CMAS3_MYCTU
ID CMAS3_MYCTU Reviewed; 287 AA.
AC P9WPB3; L0T6K4; Q6MX38; Q7D9R5;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 44.
DE RecName: Full=Cyclopropane mycolic acid synthase 3;
DE Short=CMAS;
DE EC=2.1.1.79;
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=pcaA; Synonyms=cma3, cmaA3, CMAS-3; OrderedLocusNames=Rv0470c;
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 [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 DISRUPTION PHENOTYPE, AND NOMENCLATURE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=10882107; DOI=10.1016/s1097-2765(00)80250-6;
RA Glickman M.S., Cox J.S., Jacobs W.R. Jr.;
RT "A novel mycolic acid cyclopropane synthetase is required for cording,
RT persistence, and virulence of Mycobacterium tuberculosis.";
RL Mol. Cell 5:717-727(2000).
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.
RX PubMed=19477414; DOI=10.1016/j.chembiol.2009.04.001;
RA Barkan D., Liu Z., Sacchettini J.C., Glickman M.S.;
RT "Mycolic acid cyclopropanation is essential for viability, drug resistance,
RT and cell wall integrity of Mycobacterium tuberculosis.";
RL Chem. Biol. 16:499-509(2009).
RN [6]
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 [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-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 [8]
RP FUNCTION, CATALYTIC ACTIVITY, PHOSPHORYLATION AT THR-168 AND THR-183,
RP MUTAGENESIS OF THR-168 AND THR-183, DISRUPTION PHENOTYPE, AND SUBSTRATE
RP SPECIFICITY.
RX PubMed=22621931; DOI=10.1074/jbc.m112.373209;
RA Corrales R.M., Molle V., Leiba J., Mourey L., de Chastellier C., Kremer L.;
RT "Phosphorylation of mycobacterial PcaA inhibits mycolic acid
RT cyclopropanation: consequences for intracellular survival and for phagosome
RT maturation block.";
RL J. Biol. Chem. 287:26187-26199(2012).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) IN COMPLEX WITH
RP S-ADENOSYL-L-HOMOCYSTEINE, AND SUBUNIT.
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: Involved in the phagosome maturation block (PMB). Catalyzes
CC the conversion of a double bond to a cyclopropane ring at the proximal
CC position of an alpha mycolic acid via the transfer of a methylene group
CC from S-adenosyl-L-methionine. It can use cis, cis 11,14-eicosadienoic
CC acid and linoelaidic acid as substrate. Cyclopropanated mycolic acids
CC are key factors participating in cell envelope permeability, host
CC immunomodulation and persistence. {ECO:0000269|PubMed:10882107,
CC ECO:0000269|PubMed:22621931}.
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:22621931};
CC -!- ACTIVITY REGULATION: Regulated by PknF. Inhibited by S-adenosyl-N-
CC decyl-aminoethyl (SADAE), thiacetazone (TAC) and dioctylamine.
CC {ECO:0000269|PubMed:18094751, ECO:0000269|PubMed:19439410,
CC ECO:0000269|PubMed:19477414}.
CC -!- PATHWAY: Lipid metabolism; mycolic acid biosynthesis.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:11756461}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}.
CC -!- PTM: Phosphorylation by PknF at Thr-168 and Thr-183 regulates the
CC mycolic acid profile which affects colonial cording, intramacrophage
CC replication and abrogates the PMB. {ECO:0000269|PubMed:22621931}.
CC -!- DISRUPTION PHENOTYPE: Inactivation of pcaA does not affect initial
CC growth of the organism over the first 3 weeks, but after 6 weeks, when
CC wild-type organisms persist at a constant level indefinitely, the pcaA
CC mutant is progressively eliminated from the animal. Cells lacking this
CC gene accumulates a hybrid mycolate with a cis double bond at the
CC proximal position in place of the cis cyclopropane present in wild-type
CC alpha mycolate. {ECO:0000269|PubMed:10882107,
CC ECO:0000269|PubMed:22621931}.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC -!- SIMILARITY: Belongs to the CFA/CMAS family. {ECO:0000305}.
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DR EMBL; AL123456; CCP43203.1; -; Genomic_DNA.
DR PIR; B70829; B70829.
DR RefSeq; WP_003402323.1; NZ_NVQJ01000002.1.
DR RefSeq; YP_177730.1; NC_000962.3.
DR PDB; 1L1E; X-ray; 2.00 A; A/B=1-287.
DR PDBsum; 1L1E; -.
DR AlphaFoldDB; P9WPB3; -.
DR SMR; P9WPB3; -.
DR STRING; 83332.Rv0470c; -.
DR DrugBank; DB01752; S-adenosyl-L-homocysteine.
DR iPTMnet; P9WPB3; -.
DR PaxDb; P9WPB3; -.
DR GeneID; 45424432; -.
DR GeneID; 886284; -.
DR KEGG; mtu:Rv0470c; -.
DR TubercuList; Rv0470c; -.
DR eggNOG; COG2230; Bacteria.
DR OMA; PRFFKMA; -.
DR PhylomeDB; P9WPB3; -.
DR UniPathway; UPA00915; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0008825; F:cyclopropane-fatty-acyl-phospholipid synthase activity; IMP:MTBBASE.
DR GO; GO:0042783; P:evasion of host immune response; IMP: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:0071768; P:mycolic acid biosynthetic process; IDA: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; Lipid biosynthesis; Lipid metabolism;
KW Methyltransferase; Phosphoprotein; Reference proteome;
KW S-adenosyl-L-methionine; Transferase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:21969609"
FT CHAIN 2..287
FT /note="Cyclopropane mycolic acid synthase 3"
FT /id="PRO_0000398358"
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 BINDING 68..76
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT BINDING 94..99
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT BINDING 123..124
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0007744|PubMed:21969609"
FT MOD_RES 168
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:22621931"
FT MOD_RES 183
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:22621931"
FT MUTAGEN 168
FT /note="T->A: Loss of phosphorylation; when associated with
FT A-183."
FT /evidence="ECO:0000269|PubMed:22621931"
FT MUTAGEN 183
FT /note="T->A: Loss of phosphorylation; when associated with
FT A-168."
FT /evidence="ECO:0000269|PubMed:22621931"
FT HELIX 20..23
FT /evidence="ECO:0007829|PDB:1L1E"
FT TURN 24..26
FT /evidence="ECO:0007829|PDB:1L1E"
FT HELIX 45..58
FT /evidence="ECO:0007829|PDB:1L1E"
FT TURN 59..61
FT /evidence="ECO:0007829|PDB:1L1E"
FT STRAND 67..72
FT /evidence="ECO:0007829|PDB:1L1E"
FT HELIX 77..86
FT /evidence="ECO:0007829|PDB:1L1E"
FT STRAND 89..95
FT /evidence="ECO:0007829|PDB:1L1E"
FT HELIX 97..109
FT /evidence="ECO:0007829|PDB:1L1E"
FT STRAND 116..121
FT /evidence="ECO:0007829|PDB:1L1E"
FT HELIX 123..125
FT /evidence="ECO:0007829|PDB:1L1E"
FT STRAND 131..137
FT /evidence="ECO:0007829|PDB:1L1E"
FT HELIX 139..141
FT /evidence="ECO:0007829|PDB:1L1E"
FT HELIX 144..146
FT /evidence="ECO:0007829|PDB:1L1E"
FT HELIX 147..157
FT /evidence="ECO:0007829|PDB:1L1E"
FT STRAND 163..171
FT /evidence="ECO:0007829|PDB:1L1E"
FT STRAND 177..180
FT /evidence="ECO:0007829|PDB:1L1E"
FT HELIX 189..198
FT /evidence="ECO:0007829|PDB:1L1E"
FT HELIX 208..216
FT /evidence="ECO:0007829|PDB:1L1E"
FT TURN 217..219
FT /evidence="ECO:0007829|PDB:1L1E"
FT STRAND 221..227
FT /evidence="ECO:0007829|PDB:1L1E"
FT HELIX 229..245
FT /evidence="ECO:0007829|PDB:1L1E"
FT HELIX 247..253
FT /evidence="ECO:0007829|PDB:1L1E"
FT HELIX 256..274
FT /evidence="ECO:0007829|PDB:1L1E"
FT STRAND 279..286
FT /evidence="ECO:0007829|PDB:1L1E"
SQ SEQUENCE 287 AA; 33028 MW; B8D2999A4CD81112 CRC64;
MSVQLTPHFG NVQAHYDLSD DFFRLFLDPT QTYSCAYFER DDMTLQEAQI AKIDLALGKL
NLEPGMTLLD IGCGWGATMR RAIEKYDVNV VGLTLSENQA GHVQKMFDQM DTPRSRRVLL
EGWEKFDEPV DRIVSIGAFE HFGHQRYHHF FEVTHRTLPA DGKMLLHTIV RPTFKEGREK
GLTLTHELVH FTKFILAEIF PGGWLPSIPT VHEYAEKVGF RVTAVQSLQL HYARTLDMWA
TALEANKDQA IAIQSQTVYD RYMKYLTGCA KLFRQGYTDV DQFTLEK
