Rv3823c (mmpL8)

Current annotations:
- TBCAP: (community-based annotations - see table at bottom of page)
- TBDB: membrane transporter mmpL8
- REFSEQ: integral membrane transport protein
- PATRIC: membrane protein MmpL family putative
- TUBERCULIST: Conserved integral membrane transport protein MmpL8
- NCBI: Conserved integral membrane transport protein MmpL8
- updated information (H37Rv4):
  - gene name: mmpL8
  - function: sulfolipid-1 synthesis
  - reference: Seeliger (2012) PMID: 22194604
Type: Not Target
Start: 4288260
End: 4291529
Operon:

Trans-membrane region:
Role: II.C.4 - Conserved membrane proteins
GO terms:
- GO:0071555 - cell wall organization (Uniprot)
- GO:0046506 - sulfolipid biosynthetic process (Uniprot)
- GO:0016021 - integral component of membrane (Uniprot)
- GO:0016020 - membrane (Uniprot)
- GO:0006869 - lipid transport (Uniprot)
- GO:0005886 - plasma membrane (Uniprot)
- GO:0005829 - cytosol (Uniprot)
- GO:0005618 - cell wall (Uniprot)
Reaction(s) (based on iSM810 metabolic model):
- SL1278_CYTO[c] -> SL1278_WALL[c]
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): (none with >35% aa id)
Links to additional information on mmpL8:
- TBDB (updated)
- Phyre2 structure prediction, model: final.casp.pdb (from Mao et al, 2013)
- UniProt
- AlphaFold model
- Vulnerability = 1.609 (from Jeremy Rock's lab)
- KEGG - nucleotide and amino acid sequences of gene
- Mycobrowser
- PATRIC
- BioCyc
- Systems Biology

Amino Acid Sequence

MCDVLMQPVRTPRPSTNLRSKPLRPTGDGGVFPRLGRLIVRRPWVVIAFWVALAGLLAPTVPSLDAISQRHPVAILPSDAPVLVSTRQMTAAFREAGLQS
VAVVVLSDAKGLGAADERSYKELVDALRRDTRDVVMLQDFVTTPPLRELMTSKDNQAWILPVGLPGDLGSTQSKQAYARVADIVEHQVAGSTLTANLTGP
AATVADLNLTGQRDRSRIEFAITILLLVILLIIYGNPITMVLPLITIGMSVVVAQRLVAIAGLAGLGIANQSIIFMSGMMVGAGTDYAVFLISRYHDYLR
QGADSDQAVKKALTSIGKVIAASAATVAITFLGMVFTQLGILKTVGPMLGISVAVVFFAAVTLLPALMVLTGRRGWIAPRRDLTRRFWRSSGVHIVRRPK
THLLASALVLVILAGCAGLARYNYDDRKTLPASVESSIGYAALDKHFPSNLIIPEYLFIQSSTDLRTPKALADLEQMVQRVSQVPGVAMVRGITRPAGRS
LEQARTSWQAGEVGSKLDEGSKQIAVHTGDIDKLAGGANLMASKLGDVRAQVNRAISTVGGLIDALAYLQDLLGGNRVLGELEGAEKLIGSMRALGDTID
ADASFVANNTEWASPVLGALDSSPMCTADPACASARTELQRLVTARDDGTLAKISELARQLQATRAVQTLAATVSGLRGALATVIRAMGSLGMSSPGGVR
SKINLVNKGVNDLADGSRQLAEGVQLLVDQVKKMGFGLGEASAFLLAMKDTATTPAMAGFYIPPELLSYATGESVKAETMPSEYRDLLGGLNVDQLKKVA
AAFISPDGHSIRYLIQTDLNPFSTAAMDQIDAITAAARGAQPNTALADAKVSVVGLPVVLKDTRDYSDHDLRLIIAMTVCIVLLILIVLLRAIVAPLYLI
GSVIVSYLAALGIGVIVFQFLLGQEMHWSIPGLTFVILVAVGADYNMLLISRLREEAVLGVRSGVIRTVASTGGVITAAGLIMAASMYGLVFASLGSVVQ
GAFVLGTGLLLDTFLVRTVTVPAIAVLVGQANWWLPSSWRPATWWPLGRRRGRAQRTKRKPLLPKEEEEQSPPDDDDLIGLWLHDGLRL

(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)	2.35 (0.83)	1.37 (0.69)
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

Rv3823c/mmpL8, gene len: 3269 bp, num TA sites: 79

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	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	uncertain	M9 minimal+glycerol	Gumbel	2 replicates; Padj<0.05
in-vitro (cholesterol)	Griffin 2011 PPath	uncertain	M9 minimal+cholesterol	Gumbel	3 replicates; Padj<0.05
differentially essential in cholesterol	Griffin 2011 PPath	NO (LFC=-0.12)	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	YES (LFC=-0.92)	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=0.5)	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:
- Rv0324 (-)
- Rv0757 (phoP)
Downregulates:
- Does not downregulate other genes.
Downregulated by:

Property	Value	Creator	Evidence	PMID	Comment
Citation	The Mycobacterium tuberculosis PhoPR two-component system regulates genes essential for virulence and complex lipid biosynthesis. SB. Walters, E. Dubnau et al. Mol. Microbiol. 2006	sourish10	IEP	16573683	Co-expression (Functional linkage)
Interaction	Transcription Rv0757	sourish10	IEP		Co-expression (Functional linkage) SB. Walters, E. Dubnau et al. The Mycobacterium tuberculosis PhoPR two-component system regulates genes essential for virulence and complex lipid biosynthesis. Mol. Microbiol. 2006
Interaction	RegulatedBy Rv0348	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.. B. Abomoelak, EA. Hoye et al. mosR, a novel transcriptional regulator of hypoxia and virulence in Mycobacterium tuberculosis. J. Bacteriol. 2009
Interaction	RegulatedBy Rv0757	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.. qRT-PCR. mRNA expression levels of regulated element measured and compared between wild-type and trans-element mutation (knockout, over expression etc.) performed by using qRT-PCR technique. SB. Walters, E. Dubnau et al. The Mycobacterium tuberculosis PhoPR two-component system regulates genes essential for virulence and complex lipid biosynthesis. Mol. Microbiol. 2006
Interaction	RegulatedBy Rv0757	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.. qRT-PCR. mRNA expression levels of regulated element measured and compared between wild-type and trans-element mutation (knockout, over expression etc.) performed by using qRT-PCR technique. SB. Walters, E. Dubnau et al. The Mycobacterium tuberculosis PhoPR two-component system regulates genes essential for virulence and complex lipid biosynthesis. Mol. Microbiol. 2006
Name	RND superfamily inner membrane transporter thought to be involved in the translocation of a diacylated precursor of sulfolipid I across the plasma membrane	mjackson	IMP		Polymethyl-branched acyltrehaloses
Citation	The role of MmpL8 in sulfatide biogenesis and virulence of Mycobacterium tuberculosis. P. Domenech, MB. Reed et al. J. Biol. Chem. 2004	mjackson		15001577	RND superfamily inner membrane transporter thought to be involved in the translocation of a diacylated precursor of sulfolipid I across the plasma membrane (phenotypic [mycobacterial recombinant strains])
Other	TBPWY:Polymethyl-branched acyltrehaloses	mjackson			RND superfamily inner membrane transporter thought to be involved in the translocation of a diacylated precursor of sulfolipid I across the plasma membrane (phenotypic [mycobacterial recombinant strains]) P. Domenech, MB. Reed et al. The role of MmpL8 in sulfatide biogenesis and virulence of Mycobacterium tuberculosis. J. Biol. Chem. 2004
Citation	MmpL8 is required for sulfolipid-1 biosynthesis and Mycobacterium tuberculosis virulence. SE. Converse, JD. Mougous et al. Proc. Natl. Acad. Sci. U.S.A. 2003	mjackson		12724526	RND superfamily inner membrane transporter thought to be involved in the translocation of a diacylated precursor of sulfolipid I across the plasma membrane (phenotypic [mycobacterial recombinant strains])
Other	TBPWY:Polymethyl-branched acyltrehaloses	mjackson			RND superfamily inner membrane transporter thought to be involved in the translocation of a diacylated precursor of sulfolipid I across the plasma membrane (phenotypic [mycobacterial recombinant strains]) SE. Converse, JD. Mougous et al. MmpL8 is required for sulfolipid-1 biosynthesis and Mycobacterium tuberculosis virulence. Proc. Natl. Acad. Sci. U.S.A. 2003
Citation	MmpL8 is required for sulfolipid-1 biosynthesis and Mycobacterium tuberculosis virulence. SE. Converse, JD. Mougous et al. Proc. Natl. Acad. Sci. U.S.A. 2003	jjmcfadden		12724526	Inferred from direct assay
Other	EC:	jjmcfadden			Inferred from direct assay SE. Converse, JD. Mougous et al. MmpL8 is required for sulfolipid-1 biosynthesis and Mycobacterium tuberculosis virulence. Proc. Natl. Acad. Sci. U.S.A. 2003

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