ID   METH_MYCTU              Reviewed;        1192 AA.
AC   O33259; L0T8Q3;
DT   15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT   01-JAN-1998, sequence version 1.
DT   27-MAR-2024, entry version 161.
DE   RecName: Full=Methionine synthase;
DE            EC=2.1.1.13;
DE   AltName: Full=5-methyltetrahydrofolate--homocysteine methyltransferase;
DE   AltName: Full=Methionine synthase, vitamin-B12 dependent;
DE            Short=MS;
GN   Name=metH; OrderedLocusNames=Rv2124c; ORFNames=MTCY261.20c;
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   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   [3]
RP   IDENTIFICATION BY MASS SPECTROMETRY [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).
CC   -!- FUNCTION: Catalyzes the transfer of a methyl group from methyl-
CC       cobalamin to homocysteine, yielding enzyme-bound cob(I)alamin and
CC       methionine. Subsequently, remethylates the cofactor using
CC       methyltetrahydrofolate (By similarity). {ECO:0000250}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(6S)-5-methyl-5,6,7,8-tetrahydrofolate + L-homocysteine =
CC         (6S)-5,6,7,8-tetrahydrofolate + L-methionine; Xref=Rhea:RHEA:11172,
CC         ChEBI:CHEBI:18608, ChEBI:CHEBI:57453, ChEBI:CHEBI:57844,
CC         ChEBI:CHEBI:58199; EC=2.1.1.13;
CC   -!- COFACTOR:
CC       Name=methylcob(III)alamin; Xref=ChEBI:CHEBI:28115;
CC         Evidence={ECO:0000250};
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC       Note=Binds 1 zinc ion per subunit. {ECO:0000250};
CC   -!- PATHWAY: Amino-acid biosynthesis; L-methionine biosynthesis via de novo
CC       pathway; L-methionine from L-homocysteine (MetH route): step 1/1.
CC   -!- DOMAIN: Modular enzyme with four functionally distinct domains. The
CC       isolated Hcy-binding domain catalyzes methyl transfer from free
CC       methylcobalamin to homocysteine. The Hcy-binding domain in association
CC       with the pterin-binding domain catalyzes the methylation of
CC       cob(I)alamin by methyltetrahydrofolate and the methylation of
CC       homocysteine. The B12-binding domain binds the cofactor. The AdoMet
CC       activation domain binds S-adenosyl-L-methionine. Under aerobic
CC       conditions cob(I)alamin can be converted to inactive cob(II)alamin.
CC       Reductive methylation by S-adenosyl-L-methionine and flavodoxin
CC       regenerates methylcobalamin (By similarity). {ECO:0000250}.
CC   -!- MISCELLANEOUS: L-homocysteine is bound via the zinc atom.
CC       {ECO:0000250}.
CC   -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC   -!- SIMILARITY: Belongs to the vitamin-B12 dependent methionine synthase
CC       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; CCP44899.1; -; Genomic_DNA.
DR   PIR; G70513; G70513.
DR   RefSeq; NP_216640.1; NC_000962.3.
DR   RefSeq; WP_003900472.1; NZ_NVQJ01000058.1.
DR   AlphaFoldDB; O33259; -.
DR   SMR; O33259; -.
DR   STRING; 83332.Rv2124c; -.
DR   PaxDb; 83332-Rv2124c; -.
DR   GeneID; 45426099; -.
DR   GeneID; 888711; -.
DR   KEGG; mtu:Rv2124c; -.
DR   TubercuList; Rv2124c; -.
DR   eggNOG; COG0646; Bacteria.
DR   eggNOG; COG1410; Bacteria.
DR   InParanoid; O33259; -.
DR   OrthoDB; 9803687at2; -.
DR   PhylomeDB; O33259; -.
DR   UniPathway; UPA00051; UER00081.
DR   Proteomes; UP000001584; Chromosome.
DR   GO; GO:0005829; C:cytosol; HDA:MTBBASE.
DR   GO; GO:0009274; C:peptidoglycan-based cell wall; HDA:MTBBASE.
DR   GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR   GO; GO:0031419; F:cobalamin binding; IEA:UniProtKB-KW.
DR   GO; GO:0008705; F:methionine synthase activity; IBA:GO_Central.
DR   GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR   GO; GO:0050667; P:homocysteine metabolic process; IBA:GO_Central.
DR   GO; GO:0009086; P:methionine biosynthetic process; IBA:GO_Central.
DR   GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR   GO; GO:0046653; P:tetrahydrofolate metabolic process; IBA:GO_Central.
DR   CDD; cd02069; methionine_synthase_B12_BD; 1.
DR   CDD; cd00740; MeTr; 1.
DR   Gene3D; 3.40.50.280; Cobalamin-binding domain; 1.
DR   Gene3D; 3.20.20.20; Dihydropteroate synthase-like; 1.
DR   Gene3D; 3.20.20.330; Homocysteine-binding-like domain; 1.
DR   Gene3D; 1.10.1240.10; Methionine synthase domain; 1.
DR   Gene3D; 3.10.196.10; Vitamin B12-dependent methionine synthase, activation domain; 1.
DR   InterPro; IPR003759; Cbl-bd_cap.
DR   InterPro; IPR006158; Cobalamin-bd.
DR   InterPro; IPR036724; Cobalamin-bd_sf.
DR   InterPro; IPR011005; Dihydropteroate_synth-like_sf.
DR   InterPro; IPR003726; HCY_dom.
DR   InterPro; IPR036589; HCY_dom_sf.
DR   InterPro; IPR033706; Met_synthase_B12-bd.
DR   InterPro; IPR011822; MetH.
DR   InterPro; IPR036594; Meth_synthase_dom.
DR   InterPro; IPR000489; Pterin-binding_dom.
DR   InterPro; IPR004223; VitB12-dep_Met_synth_activ_dom.
DR   InterPro; IPR037010; VitB12-dep_Met_synth_activ_sf.
DR   NCBIfam; TIGR02082; metH; 1.
DR   PANTHER; PTHR45833; METHIONINE SYNTHASE; 1.
DR   PANTHER; PTHR45833:SF1; METHIONINE SYNTHASE; 1.
DR   Pfam; PF02310; B12-binding; 1.
DR   Pfam; PF02607; B12-binding_2; 1.
DR   Pfam; PF02965; Met_synt_B12; 1.
DR   Pfam; PF00809; Pterin_bind; 1.
DR   Pfam; PF02574; S-methyl_trans; 1.
DR   PIRSF; PIRSF000381; MetH; 1.
DR   SMART; SM01018; B12-binding_2; 1.
DR   SUPFAM; SSF52242; Cobalamin (vitamin B12)-binding domain; 1.
DR   SUPFAM; SSF51717; Dihydropteroate synthetase-like; 1.
DR   SUPFAM; SSF82282; Homocysteine S-methyltransferase; 1.
DR   SUPFAM; SSF56507; Methionine synthase activation domain-like; 1.
DR   SUPFAM; SSF47644; Methionine synthase domain; 1.
DR   PROSITE; PS50974; ADOMET_ACTIVATION; 1.
DR   PROSITE; PS51332; B12_BINDING; 1.
DR   PROSITE; PS51337; B12_BINDING_NTER; 1.
DR   PROSITE; PS50970; HCY; 1.
DR   PROSITE; PS50972; PTERIN_BINDING; 1.
PE   1: Evidence at protein level;
KW   Amino-acid biosynthesis; Cobalamin; Cobalt; Metal-binding;
KW   Methionine biosynthesis; Methyltransferase; Reference proteome; Repeat;
KW   S-adenosyl-L-methionine; Transferase; Zinc.
FT   CHAIN           1..1192
FT                   /note="Methionine synthase"
FT                   /id="PRO_0000204534"
FT   DOMAIN          1..312
FT                   /note="Hcy-binding"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT   DOMAIN          343..601
FT                   /note="Pterin-binding"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00334"
FT   DOMAIN          635..728
FT                   /note="B12-binding N-terminal"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00667"
FT   DOMAIN          729..866
FT                   /note="B12-binding"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00666"
FT   DOMAIN          893..1192
FT                   /note="AdoMet activation"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00346"
FT   REGION          860..904
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        860..885
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         231
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT   BINDING         297
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT   BINDING         298
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT   BINDING         739..743
FT                   /ligand="methylcob(III)alamin"
FT                   /ligand_id="ChEBI:CHEBI:28115"
FT                   /evidence="ECO:0000250|UniProtKB:P13009"
FT   BINDING         742
FT                   /ligand="methylcob(III)alamin"
FT                   /ligand_id="ChEBI:CHEBI:28115"
FT                   /ligand_part="Co"
FT                   /ligand_part_id="ChEBI:CHEBI:27638"
FT                   /note="axial binding residue"
FT                   /evidence="ECO:0000250|UniProtKB:P13009"
FT   BINDING         787
FT                   /ligand="methylcob(III)alamin"
FT                   /ligand_id="ChEBI:CHEBI:28115"
FT                   /evidence="ECO:0000250|UniProtKB:P13009"
FT   BINDING         845
FT                   /ligand="methylcob(III)alamin"
FT                   /ligand_id="ChEBI:CHEBI:28115"
FT                   /evidence="ECO:0000250|UniProtKB:P13009"
FT   BINDING         940
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000250"
FT   BINDING         1135
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000250"
FT   BINDING         1189..1190
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000250"
SQ   SEQUENCE   1192 AA;  130323 MW;  820450DCE77BE15B CRC64;
     MTAADKHLYD TDLLDVLSQR VMVGDGAMGT QLQAADLTLD DFRGLEGCNE ILNETRPDVL
     ETIHRNYFEA GADAVETNTF GCNLSNLGDY DIADRIRDLS QKGTAIARRV ADELGSPDRK
     RYVLGSMGPG TKLPTLGHTE YAVIRDAYTE AALGMLDGGA DAILVETCQD LLQLKAAVLG
     SRRAMTRAGR HIPVFAHVTV ETTGTMLLGS EIGAALTAVE PLGVDMIGLN CATGPAEMSE
     HLRHLSRHAR IPVSVMPNAG LPVLGAKGAE YPLLPDELAE ALAGFIAEFG LSLVGGCCGT
     TPAHIREVAA AVANIKRPER QVSYEPSVSS LYTAIPFAQD ASVLVIGERT NANGSKGFRE
     AMIAEDYQKC LDIAKDQTRD GAHLLDLCVD YVGRDGVADM KALASRLATS STLPIMLDST
     ETAVLQAGLE HLGGRCAINS VNYEDGDGPE SRFAKTMALV AEHGAAVVAL TIDEEGQART
     AQKKVEIAER LINDITGNWG VDESSILIDT LTFTIATGQE ESRRDGIETI EAIRELKKRH
     PDVQTTLGLS NISFGLNPAA RQVLNSVFLH ECQEAGLDSA IVHASKILPM NRIPEEQRNV
     ALDLVYDRRR EDYDPLQELM RLFEGVSAAS SKEDRLAELA GLPLFERLAQ RIVDGERNGL
     DADLDEAMTQ KPPLQIINEH LLAGMKTVGE LFGSGQMQLP FVLQSAEVMK AAVAYLEPHM
     ERSDDDSGKG RIVLATVKGD VHDIGKNLVD IILSNNGYEV VNIGIKQPIA TILEVAEDKS
     ADVVGMSGLL VKSTVVMKEN LEEMNTRGVA EKFPVLLGGA ALTRSYVEND LAEIYQGEVH
     YARDAFEGLK LMDTIMSAKR GEAPDENSPE AIKAREKEAE RKARHQRSKR IAAQRKAAEE
     PVEVPERSDV AADIEVPAPP FWGSRIVKGL AVADYTGLLD ERALFLGQWG LRGQRGGEGP
     SYEDLVETEG RPRLRYWLDR LSTDGILAHA AVVYGYFPAV SEGNDIVVLT EPKPDAPVRY
     RFHFPRQQRG RFLCIADFIR SRELAAERGE VDVLPFQLVT MGQPIADFAN ELFASNAYRD
     YLEVHGIGVQ LTEALAEYWH RRIREELKFS GDRAMAAEDP EAKEDYFKLG YRGARFAFGY
     GACPDLEDRA KMMALLEPER IGVTLSEELQ LHPEQSTDAF VLHHPEAKYF NV
//