MMAA4_MYCTU
ID MMAA4_MYCTU Reviewed; 301 AA.
AC Q79FX8; L0T4B4;
DT 05-OCT-2010, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 111.
DE RecName: Full=Hydroxymycolate synthase MmaA4;
DE EC=2.1.1.-;
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=mmaA4; Synonyms=hma, mma4; OrderedLocusNames=Rv0642c;
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 OXYGEN-CONTAINING MYCOLATES BIOSYNTHESIS, AND DISRUPTION
RP PHENOTYPE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=10844652; DOI=10.1046/j.1365-2958.2000.01882.x;
RA Dubnau E., Chan J., Raynaud C., Mohan V.P., Laneelle M.A., Yu K.,
RA Quemard A., Smith I., Daffe M.;
RT "Oxygenated mycolic acids are necessary for virulence of Mycobacterium
RT tuberculosis in mice.";
RL Mol. Microbiol. 36:630-637(2000).
RN [3]
RP FUNCTION AS A HYDROXYMYCOLATE SYNTHASE, AND DISRUPTION PHENOTYPE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=12473649; DOI=10.1074/jbc.m210501200;
RA Dinadayala P., Laval F., Raynaud C., Lemassu A., Laneelle M.A.,
RA Laneelle G., Daffe M.;
RT "Tracking the putative biosynthetic precursors of oxygenated mycolates of
RT Mycobacterium tuberculosis. Structural analysis of fatty acids of a mutant
RT strain deviod of methoxy- and ketomycolates.";
RL J. Biol. Chem. 278:7310-7319(2003).
RN [4]
RP IDENTIFICATION AS A DRUG TARGET [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 25618 / H37Rv;
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 DISRUPTION PHENOTYPE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=18535659; DOI=10.1371/journal.ppat.1000081;
RA Dao D.N., Sweeney K., Hsu T., Gurcha S.S., Nascimento I.P., Roshevsky D.,
RA Besra G.S., Chan J., Porcelli S.A., Jacobs W.R.;
RT "Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates
RT IL-12 production.";
RL PLoS Pathog. 4:E1000081-E1000081(2008).
RN [6]
RP THIACETAZONE SUSCEPTIBILITY.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=19183278; DOI=10.1111/j.1365-2958.2009.06604.x;
RA Alahari A., Alibaud L., Trivelli X., Gupta R., Lamichhane G.,
RA Reynolds R.C., Bishai W.R., Guerardel Y., Kremer L.;
RT "Mycolic acid methyltransferase, MmaA4, is necessary for thiacetazone
RT susceptibility in Mycobacterium tuberculosis.";
RL Mol. Microbiol. 71:1263-1277(2009).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [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 X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) IN COMPLEX WITH S-ADENOSYLMETHIONINE,
RP SUBUNIT, AND MASS SPECTROMETRY.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=16356931; DOI=10.1074/jbc.m510250200;
RA Boissier F., Bardou F., Guillet V., Uttenweiler-Joseph S., Daffe M.,
RA Quemard A., Mourey L.;
RT "Further insight into S-adenosylmethionine-dependent methyltransferases:
RT structural characterization of Hma, an enzyme essential for the
RT biosynthesis of oxygenated mycolic acids in Mycobacterium tuberculosis.";
RL J. Biol. Chem. 281:4434-4445(2006).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) IN COMPLEX WITH S-ADENOSYLMETHIONINE
RP ANALOG, AND 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).
CC -!- FUNCTION: Involved in the biosynthesis of hydroxymycolate, a common
CC precursor of oxygenated mycolic acids (methoxy-mycolate and keto-
CC mycolate). Probably transfers a methyl group from the S-
CC adenosylmethionine (SAM) cofactor and, subsequently or simultaneously,
CC a water molecule onto the double bound of ethylene substrates, leading
CC to the formation of the hydroxylated product at the distal position.
CC Involved in the activation of the antitubercular drug thiacetazone
CC (TAC). {ECO:0000269|PubMed:10844652, ECO:0000269|PubMed:12473649}.
CC -!- ACTIVITY REGULATION: Inhibited by S-adenosyl-N-decyl-aminoethyl
CC (SADAE). {ECO:0000269|PubMed:19439410}.
CC -!- PATHWAY: Lipid metabolism; mycolic acid biosynthesis.
CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:16356931,
CC ECO:0000269|PubMed:19439410}.
CC -!- MASS SPECTROMETRY: Mass=34561; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:16356931};
CC -!- DISRUPTION PHENOTYPE: Cells lacking this gene result in a decreased
CC permeability and fluidity of the cell envelope due to a drastic
CC difference in the mycolates pattern. The parent strain makes three
CC types of mycolates (alpha-mycolate, methoxymycolates and
CC ketomycolates), but the mutant contains most exclusively alpha-
CC mycolates. The mutated strain grows more slowly in the lungs, spleen
CC and liver of mouse and is cleared more rapidly from the liver than the
CC wild-type strain. Cells lacking this gene show also an increased
CC production of interleukin-12p40 which probably mediated by the
CC mycolate-containing glycolipid trehalose 6,6'-dimycolate (TDM), which
CC is known to be secreted as a potential immunomodulator into the cytosol
CC of infected macrophages. Inactivation of MmaA4 confers a strong TAC
CC resistance. {ECO:0000269|PubMed:10844652, ECO:0000269|PubMed:12473649,
CC ECO:0000269|PubMed:18535659}.
CC -!- MISCELLANEOUS: Susceptibility of M.tuberculosis to the second-line
CC antitubercular drug thiacetazone (TAC) requires primary activation by
CC the monooxygenase, EthA, but is not sufficient to hit the lethal
CC target. TAC must be secondarily modified (methylation) to its lethal
CC form which causes growth arrest. MmaA4 activates TAC by interacting
CC directly with TAC or with EthA to produce lethal TAC, but the
CC methylation of the drug appears independent of MmaA4.
CC -!- SIMILARITY: Belongs to the CFA/CMAS family. {ECO:0000305}.
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DR EMBL; AL123456; CCP43385.1; -; Genomic_DNA.
DR RefSeq; NP_215156.1; NC_000962.3.
DR RefSeq; WP_003900195.1; NZ_NVQJ01000007.1.
DR PDB; 2FK7; X-ray; 2.10 A; A=4-301.
DR PDB; 2FK8; X-ray; 2.00 A; A=4-301.
DR PDB; 3HA3; X-ray; 2.20 A; A=4-301.
DR PDB; 3HA5; X-ray; 2.30 A; A=4-301.
DR PDB; 3HA7; X-ray; 2.35 A; A=4-301.
DR PDB; 7Q2B; X-ray; 1.85 A; A=4-301.
DR PDB; 7Q2C; X-ray; 1.90 A; A=4-301.
DR PDB; 7Q2D; X-ray; 1.89 A; A=4-301.
DR PDB; 7Q2E; X-ray; 1.93 A; A=4-301.
DR PDB; 7Q2F; X-ray; 1.85 A; A=4-301.
DR PDB; 7Q2G; X-ray; 2.00 A; A=4-301.
DR PDB; 7Q2H; X-ray; 1.75 A; A=4-301.
DR PDBsum; 2FK7; -.
DR PDBsum; 2FK8; -.
DR PDBsum; 3HA3; -.
DR PDBsum; 3HA5; -.
DR PDBsum; 3HA7; -.
DR PDBsum; 7Q2B; -.
DR PDBsum; 7Q2C; -.
DR PDBsum; 7Q2D; -.
DR PDBsum; 7Q2E; -.
DR PDBsum; 7Q2F; -.
DR PDBsum; 7Q2G; -.
DR PDBsum; 7Q2H; -.
DR AlphaFoldDB; Q79FX8; -.
DR SMR; Q79FX8; -.
DR STRING; 83332.Rv0642c; -.
DR DrugBank; DB07413; 5'-S-[2-(decylamino)ethyl]-5'-thioadenosine.
DR PaxDb; Q79FX8; -.
DR DNASU; 888056; -.
DR GeneID; 45424602; -.
DR GeneID; 888056; -.
DR KEGG; mtu:Rv0642c; -.
DR PATRIC; fig|83332.111.peg.713; -.
DR TubercuList; Rv0642c; -.
DR eggNOG; COG2230; Bacteria.
DR InParanoid; Q79FX8; -.
DR OMA; YHPYDLA; -.
DR PhylomeDB; Q79FX8; -.
DR UniPathway; UPA00915; -.
DR EvolutionaryTrace; Q79FX8; -.
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:0008168; F:methyltransferase activity; IMP:UniProtKB.
DR GO; GO:0008757; F:S-adenosylmethionine-dependent methyltransferase activity; IDA:MTBBASE.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0071768; P:mycolic acid biosynthetic 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; Lipid biosynthesis; Lipid metabolism; Methyltransferase;
KW Reference proteome; S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..301
FT /note="Hydroxymycolate synthase MmaA4"
FT /id="PRO_0000398365"
FT ACT_SITE 278
FT /evidence="ECO:0000250"
FT BINDING 42..43
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT BINDING 81..83
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT BINDING 103..108
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT BINDING 132..133
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT BINDING 145
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT HELIX 22..25
FT /evidence="ECO:0007829|PDB:2FK8"
FT HELIX 29..32
FT /evidence="ECO:0007829|PDB:2FK8"
FT TURN 33..35
FT /evidence="ECO:0007829|PDB:2FK8"
FT HELIX 54..66
FT /evidence="ECO:0007829|PDB:2FK8"
FT STRAND 76..81
FT /evidence="ECO:0007829|PDB:2FK8"
FT HELIX 86..95
FT /evidence="ECO:0007829|PDB:2FK8"
FT STRAND 98..104
FT /evidence="ECO:0007829|PDB:2FK8"
FT HELIX 106..117
FT /evidence="ECO:0007829|PDB:2FK8"
FT STRAND 125..130
FT /evidence="ECO:0007829|PDB:2FK8"
FT HELIX 132..134
FT /evidence="ECO:0007829|PDB:2FK8"
FT STRAND 140..146
FT /evidence="ECO:0007829|PDB:2FK8"
FT HELIX 148..150
FT /evidence="ECO:0007829|PDB:2FK8"
FT HELIX 153..155
FT /evidence="ECO:0007829|PDB:2FK8"
FT HELIX 156..166
FT /evidence="ECO:0007829|PDB:2FK8"
FT STRAND 172..179
FT /evidence="ECO:0007829|PDB:2FK8"
FT HELIX 183..187
FT /evidence="ECO:0007829|PDB:2FK8"
FT HELIX 191..207
FT /evidence="ECO:0007829|PDB:2FK8"
FT HELIX 217..226
FT /evidence="ECO:0007829|PDB:2FK8"
FT HELIX 238..254
FT /evidence="ECO:0007829|PDB:2FK8"
FT HELIX 256..262
FT /evidence="ECO:0007829|PDB:2FK8"
FT HELIX 265..283
FT /evidence="ECO:0007829|PDB:2FK8"
FT STRAND 288..295
FT /evidence="ECO:0007829|PDB:2FK8"
SQ SEQUENCE 301 AA; 34670 MW; 827ED04835956802 CRC64;
MTRMAEKPIS PTKTRTRFED IQAHYDVSDD FFALFQDPTR TYSCAYFEPP ELTLEEAQYA
KVDLNLDKLD LKPGMTLLDI GCGWGTTMRR AVERFDVNVI GLTLSKNQHA RCEQVLASID
TNRSRQVLLQ GWEDFAEPVD RIVSIEAFEH FGHENYDDFF KRCFNIMPAD GRMTVQSSVS
YHPYEMAARG KKLSFETARF IKFIVTEIFP GGRLPSTEMM VEHGEKAGFT VPEPLSLRPH
YIKTLRIWGD TLQSNKDKAI EVTSEEVYNR YMKYLRGCEH YFTDEMLDCS LVTYLKPGAA
A
