CMAS2_MYCTU
ID CMAS2_MYCTU Reviewed; 302 AA.
AC P9WPB5; L0T3U0; P0A5P0; Q11196;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 42.
DE RecName: Full=Cyclopropane mycolic acid synthase 2 {ECO:0000303|PubMed:7592990};
DE Short=CMAS-2 {ECO:0000303|PubMed:7592990};
DE EC=2.1.1.79 {ECO:0000269|PubMed:11092877, ECO:0000269|PubMed:7592990};
DE AltName: Full=Cyclopropane-fatty-acyl-phospholipid synthase;
DE Short=CFA synthase;
DE Short=Cyclopropane fatty acid 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=cmaA2 {ECO:0000303|PubMed:7592990}; Synonyms=cma2, CMAS-2;
GN OrderedLocusNames=Rv0503c; ORFNames=MTCY20G9.30c;
OS Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83332;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION AS A CYCLOPROPANE SYNTHASE,
RP CATALYTIC ACTIVITY, AND NOMENCLATURE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=7592990; DOI=10.1074/jbc.270.45.27292;
RA George K.M., Yuan Y., Sherman D.R., Barry C.E. III;
RT "The biosynthesis of cyclopropanated mycolic acids in Mycobacterium
RT tuberculosis. Identification and functional analysis of CMAS-2.";
RL J. Biol. Chem. 270:27292-27298(1995).
RN [2]
RP PROTEIN SEQUENCE OF 2-21.
RC STRAIN=H37Rv;
RX PubMed=34915127; DOI=10.1016/j.ygeno.2021.12.001;
RA Shi J., Meng S., Wan L., Zhang Z., Jiang S., Zhu H., Dai E., Chang L.,
RA Gao H., Wan K., Zhang L., Zhao X., Liu H., Lyu Z., Zhang Y., Xu P.;
RT "Deep N-terminomics of Mycobacterium tuberculosis H37Rv extensively correct
RT annotated encoding genes.";
RL Genomics 114:292-304(2022).
RN [3]
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 [4]
RP FUNCTION AS A TRANS-CYCLOPROPANE SYNTHASE, CATALYTIC ACTIVITY, AND
RP DISRUPTION PHENOTYPE.
RC STRAIN=ATCC 35801 / TMC 107 / Erdman;
RX PubMed=11092877; DOI=10.1074/jbc.c000652200;
RA Glickman M.S., Cahill S.M., Jacobs W.R. Jr.;
RT "The Mycobacterium tuberculosis cmaA2 gene encodes a mycolic acid trans-
RT cyclopropane synthetase.";
RL J. Biol. Chem. 276:2228-2233(2001).
RN [5]
RP DISRUPTION PHENOTYPE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=16741578; DOI=10.1172/jci27335;
RA Rao V., Gao F., Chen B., Jacobs W.R. Jr., Glickman M.S.;
RT "Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses
RT Mycobacterium tuberculosis -induced inflammation and virulence.";
RL J. Clin. Invest. 116:1660-1667(2006).
RN [6]
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 [7]
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 [8]
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 [9]
RP DISRUPTION PHENOTYPE.
RC STRAIN=ATCC 25618 / H37Rv;
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 [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT THR-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.m111.011627;
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 [11] {ECO:0007744|PDB:1KPI}
RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) IN COMPLEX WITH
RP S-ADENOSYL-L-METHIONINE AND SUBSTRATE ANALOG.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=11756461; DOI=10.1074/jbc.m111698200;
RA Huang C.-C., Smith C.V., Glickman M.S., Jacobs W.R. Jr., Sacchettini J.C.;
RT "Crystal structures of mycolic acid cyclopropane synthases from
RT Mycobacterium tuberculosis.";
RL J. Biol. Chem. 277:11559-11569(2002).
CC -!- FUNCTION: Catalyzes the formation of trans cyclopropanated ketomycolate
CC or methoxymycolate through the conversion of a double bond to a
CC cyclopropane ring at the proximal position of an oxygenated mycolic
CC acid via the transfer of a methylene group from S-adenosyl-L-
CC methionine. In the absence of MmaA2, CmaA2 has a non-specific cis-
CC cyclopropanating activity and is able to catalyze the conversion of a
CC double bond to a cis cyclopropane ring at the distal position of an
CC alpha mycolic acid. Cyclopropanated mycolic acids are key factors
CC participating in cell envelope permeability, host immunomodulation and
CC persistence. {ECO:0000269|PubMed:11092877, ECO:0000269|PubMed:7592990}.
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:11092877, ECO:0000269|PubMed:7592990};
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:11092877, ECO:0000305|PubMed:7592990}.
CC -!- SUBUNIT: Homodimer. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- DISRUPTION PHENOTYPE: Inactivation of cmaA2 causes accumulation of
CC unsaturated derivatives of both the methoxy- and ketomycolates. The
CC mycolic acids of the cmaA2 mutant lack trans-cyclopropane rings but are
CC otherwise intact with respect to cyclopropane and methyl branch
CC content. Deletion of cmaA2 has no effect on bacterial loads during
CC mouse infection but causes hypervirulence due to an excessive immune
CC activation which produces more-severe granulomatous pathology than
CC wild-type, and increases both the macrophage activation and the
CC macrophage inflammatory response. {ECO:0000269|PubMed:11092877,
CC ECO:0000269|PubMed:16741578, ECO:0000269|PubMed:20472794}.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC -!- SIMILARITY: Belongs to the CFA/CMAS family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC43488.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; U34637; AAC43488.1; ALT_INIT; Genomic_DNA.
DR EMBL; AL123456; CCP43240.1; -; Genomic_DNA.
DR PIR; B70746; B70746.
DR RefSeq; NP_215017.1; NC_000962.3.
DR RefSeq; WP_003402621.1; NZ_NVQJ01000002.1.
DR PDB; 1KPI; X-ray; 2.65 A; A=1-302.
DR PDB; 3HEM; X-ray; 2.39 A; A=1-302.
DR PDBsum; 1KPI; -.
DR PDBsum; 3HEM; -.
DR AlphaFoldDB; P9WPB5; -.
DR SMR; P9WPB5; -.
DR STRING; 83332.Rv0503c; -.
DR DrugBank; DB04221; Didecyldimethylammonium.
DR DrugBank; DB01752; S-adenosyl-L-homocysteine.
DR iPTMnet; P9WPB5; -.
DR PaxDb; P9WPB5; -.
DR DNASU; 887264; -.
DR GeneID; 887264; -.
DR KEGG; mtu:Rv0503c; -.
DR TubercuList; Rv0503c; -.
DR eggNOG; COG2230; Bacteria.
DR OMA; ERHHFIG; -.
DR PhylomeDB; P9WPB5; -.
DR BioCyc; MetaCyc:G185E-4635-MON; -.
DR UniPathway; UPA00915; -.
DR PHI-base; PHI:4472; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005829; C:cytosol; HDA:MTBBASE.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR GO; GO:0008825; F:cyclopropane-fatty-acyl-phospholipid synthase activity; IDA:MTBBASE.
DR GO; GO:0071766; P:Actinobacterium-type cell wall biogenesis; IDA:MTBBASE.
DR GO; GO:0008610; P:lipid biosynthetic process; IMP:UniProtKB.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0052167; P:modulation by symbiont of host innate immune response; IMP:MTBBASE.
DR GO; GO:0071769; P:mycolate cell wall layer assembly; IDA:MTBBASE.
DR GO; GO:0071768; P:mycolic acid biosynthetic process; IDA:MTBBASE.
DR GO; GO:0001666; P:response to hypoxia; IEP:MTBBASE.
DR GO; GO:0046500; P:S-adenosylmethionine metabolic process; IDA:MTBBASE.
DR Gene3D; 3.40.50.150; -; 1.
DR InterPro; IPR003333; Mycolic_cyclopropane_synthase.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR PIRSF; PIRSF003085; CMAS; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cytoplasm; Direct protein sequencing;
KW Lipid biosynthesis; Lipid metabolism; Methyltransferase;
KW Reference proteome; S-adenosyl-L-methionine; Transferase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:34915127,
FT ECO:0007744|PubMed:21969609"
FT CHAIN 2..302
FT /note="Cyclopropane mycolic acid synthase 2"
FT /id="PRO_0000089569"
FT ACT_SITE 284
FT /evidence="ECO:0000250"
FT BINDING 41..42
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:11756461"
FT BINDING 76..84
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:11756461"
FT BINDING 102..107
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:11756461"
FT BINDING 131..132
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:11756461"
FT MOD_RES 2
FT /note="N-acetylthreonine"
FT /evidence="ECO:0007744|PubMed:21969609"
FT HELIX 17..24
FT /evidence="ECO:0007829|PDB:3HEM"
FT HELIX 28..34
FT /evidence="ECO:0007829|PDB:3HEM"
FT HELIX 53..66
FT /evidence="ECO:0007829|PDB:3HEM"
FT STRAND 75..80
FT /evidence="ECO:0007829|PDB:3HEM"
FT HELIX 85..94
FT /evidence="ECO:0007829|PDB:3HEM"
FT STRAND 97..102
FT /evidence="ECO:0007829|PDB:3HEM"
FT HELIX 105..117
FT /evidence="ECO:0007829|PDB:3HEM"
FT STRAND 124..128
FT /evidence="ECO:0007829|PDB:3HEM"
FT HELIX 131..133
FT /evidence="ECO:0007829|PDB:3HEM"
FT STRAND 139..145
FT /evidence="ECO:0007829|PDB:3HEM"
FT HELIX 147..149
FT /evidence="ECO:0007829|PDB:3HEM"
FT HELIX 161..171
FT /evidence="ECO:0007829|PDB:3HEM"
FT STRAND 178..185
FT /evidence="ECO:0007829|PDB:3HEM"
FT HELIX 189..195
FT /evidence="ECO:0007829|PDB:3HEM"
FT HELIX 201..213
FT /evidence="ECO:0007829|PDB:3HEM"
FT HELIX 223..232
FT /evidence="ECO:0007829|PDB:3HEM"
FT STRAND 236..242
FT /evidence="ECO:0007829|PDB:3HEM"
FT HELIX 244..246
FT /evidence="ECO:0007829|PDB:3HEM"
FT HELIX 247..260
FT /evidence="ECO:0007829|PDB:3HEM"
FT HELIX 262..269
FT /evidence="ECO:0007829|PDB:3HEM"
FT HELIX 271..289
FT /evidence="ECO:0007829|PDB:3HEM"
FT STRAND 292..301
FT /evidence="ECO:0007829|PDB:3HEM"
SQ SEQUENCE 302 AA; 34660 MW; 63AAA95627F95755 CRC64;
MTSQGDTTSG TQLKPPVEAV RSHYDKSNEF FKLWLDPSMT YSCAYFERPD MTLEEAQYAK
RKLALDKLNL EPGMTLLDIG CGWGSTMRHA VAEYDVNVIG LTLSENQYAH DKAMFDEVDS
PRRKEVRIQG WEEFDEPVDR IVSLGAFEHF ADGAGDAGFE RYDTFFKKFY NLTPDDGRML
LHTITIPDKE EAQELGLTSP MSLLRFIKFI LTEIFPGGRL PRISQVDYYS SNAGWKVERY
HRIGANYVPT LNAWADALQA HKDEAIALKG QETYDIYMHY LRGCSDLFRD KYTDVCQFTL
VK
