ID A0A3B4GUS5_9CICH Unreviewed; 1269 AA.
AC A0A3B4GUS5;
DT 05-DEC-2018, integrated into UniProtKB/TrEMBL.
DT 05-DEC-2018, sequence version 1.
DT 27-MAR-2024, entry version 27.
DE RecName: Full=Methionine synthase {ECO:0000256|ARBA:ARBA00012032, ECO:0000256|PIRNR:PIRNR000381};
DE EC=2.1.1.13 {ECO:0000256|ARBA:ARBA00012032, ECO:0000256|PIRNR:PIRNR000381};
DE AltName: Full=5-methyltetrahydrofolate--homocysteine methyltransferase {ECO:0000256|PIRNR:PIRNR000381};
GN Name=mtr {ECO:0000313|RefSeq:XP_005748796.1};
OS Pundamilia nyererei.
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Neoteleostei; Acanthomorphata;
OC Ovalentaria; Cichlomorphae; Cichliformes; Cichlidae; African cichlids;
OC Pseudocrenilabrinae; Haplochromini; Pundamilia.
OX NCBI_TaxID=303518 {ECO:0000313|Ensembl:ENSPNYP00000025168.1, ECO:0000313|Proteomes:UP000261460};
RN [1] {ECO:0000313|Ensembl:ENSPNYP00000025168.1}
RP IDENTIFICATION.
RG Ensembl;
RL Submitted (SEP-2023) to UniProtKB.
RN [2] {ECO:0000313|RefSeq:XP_005748796.1}
RP IDENTIFICATION.
RG RefSeq;
RL Submitted (NOV-2023) to UniProtKB.
CC -!- FUNCTION: Catalyzes the transfer of a methyl group from
CC methylcob(III)alamin (MeCbl) to homocysteine, yielding enzyme-bound
CC cob(I)alamin and methionine in the cytosol. MeCbl is an active form of
CC cobalamin (vitamin B12) used as a cofactor for methionine biosynthesis.
CC Cob(I)alamin form is regenerated to MeCbl by a transfer of a methyl
CC group from 5-methyltetrahydrofolate. The processing of cobalamin in the
CC cytosol occurs in a multiprotein complex composed of at least MMACHC,
CC MMADHC, MTRR (methionine synthase reductase) and MTR which may
CC contribute to shuttle safely and efficiently cobalamin towards MTR in
CC order to produce methionine. {ECO:0000256|PIRNR:PIRNR000381}.
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 Evidence={ECO:0000256|PIRNR:PIRNR000381};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000256|ARBA:ARBA00001947,
CC ECO:0000256|PIRNR:PIRNR000381, ECO:0000256|PROSITE-ProRule:PRU00333};
CC -!- COFACTOR:
CC Name=methylcob(III)alamin; Xref=ChEBI:CHEBI:28115;
CC Evidence={ECO:0000256|ARBA:ARBA00001956,
CC ECO:0000256|PIRNR:PIRNR000381, ECO:0000256|PIRSR:PIRSR000381-1};
CC -!- PATHWAY: Amino-acid biosynthesis; L-methionine biosynthesis via de novo
CC pathway; L-methionine from L-homocysteine (MetH route): step 1/1.
CC {ECO:0000256|ARBA:ARBA00005178, ECO:0000256|PIRNR:PIRNR000381}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000256|PIRNR:PIRNR000381}.
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. {ECO:0000256|PIRNR:PIRNR000381}.
CC -!- SIMILARITY: Belongs to the vitamin-B12 dependent methionine synthase
CC family. {ECO:0000256|ARBA:ARBA00010398}.
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DR RefSeq; XP_005748796.1; XM_005748739.1.
DR AlphaFoldDB; A0A3B4GUS5; -.
DR STRING; 303518.ENSPNYP00000025168; -.
DR Ensembl; ENSPNYT00000025785.1; ENSPNYP00000025168.1; ENSPNYG00000018947.1.
DR GeneID; 102192354; -.
DR CTD; 4548; -.
DR GeneTree; ENSGT00420000029824; -.
DR OrthoDB; 66796at2759; -.
DR UniPathway; UPA00051; UER00081.
DR Proteomes; UP000261460; Unplaced.
DR Proteomes; UP000695023; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0031419; F:cobalamin binding; IEA:UniProtKB-UniRule.
DR GO; GO:0008705; F:methionine synthase activity; IEA:UniProtKB-UniRule.
DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-UniRule.
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; 1.10.288.10; Cobalamin-dependent Methionine Synthase, domain 2; 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 {ECO:0000256|ARBA:ARBA00022605,
KW ECO:0000256|PIRNR:PIRNR000381};
KW Cobalamin {ECO:0000256|ARBA:ARBA00022628, ECO:0000256|PIRNR:PIRNR000381};
KW Cobalt {ECO:0000256|ARBA:ARBA00023285, ECO:0000256|PIRNR:PIRNR000381};
KW Cytoplasm {ECO:0000256|PIRNR:PIRNR000381};
KW Metal-binding {ECO:0000256|ARBA:ARBA00022723,
KW ECO:0000256|PIRNR:PIRNR000381};
KW Methionine biosynthesis {ECO:0000256|ARBA:ARBA00023167,
KW ECO:0000256|PIRNR:PIRNR000381};
KW Methyltransferase {ECO:0000256|ARBA:ARBA00022603,
KW ECO:0000256|PIRNR:PIRNR000381};
KW Reference proteome {ECO:0000313|Proteomes:UP000695023};
KW Repeat {ECO:0000256|ARBA:ARBA00022737};
KW S-adenosyl-L-methionine {ECO:0000256|ARBA:ARBA00022691,
KW ECO:0000256|PIRNR:PIRNR000381};
KW Transferase {ECO:0000256|ARBA:ARBA00022679, ECO:0000256|PIRNR:PIRNR000381};
KW Zinc {ECO:0000256|ARBA:ARBA00022833, ECO:0000256|PIRNR:PIRNR000381}.
FT DOMAIN 21..340
FT /note="Hcy-binding"
FT /evidence="ECO:0000259|PROSITE:PS50970"
FT DOMAIN 373..633
FT /note="Pterin-binding"
FT /evidence="ECO:0000259|PROSITE:PS50972"
FT DOMAIN 664..761
FT /note="B12-binding N-terminal"
FT /evidence="ECO:0000259|PROSITE:PS51337"
FT DOMAIN 774..909
FT /note="B12-binding"
FT /evidence="ECO:0000259|PROSITE:PS51332"
FT DOMAIN 925..1268
FT /note="AdoMet activation"
FT /evidence="ECO:0000259|PROSITE:PS50974"
FT BINDING 262
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000256|PIRSR:PIRSR000381-1,
FT ECO:0000256|PROSITE-ProRule:PRU00333"
FT BINDING 325
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000256|PIRSR:PIRSR000381-1,
FT ECO:0000256|PROSITE-ProRule:PRU00333"
FT BINDING 326
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000256|PIRSR:PIRSR000381-1,
FT ECO:0000256|PROSITE-ProRule:PRU00333"
FT BINDING 711
FT /ligand="methylcob(III)alamin"
FT /ligand_id="ChEBI:CHEBI:28115"
FT /evidence="ECO:0000256|PIRSR:PIRSR000381-2"
FT BINDING 784..788
FT /ligand="methylcob(III)alamin"
FT /ligand_id="ChEBI:CHEBI:28115"
FT /evidence="ECO:0000256|PIRSR:PIRSR000381-2"
FT BINDING 787
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:0000256|PIRSR:PIRSR000381-1"
FT BINDING 832
FT /ligand="methylcob(III)alamin"
FT /ligand_id="ChEBI:CHEBI:28115"
FT /evidence="ECO:0000256|PIRSR:PIRSR000381-2"
FT BINDING 836
FT /ligand="methylcob(III)alamin"
FT /ligand_id="ChEBI:CHEBI:28115"
FT /evidence="ECO:0000256|PIRSR:PIRSR000381-2"
FT BINDING 888
FT /ligand="methylcob(III)alamin"
FT /ligand_id="ChEBI:CHEBI:28115"
FT /evidence="ECO:0000256|PIRSR:PIRSR000381-2"
FT BINDING 976
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000256|PIRSR:PIRSR000381-2"
FT BINDING 1175
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000256|PIRSR:PIRSR000381-2"
FT BINDING 1230..1231
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000256|PIRSR:PIRSR000381-2"
SQ SEQUENCE 1269 AA; 140381 MW; 3508F59EADB70E81 CRC64;
MAPTNVFQPF SSEAGCSCPL ESELRAVLQQ RIMVLDGGMG TMIQQQKLEE EDFRGEEFKT
HTLPLKGNND ILSITQPDII YKIHKEYLLA GADIIETNTF SSTSIAQADY GLEHMAYRLN
KASAQLARRA ADDVAKQCGD KRYVAGAVGP TNKTLSVSPC VERPDFRNIT FDELVEAYSE
QVRGLLDGGV DILLVETIFD TANAKAALFA IDLLFEKSYE RKPVFISGTI VDRSGRTLSG
QTGEAFVVSV SHAEPLCIGL NCALGAKEMR PFIEAIGKST TAFIICYPNA GLPNTFGGYD
ETPQVTASNL KEFAMDGLVN IVGGCCGTTP SHIRAIAEAV RHCVPRAPAA DIYQDYLLLS
GLEPFTVGPH TNFVNIGERC NVAGSRKFAK LIMAGNYEEA LSIAKAQVEM GAQVLDINMD
EGMLDGPKAM ARFCSFIASE PDIARVPLCI DSSNFSVIEA GLKCCQGKCI VNSISLKEGE
QEFLLRAATV KRYGAAVVVM AFDEEGQATD TERKVEICTR AYKLLVNKVG FDPNNIIFDP
NILTIGTGME EHNEYAISFI AATKLIKETL PRARVSGGLS NLSFSFRGME VIREAMHGVF
LYRAIKNGMD MGIVNAGNLP VYDDIDKELL TLCENLIWNR DGDATEKLLA YAQNNTKGGK
QIIRTDEWRE GSVEERLEYA LIKGIEKYVV EDVEECRAQV HRYTRPLRII EGPLMNGMKA
VGDLFGAGKM FLPQVIKSAR VMKKAVSYLI PFMEKERQEL MAASGSCDET DPYQGTIVLA
TVKGDVHDIG KNIVGVVLGC NNFRVIDLGV MVPCDQILRE AVTQKADVIG LSGLITPSLD
EMIYVAKEME RLGMTTPLLI GGATTSKVHT AVKIAPRYSC PVIHVLDASR SVVVCSQLLD
ETAKEEYFEE LKEEYEEIRQ EHYDSLKDRC YLSLSQAREK ALKVDWHSLP QPVCPQFLGT
RVFDLYDLNS LLDFIDWKPF FDVWQLRGKY PNRGYPKIFN DKTVGSEARK LFDDAQQLIH
HMIDDCRLKG RGLVGFWRAQ SNGDDIRVYK DDAAVDGDTE PIATFHGLRQ QVEKDGSSSE
PYLCVSDFVA PVDSGVADYI GLFAVGVFGA EELSQQFQAQ GDDYNSIMVK ALADRLAEAF
AEELHARVRK ELWGYSTDEA LHTLDLHRVR YKGIRPAAGY PSQPDHTEKT MMWSLANIQE
KTGIGLTESL AMTPAASVSG LYFSNPQASY FAVGKITKEQ VEDYASRKEM NVEEVERWLA
PILGYDNEV
//
