interaction) J. Lynett & RW. Stokes Selection of transposon mutants of Mycobacterium tuberculosis with increased macrophage infectivity identifies fadD23 to be involved in sulfolipid production and association with macrophages. Microbiology (Reading, Engl.) 2007
Interaction	PhysicalInteraction Rv3827c	ashwinigbhat	IMP		Affinity purification (Physical interaction) J. Lynett & RW. Stokes Selection of transposon mutants of Mycobacterium tuberculosis with increased macrophage infectivity identifies fadD23 to be involved in sulfolipid production and association with macrophages. Microbiology (Reading, Engl.) 2007
Citation	Selection of transposon mutants of Mycobacterium tuberculosis with increased macrophage infectivity identifies fadD23 to be involved in sulfolipid production and association with macrophages. J. Lynett & RW. Stokes Microbiology (Reading, Engl.) 2007	priti.priety	IEP	17768256	Co-expression (Functional linkage)
Interaction	Transcription Rv1221	priti.priety	IEP		Co-expression (Functional linkage) J. Lynett & RW. Stokes Selection of transposon mutants of Mycobacterium tuberculosis with increased macrophage infectivity identifies fadD23 to be involved in sulfolipid production and association with macrophages. Microbiology (Reading, Engl.) 2007
Citation	[Prevention and therapy of disorders of pulmonary microcirculation]. authors,KT. Schricker Klin Anasthesiol Intensivther 1979	priti.priety	IEP	94119	Co-expression (Functional linkage)
Interaction	Transcription Rv1221	priti.priety	IEP		Co-expression (Functional linkage) authors,KT. Schricker [Prevention and therapy of disorders of pulmonary microcirculation]. Klin Anasthesiol Intensivther 1979
Interaction	RegulatedBy Rv1221	yamir.moreno	IEP		Microarrays. mRNA levels of regulated element measured and compared between wild-type and trans-element mutation (knockout, over expression etc.) performed by using microarray (or macroarray) experiments.. PA. Fontn, V. Aris et al. Mycobacterium tuberculosis Sigma Factor E Regulon Modulates the Host Inflammatory Response. J. Infect. Dis. 2008
Name	Probable fatty-acyl AMP ligase responsible for providing the long-chain fatty acid starter unit to Pks2 for the generation of phthioceranic and hydroxyphthioceranic acids	mjackson	ISS		Polymethyl-branched acyltrehaloses
Other	TBPWY:Polymethyl-branched acyltrehaloses	mjackson			Probable fatty-acyl AMP ligase responsible for providing the long-chain fatty acid starter unit to Pks2 for the generation of phthioceranic and hydroxyphthioceranic acids

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