ID   MMAA2_MYCTU             Reviewed;         287 AA.
AC   Q79FX6; L0T7B6;
DT   05-OCT-2010, integrated into UniProtKB/Swiss-Prot.
DT   05-JUL-2004, sequence version 1.
DT   27-MAR-2024, entry version 120.
DE   RecName: Full=Cyclopropane mycolic acid synthase MmaA2;
DE            Short=CMAS;
DE            EC=2.1.1.79 {ECO:0000269|PubMed:12502719, ECO:0000269|PubMed:20472794};
DE   AltName: Full=Cyclopropane-fatty-acyl-phospholipid synthase;
DE            Short=CFA synthase;
DE   AltName: Full=Mycolic acid methyltransferase;
DE            Short=MA-MT;
DE   AltName: Full=S-adenosylmethionine-dependent methyltransferase;
DE            Short=AdoMet-MT;
DE            Short=SAM-MT;
GN   Name=mmaA2; Synonyms=mma2; OrderedLocusNames=Rv0644c;
OS   Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC   Bacteria; Actinomycetota; Actinomycetes; Mycobacteriales; Mycobacteriaceae;
OC   Mycobacterium; Mycobacterium tuberculosis complex.
OX   NCBI_TaxID=83332;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 25618 / H37Rv;
RX   PubMed=9634230; DOI=10.1038/31159;
RA   Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA   Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA   Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA   Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA   Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA   Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA   Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA   Barrell B.G.;
RT   "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT   genome sequence.";
RL   Nature 393:537-544(1998).
RN   [2]
RP   FUNCTION IN THE BIOSYNTHESIS OF CYCLOPROPANE RING IN THE ALPHA MYCOLATE,
RP   CATALYTIC ACTIVITY, PATHWAY, AND DISRUPTION PHENOTYPE.
RC   STRAIN=ATCC 35801 / TMC 107 / Erdman;
RX   PubMed=12502719; DOI=10.1074/jbc.m212458200;
RA   Glickman M.S.;
RT   "The mmaA2 gene of Mycobacterium tuberculosis encodes the distal
RT   cyclopropane synthase of the alpha-mycolic acid.";
RL   J. Biol. Chem. 278:7844-7849(2003).
RN   [3]
RP   ACTIVITY REGULATION.
RC   STRAIN=ATCC 25618 / H37Rv;
RX   PubMed=18094751; DOI=10.1371/journal.pone.0001343;
RA   Alahari A., Trivelli X., Guerardel Y., Dover L.G., Besra G.S.,
RA   Sacchettini J.C., Reynolds R.C., Coxon G.D., Kremer L.;
RT   "Thiacetazone, an antitubercular drug that inhibits cyclopropanation of
RT   cell wall mycolic acids in mycobacteria.";
RL   PLoS ONE 2:E1343-E1343(2007).
RN   [4]
RP   IDENTIFICATION AS A DRUG TARGET [LARGE SCALE ANALYSIS].
RX   PubMed=19099550; DOI=10.1186/1752-0509-2-109;
RA   Raman K., Yeturu K., Chandra N.;
RT   "targetTB: a target identification pipeline for Mycobacterium tuberculosis
RT   through an interactome, reactome and genome-scale structural analysis.";
RL   BMC Syst. Biol. 2:109-109(2008).
RN   [5]
RP   ACTIVITY REGULATION.
RC   STRAIN=ATCC 25618 / H37Rv;
RX   PubMed=19439410; DOI=10.1074/jbc.m809599200;
RA   Vaubourgeix J., Bardou F., Boissier F., Julien S., Constant P., Ploux O.,
RA   Daffe M., Quemard A., Mourey L.;
RT   "S-adenosyl-N-decyl-aminoethyl, a potent bisubstrate inhibitor of
RT   mycobacterium tuberculosis mycolic acid methyltransferases.";
RL   J. Biol. Chem. 284:19321-19330(2009).
RN   [6]
RP   FUNCTION IN OXYGEN-CONTAINING MYCOLATES AND IN ALPHA-MYCOLATES
RP   BIOSYNTHESIS, CATALYTIC ACTIVITY, PATHWAY, AND DISRUPTION PHENOTYPE.
RX   PubMed=20472794; DOI=10.1128/jb.00312-10;
RA   Barkan D., Rao V., Sukenick G.D., Glickman M.S.;
RT   "Redundant function of cmaA2 and mmaA2 in Mycobacterium tuberculosis cis
RT   cyclopropanation of oxygenated mycolates.";
RL   J. Bacteriol. 192:3661-3668(2010).
RN   [7]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT VAL-2, CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RC   STRAIN=ATCC 25618 / H37Rv;
RX   PubMed=21969609; DOI=10.1074/mcp.m111.011445;
RA   Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA   Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA   Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA   Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT   "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT   mass spectrometry.";
RL   Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN   [8] {ECO:0007744|PDB:1TPY}
RP   X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) IN COMPLEX WITH
RP   S-ADENOSYL-L-HOMOCYSTEINE.
RC   STRAIN=ATCC 25618 / H37Rv;
RA   Smith C.V., Sacchettini J.C.;
RT   "Structure of the cyclopropane synthase mmaA2 from Mycobacterium
RT   tuberculosis.";
RL   Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
CC   -!- FUNCTION: Catalyzes the conversion of a double bond to a cis
CC       cyclopropane ring at the distal position of an alpha mycolic acid via
CC       the transfer of a methylene group from S-adenosyl-L-methionine. MmaA2
CC       also catalyzes the biosynthesis of the cis-cyclopropanated
CC       methoxymycolates. Cyclopropanated mycolic acids are key factors
CC       participating in cell envelope permeability, host immunomodulation and
CC       persistence. {ECO:0000269|PubMed:12502719,
CC       ECO:0000269|PubMed:20472794}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=1-acyl-2-(9Z)-enoyl-sn-glycero-3-phospholipid + S-adenosyl-L-
CC         methionine = 1-acyl-2-(9-cyclopronane)-acyl-sn-glycero-3-phospholipid
CC         + H(+) + S-adenosyl-L-homocysteine; Xref=Rhea:RHEA:11988,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC         ChEBI:CHEBI:76593, ChEBI:CHEBI:76594; EC=2.1.1.79;
CC         Evidence={ECO:0000269|PubMed:12502719, ECO:0000269|PubMed:20472794};
CC   -!- ACTIVITY REGULATION: Inhibited by S-adenosyl-N-decyl-aminoethyl (SADAE)
CC       and thiacetazone (TAC). {ECO:0000269|PubMed:18094751,
CC       ECO:0000269|PubMed:19439410}.
CC   -!- PATHWAY: Lipid metabolism; mycolic acid biosynthesis.
CC       {ECO:0000305|PubMed:12502719, ECO:0000305|PubMed:20472794}.
CC   -!- DISRUPTION PHENOTYPE: Disruption of this gene suppresses a cyclopropane
CC       group at the distal position of alpha mycolic acid. Mutant produces
CC       fully cyclopropanated methoxymycolates, but the efficiency of cis-
CC       methoxymycolate cyclopropanation is reduced, leading to accumulation of
CC       unsaturated methoxymycolate derivatives. Cis/trans ratios in purified
CC       ketomycolates are unchanged (PubMed:12502719). Cells lacking both cmaA2
CC       and mmaA2 genes cannot cis cyclopropanate methoxymycolates or
CC       ketomycolates (PubMed:20472794). {ECO:0000269|PubMed:12502719,
CC       ECO:0000269|PubMed:20472794}.
CC   -!- SIMILARITY: Belongs to the CFA/CMAS family. {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; AL123456; CCP43387.1; -; Genomic_DNA.
DR   RefSeq; NP_215158.1; NC_000962.3.
DR   RefSeq; WP_003900985.1; NZ_NVQJ01000007.1.
DR   PDB; 1TPY; X-ray; 2.20 A; A=1-287.
DR   PDBsum; 1TPY; -.
DR   AlphaFoldDB; Q79FX6; -.
DR   SMR; Q79FX6; -.
DR   STRING; 83332.Rv0644c; -.
DR   DrugBank; DB01718; Cetrimonium.
DR   DrugBank; DB01752; S-adenosyl-L-homocysteine.
DR   iPTMnet; Q79FX6; -.
DR   PaxDb; 83332-Rv0644c; -.
DR   DNASU; 888061; -.
DR   GeneID; 45424604; -.
DR   GeneID; 888061; -.
DR   KEGG; mtu:Rv0644c; -.
DR   TubercuList; Rv0644c; -.
DR   eggNOG; COG2230; Bacteria.
DR   InParanoid; Q79FX6; -.
DR   OrthoDB; 9782855at2; -.
DR   PhylomeDB; Q79FX6; -.
DR   BioCyc; MetaCyc:G185E-4787-MONOMER; -.
DR   UniPathway; UPA00915; -.
DR   EvolutionaryTrace; Q79FX6; -.
DR   Proteomes; UP000001584; Chromosome.
DR   GO; GO:0009274; C:peptidoglycan-based cell wall; HDA:MTBBASE.
DR   GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR   GO; GO:0008825; F:cyclopropane-fatty-acyl-phospholipid synthase activity; IMP:UniProtKB.
DR   GO; GO:0008168; F:methyltransferase activity; IMP:UniProtKB.
DR   GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR   GO; GO:0071768; P:mycolic acid biosynthetic process; IDA:MTBBASE.
DR   CDD; cd02440; AdoMet_MTases; 1.
DR   Gene3D; 3.40.50.150; Vaccinia Virus protein VP39; 1.
DR   InterPro; IPR003333; CMAS.
DR   InterPro; IPR047672; CMAS_actinobact.
DR   InterPro; IPR029063; SAM-dependent_MTases_sf.
DR   NCBIfam; NF040660; mycolic_MTase; 1.
DR   PANTHER; PTHR43667; CYCLOPROPANE-FATTY-ACYL-PHOSPHOLIPID SYNTHASE; 1.
DR   PANTHER; PTHR43667:SF1; CYCLOPROPANE-FATTY-ACYL-PHOSPHOLIPID SYNTHASE; 1.
DR   Pfam; PF02353; CMAS; 1.
DR   PIRSF; PIRSF003085; CMAS; 1.
DR   SUPFAM; SSF53335; S-adenosyl-L-methionine-dependent methyltransferases; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Lipid biosynthesis; Lipid metabolism;
KW   Methyltransferase; Reference proteome; S-adenosyl-L-methionine;
KW   Transferase.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0007744|PubMed:21969609"
FT   CHAIN           2..287
FT                   /note="Cyclopropane mycolic acid synthase MmaA2"
FT                   /id="PRO_0000398359"
FT   ACT_SITE        269
FT                   /evidence="ECO:0000250"
FT   BINDING         33..34
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000269|Ref.8"
FT   BINDING         72..74
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000269|Ref.8"
FT   BINDING         94..99
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000269|Ref.8"
FT   BINDING         123..124
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000269|Ref.8"
FT   BINDING         136
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000269|Ref.8"
FT   MOD_RES         2
FT                   /note="N-acetylvaline"
FT                   /evidence="ECO:0007744|PubMed:21969609"
FT   HELIX           9..16
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   HELIX           20..24
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   HELIX           45..57
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   TURN            58..61
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   STRAND          67..72
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   HELIX           77..86
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   STRAND          89..95
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   HELIX           97..108
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   STRAND          116..121
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   HELIX           123..125
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   STRAND          131..137
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   HELIX           139..142
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   HELIX           144..146
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   HELIX           147..157
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   STRAND          163..171
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   HELIX           174..179
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   HELIX           186..198
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   HELIX           208..218
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   STRAND          221..227
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   HELIX           229..245
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   HELIX           247..253
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   HELIX           256..275
FT                   /evidence="ECO:0007829|PDB:1TPY"
FT   STRAND          277..286
FT                   /evidence="ECO:0007829|PDB:1TPY"
SQ   SEQUENCE   287 AA;  32724 MW;  669C3224C6B178C0 CRC64;
     MVNDLTPHFE DVQAHYDLSD DFFRLFLDPT QTYSCAHFER EDMTLEEAQI AKIDLALGKL
     GLQPGMTLLD IGCGWGATMR RAIAQYDVNV VGLTLSKNQA AHVQKSFDEM DTPRDRRVLL
     AGWEQFNEPV DRIVSIGAFE HFGHDRHADF FARAHKILPP DGVLLLHTIT GLTRQQMVDH
     GLPLTLWLAR FLKFIATEIF PGGQPPTIEM VEEQSAKTGF TLTRRQSLQP HYARTLDLWA
     EALQEHKSEA IAIQSEEVYE RYMKYLTGCA KLFRVGYIDV NQFTLAK
//