Rv0642c (mmaA4)

Current annotations:
- TBCAP: (community-based annotations - see table at bottom of page)
- TBDB: hydroxymycolate synthase MmaA4
- REFSEQ: methoxy mycolic acid synthase
- PATRIC: Cyclopropane-fatty-acyl-phospholipid synthase (EC 2.1.1.79)
- TUBERCULIST: Methoxy mycolic acid synthase 4 MmaA4 (methyl mycolic acid synthase 4) (MMA4) (hydroxy mycolic acid synthase)
- NCBI: Methoxy mycolic acid synthase 4 MmaA4 (methyl mycolic acid synthase 4) (MMA4) (hydroxy mycolic acid synthase)
- updated information (H37Rv4):
  - gene name: mmaA4
  - function:
  - reference:
Type: Not Target
Start: 736298
End: 737203
Operon:

Trans-membrane region:
Role: I.H.2 - Modification of fatty and mycolic acids
GO terms:
- GO:0071768 - mycolic acid biosynthetic process (Uniprot)
- GO:0032259 - methylation (Uniprot)
- GO:0016740 - transferase activity (Uniprot)
- GO:0008757 - S-adenosylmethionine-dependent methyltransferase activity (Uniprot)
- GO:0008610 - lipid biosynthetic process (Uniprot)
- GO:0008168 - methyltransferase activity (Uniprot)
- GO:0006629 - lipid metabolic process (Uniprot)
- GO:0005886 - plasma membrane (Uniprot)
- GO:0005618 - cell wall (Uniprot)
- GO:0005515 - protein binding (Uniprot)
Reaction(s) (based on iSM810 metabolic model):
- SAM[c] + CIS_DELTA_2_19_44_37_ENOYL_C56_ACYL_ACP[c] -> SAH[c] + CIS_DELTA_37_ENOYL_METHY_HYDROXY_C56_ACYL_ACP[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: 3ha5, 2fk8, 2fk7, 3ha3, 3ha7
Search for Homologs in PDB

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

PDB	aa ident	species	PDB title
3HA7	100%	Mycobacterium tuberculosis	Crystal structure of HMA (MMAA4) from mycobacterium tuberculosis complexed with S-adenosyl-N-decyl-aminoethyl (SADAE)
3HA5	100%	Mycobacterium tuberculosis	Crystal structure of HMA (MMAA4) from mycobacterium tuberculosis complexed with sinefungin
3HA3	100%	Mycobacterium tuberculosis	Crystal structure of HMA (MMAA4) from mycobacterium tuberculosis complexed with S-adenosylhomocysteine
2FK8	100%	Mycobacterium tuberculosis	Crystal structure of Hma (MmaA4) from Mycobacterium tuberculosis complexed with S-adenosylmethionine
2FK7	100%	Mycobacterium tuberculosis	Crystal structure of Hma (MmaA4) from Mycobacterium tuberculosis, apo-form
1KPH	58%	Mycobacterium tuberculosis	Crystal Structure of mycolic acid cyclopropane synthase CmaA1 complexed with SAH and DDDMAB
1KPG	58%	Mycobacterium tuberculosis	Crystal Structure of mycolic acid cyclopropane synthase CmaA1 complexed with SAH and CTAB
1KP9	58%	Mycobacterium tuberculosis	Crystal structure of mycolic acid cyclopropane synthase CmaA1, apo-form
1TPY	56%	Mycobacterium tuberculosis	Structure of the cyclopropane synthase MmaA2 from Mycobacterium tuberculosis
1L1E	55%	Mycobacterium tuberculosis	Crystal Structure of Mycolic Acid Cyclopropane Synthase PcaA Complexed with S-adenosyl-L-homocysteine

Links to additional information on mmaA4:
- KEGG - nucleotide and amino acid sequences of gene
- TBDB (updated)
- Phyre2 structure prediction, model: final.casp.pdb (from Mao et al, 2013)
- UniProt
- AlphaFold model
- Vulnerability = 0.91 (from Jeremy Rock's lab)
- Mycobrowser
- PATRIC
- BioCyc
- Systems Biology

Amino Acid Sequence

MTRMAEKPISPTKTRTRFEDIQAHYDVSDDFFALFQDPTRTYSCAYFEPPELTLEEAQYAKVDLNLDKLDLKPGMTLLDIGCGWGTTMRRAVERFDVNVI
GLTLSKNQHARCEQVLASIDTNRSRQVLLQGWEDFAEPVDRIVSIEAFEHFGHENYDDFFKRCFNIMPADGRMTVQSSVSYHPYEMAARGKKLSFETARF
IKFIVTEIFPGGRLPSTEMMVEHGEKAGFTVPEPLSLRPHYIKTLRIWGDTLQSNKDKAIEVTSEEVYNRYMKYLRGCEHYFTDEMLDCSLVTYLKPGAA
A

(Nucleotide sequence available on KEGG)

Additional Information

ESSENTIALITY

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

TnSeqCorr - genes with correlated TnSeq profiles across >100 conditions *new*

Classification	Condition	Strain	Method	Reference	Notes
Non-Essential	Sodium Oleate	H37RvMA	Gumbel	Subhalaxmi Nambi	Probability of Essentiality: 0.000000; 3 non-insertions in a row out of 18 sites
Non-Essential	Lignoceric Acid	H37RvMA	Gumbel	Subhalaxmi Nambi	Probability of Essentiality: 0.008950; 6 non-insertions in a row out of 18 sites
Essential	Phosphatidylcholine	H37RvMA	Gumbel	Subhalaxmi Nambi	Probability of Essentiality: 1.000000; 18 non-insertions in a row out of 18 sites
Uncertain	minimal media + 0.1% glycerol	H37RvMA	Gumbel	Griffin et al. (2011)	Probability of Essentiality: 0.987900; 9 non-insertions in a row out of 19 sites
Essential	minimal media + 0.01% cholesterol	H37RvMA	Gumbel	Griffin et al. (2011)	Probability of Essentiality: 1.000000; 15 non-insertions in a row out of 19 sites
Non-Essential	7H10-glycerol	H37RvMA	TraSH	Sassetti et al. (2003a)
Non-Essential	C57BL/6J mice (8 weeks)	H37RvMA	TraSH	Sassetti et al. (2003b)	Hybridization Ratio: 2.06
Growth-Advantage	7H09/7H10 + rich media	H37RvMA	MotifHMM	DeJesus et al. (2017)	Fully saturated (14 reps).

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

RNA processing and modification

Energy production and conversion

Chromatin structure and dynamics

Amino acid transport and metabolism

Cell cycle control, cell division, chromosome partitioning

Carbohydrate transport and metabolism

Nucleotide transport and metabolism

Lipid transport and metabolism

Coenzyme transport and metabolism

Transcription

Translation, ribosomal structure and biogenesis

Cell wall/membrane/envelope biogenesis

Replication, recombination and repair

Posttranslational modification, protein turnover, chaperones

Cell motility

Secondary metabolites biosynthesis, transport and catabolism

Inorganic ion transport and metabolism

Function unknown

General function prediction only

Intracellular trafficking, secretion, and vesicular transport

Signal transduction mechanisms

Extracellular structures

Defense mechanisms

Nuclear structure

Cytoskeleton

BioCyc Co-regulated genes based on gene expression profiling (Systems Biology, Inferelator Network)

Differentially expressed as result of RNASeq in glycerol environment (Only top 20 genes shown sorted by log fold change with p_adj 0.05).

Conditionally essential as result of TNSeq (Only top 20 genes shown sorted by log fold change with p_adj 0.05).

BioCyc Transcription factor binding based on ChIP-Seq (Systems Biology)

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

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

Binds To:
- No bindings to other targets were found.
Bound By:
- Rv0691c (-) (Direct binding)
- Rv3574 (kstR) (Direct binding)

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:
- Not downregulated by other genes.

Property	Value	Creator	Evidence	PMID	Comment
Term	TBRXN:MYC1M2 Mycolic Acid Methyl Hydroxyl Addition - IDA	njamshidi	IDA	16356931	PMID: 16356931 F. Boissier, F. Bardou et al. Further insight into S-adenosylmethionine-dependent methyltransferases: structural characterization of Hma, an enzyme essential for the biosynthesis of oxygenated mycolic acids in Mycobacterium tuberculosis. J. Biol. Chem. 2006
Citation	Further insight into S-adenosylmethionine-dependent methyltransferases: structural characterization of Hma, an enzyme essential for the biosynthesis of oxygenated mycolic acids in Mycobacterium tuberculosis. F. Boissier, F. Bardou et al. J. Biol. Chem. 2006	njamshidi	ISS	16356931	PMID: 16356931
Term	TBRXN:MYC1M2 Mycolic Acid Methyl Hydroxyl Addition - ISS	njamshidi	ISS	16356931	PMID: 16356931 F. Boissier, F. Bardou et al. Further insight into S-adenosylmethionine-dependent methyltransferases: structural characterization of Hma, an enzyme essential for the biosynthesis of oxygenated mycolic acids in Mycobacterium tuberculosis. J. Biol. Chem. 2006
Citation	Further insight into S-adenosylmethionine-dependent methyltransferases: structural characterization of Hma, an enzyme essential for the biosynthesis of oxygenated mycolic acids in Mycobacterium tuberculosis. F. Boissier, F. Bardou et al. J. Biol. Chem. 2006	njamshidi	IDA	16356931	PMID: 16356931
Citation	Further insight into S-adenosylmethionine-dependent methyltransferases: structural characterization of Hma, an enzyme essential for the biosynthesis of oxygenated mycolic acids in Mycobacterium tuberculosis. F. Boissier, F. Bardou et al. J. Biol. Chem. 2006	njamshidi	IDA	16356931	PMID: 16356931
Term	TBRXN:MYC1M1 Mycolic Acid Methyl Hydroxyl Addition - IDA	njamshidi	IDA	16356931	PMID: 16356931 F. Boissier, F. Bardou et al. Further insight into S-adenosylmethionine-dependent methyltransferases: structural characterization of Hma, an enzyme essential for the biosynthesis of oxygenated mycolic acids in Mycobacterium tuberculosis. J. Biol. Chem. 2006
Citation	Further insight into S-adenosylmethionine-dependent methyltransferases: structural characterization of Hma, an enzyme essential for the biosynthesis of oxygenated mycolic acids in Mycobacterium tuberculosis. F. Boissier, F. Bardou et al. J. Biol. Chem. 2006	njamshidi	ISS	16356931	PMID: 16356931
Term	TBRXN:MYC1M1 Mycolic Acid Methyl Hydroxyl Addition - ISS	njamshidi	ISS	16356931	PMID: 16356931 F. Boissier, F. Bardou et al. Further insight into S-adenosylmethionine-dependent methyltransferases: structural characterization of Hma, an enzyme essential for the biosynthesis of oxygenated mycolic acids in Mycobacterium tuberculosis. J. Biol. Chem. 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
Name	MmaA4 METHOXY MYCOLIC ACID SYNTHASE 4; synthesis of oxygenated mycolates	mjackson	IMP		S-adenosyl-methionine-dependent mycolic acid methyltransferases
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
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
Citation	Tracking the putative biosynthetic precursors of oxygenated mycolates of Mycobacterium tuberculosis. Structural analysis of fatty acids of a mutant strain deviod of methoxy- and ketomycolates. authors,P. Dinadayala,F. Laval,C. Raynaud,A. Lemassu,MA. Laneelle,G. Laneelle,M. Daffe J. Biol. Chem. 2003	extern:JZUCKER		12473649	Reaction blocked in mutant
Term	EC:2.1.1.- Transferases. Transferring one-carbon groups. Methyltransferases. - NR	extern:JZUCKER	NR		Reaction blocked in mutant authors,P. Dinadayala,F. Laval,C. Raynaud,A. Lemassu,MA. Laneelle,G. Laneelle,M. Daffe Tracking the putative biosynthetic precursors of oxygenated mycolates of Mycobacterium tuberculosis. Structural analysis of fatty acids of a mutant strain deviod of methoxy- and ketomycolates. J. Biol. Chem. 2003
Term	EC:2.1.1.79 Cyclopropane-fatty-acyl-phospholipid synthase. - NR	extern:JZUCKER	NR		Reaction blocked in mutant authors,P. Dinadayala,F. Laval,C. Raynaud,A. Lemassu,MA. Laneelle,G. Laneelle,M. Daffe Tracking the putative biosynthetic precursors of oxygenated mycolates of Mycobacterium tuberculosis. Structural analysis of fatty acids of a mutant strain deviod of methoxy- and ketomycolates. J. Biol. Chem. 2003

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