ID   METH_MYCLE              Reviewed;        1206 AA.
AC   Q49775; Q9CC37; Q9S378;
DT   15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT   27-APR-2001, sequence version 3.
DT   27-MAR-2024, entry version 151.
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=ML1307;
GN   ORFNames=B2126_C1_157, MLCB2533.04;
OS   Mycobacterium leprae (strain TN).
OC   Bacteria; Actinomycetota; Actinomycetes; Mycobacteriales; Mycobacteriaceae;
OC   Mycobacterium.
OX   NCBI_TaxID=272631;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA   Smith D.R., Robison K.;
RL   Submitted (MAR-1994) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=TN;
RX   PubMed=11234002; DOI=10.1038/35059006;
RA   Cole S.T., Eiglmeier K., Parkhill J., James K.D., Thomson N.R.,
RA   Wheeler P.R., Honore N., Garnier T., Churcher C.M., Harris D.E.,
RA   Mungall K.L., Basham D., Brown D., Chillingworth T., Connor R.,
RA   Davies R.M., Devlin K., Duthoy S., Feltwell T., Fraser A., Hamlin N.,
RA   Holroyd S., Hornsby T., Jagels K., Lacroix C., Maclean J., Moule S.,
RA   Murphy L.D., Oliver K., Quail M.A., Rajandream M.A., Rutherford K.M.,
RA   Rutter S., Seeger K., Simon S., Simmonds M., Skelton J., Squares R.,
RA   Squares S., Stevens K., Taylor K., Whitehead S., Woodward J.R.,
RA   Barrell B.G.;
RT   "Massive gene decay in the leprosy bacillus.";
RL   Nature 409:1007-1011(2001).
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   -!- SIMILARITY: Belongs to the vitamin-B12 dependent methionine synthase
CC       family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAA17182.1; Type=Frameshift; Evidence={ECO:0000305};
CC       Sequence=CAA22918.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR   EMBL; U00017; AAA17182.1; ALT_FRAME; Genomic_DNA.
DR   EMBL; AL035310; CAA22918.1; ALT_INIT; Genomic_DNA.
DR   EMBL; AL583921; CAC31688.1; -; Genomic_DNA.
DR   PIR; E87072; E87072.
DR   PIR; S72842; S72842.
DR   RefSeq; NP_301940.1; NC_002677.1.
DR   RefSeq; WP_010908261.1; NC_002677.1.
DR   AlphaFoldDB; Q49775; -.
DR   SMR; Q49775; -.
DR   STRING; 272631.gene:17575141; -.
DR   KEGG; mle:ML1307; -.
DR   PATRIC; fig|272631.5.peg.2411; -.
DR   Leproma; ML1307; -.
DR   eggNOG; COG0646; Bacteria.
DR   eggNOG; COG1410; Bacteria.
DR   HOGENOM; CLU_004914_4_0_11; -.
DR   OrthoDB; 9803687at2; -.
DR   UniPathway; UPA00051; UER00081.
DR   Proteomes; UP000000806; Chromosome.
DR   GO; GO:0031419; F:cobalamin binding; IEA:UniProtKB-KW.
DR   GO; GO:0008705; F:methionine synthase activity; IEA:UniProtKB-EC.
DR   GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR   GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR   GO; GO:0042558; P:pteridine-containing compound metabolic process; IEA:InterPro.
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   3: Inferred from homology;
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..1206
FT                   /note="Methionine synthase"
FT                   /id="PRO_0000204533"
FT   DOMAIN          1..314
FT                   /note="Hcy-binding"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT   DOMAIN          350..609
FT                   /note="Pterin-binding"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00334"
FT   DOMAIN          642..735
FT                   /note="B12-binding N-terminal"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00667"
FT   DOMAIN          740..877
FT                   /note="B12-binding"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00666"
FT   DOMAIN          907..1206
FT                   /note="AdoMet activation"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00346"
FT   REGION          873..925
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        885..924
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         233
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT   BINDING         299
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT   BINDING         300
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT   BINDING         750..754
FT                   /ligand="methylcob(III)alamin"
FT                   /ligand_id="ChEBI:CHEBI:28115"
FT                   /evidence="ECO:0000250|UniProtKB:P13009"
FT   BINDING         753
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         798
FT                   /ligand="methylcob(III)alamin"
FT                   /ligand_id="ChEBI:CHEBI:28115"
FT                   /evidence="ECO:0000250|UniProtKB:P13009"
FT   BINDING         856
FT                   /ligand="methylcob(III)alamin"
FT                   /ligand_id="ChEBI:CHEBI:28115"
FT                   /evidence="ECO:0000250|UniProtKB:P13009"
FT   BINDING         954
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000250"
FT   BINDING         1149
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000250"
FT   BINDING         1203..1204
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000250"
SQ   SEQUENCE   1206 AA;  132392 MW;  7786CE5307D7CA86 CRC64;
     MRVTAANQHQ YDTDLLETLA QRVMVGDGAM GTQLQDAELT LDDFRGLEGC NEILNETRPD
     VLETIHRRYF EAGADLVETN TFGCNLSNLG DYDIADKIRD LSQRGTVIAR RVADELTTPD
     HKRYVLGSMG PGTKLPTLGH TEYRVVRDAY TESALGMLDG GADAVLVETC QDLLQLKAAV
     LGSRRAMTQA GRHIPVFVHV TVETTGTMLL GSEIGAALAA VEPLGVDMIG LNCATGPAEM
     SEHLRHLSKH ARIPVSVMPN AGLPVLGAKG AEYPLQPDEL AEALAGFIAE FGLSLVGGCC
     GTTPDHIREV AAAVARCNDG TVPRGERHVT YEPSVSSLYT AIPFAQKPSV LMIGERTNAN
     GSKVFREAMI AEDYQKCLDI AKDQTRGGAH LLDLCVDYVG RNGVADMKAL AGRLATVSTL
     PIMLDSTEIP VLQAGLEHLG GRCVINSVNY EDGDGPESRF VKTMELVAEH GAAVVALTID
     EQGQARTVEK KVEVAERLIN DITSNWGVDK SAILIDCLTF TIATGQEESR KDGIETIDAI
     RELKKRHPAV QTTLGLSNIS FGLNPSARQV LNSVFLHECQ EAGLDSAIVH ASKILPINRI
     PEEQRQAALD LVYDRRREGY DPLQKLMWLF KGVSSPSSKE TREAELAKLP LFDRLAQRIV
     DGERNGLDVD LDEAMTQKPP LAIINENLLD GMKTVGELFG SGQMQLPFVL QSAEVMKAAV
     AYLEPHMEKS DCDFGKGLAK GRIVLATVKG DVHDIGKNLV DIILSNNGYE VVNLGIKQPI
     TNILEVAEDK SADVVGMSGL LVKSTVIMKE NLEEMNTRGV AEKFPVLLGG AALTRSYVEN
     DLAEVYEGEV HYARDAFEGL KLMDTIMSAK RGEALAPGSP ESLAAEADRN KETERKARHE
     RSKRIAVQRK AAEEPVEVPE RSDVPSDVEV PAPPFWGSRI IKGLAVADYT GFLDERALFL
     GQWGLRGVRG GAGPSYEDLV QTEGRPRLRY WLDRLSTYGV LAYAAVVYGY FPAVSEDNDI
     VVLAEPRPDA EQRYRFTFPR QQRGRFLCIA DFIRSRDLAT ERSEVDVLPF QLVTMGQPIA
     DFVGELFVSN SYRDYLEVHG IGVQLTEALA EYWHRRIREE LKFSGNRTMS ADDPEAVEDY
     FKLGYRGARF AFGYGACPDL EDRIKMMELL QPERIGVTIS EELQLHPEQS TDAFVLHHPA
     AKYFNV
//