BHMT1_HUMAN
ID BHMT1_HUMAN Reviewed; 406 AA.
AC Q93088; Q9UNI9;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 17-APR-2007, sequence version 2.
DT 03-AUG-2022, entry version 193.
DE RecName: Full=Betaine--homocysteine S-methyltransferase 1 {ECO:0000303|PubMed:8798461};
DE EC=2.1.1.5 {ECO:0000269|PubMed:10529246, ECO:0000269|PubMed:8798461, ECO:0000269|PubMed:9681996};
GN Name=BHMT {ECO:0000303|PubMed:8798461};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], VARIANT GLN-239, FUNCTION, AND CATALYTIC
RP ACTIVITY.
RC TISSUE=Liver;
RX PubMed=8798461; DOI=10.1074/jbc.271.37.22831;
RA Garrow T.A.;
RT "Purification, kinetic properties, and cDNA cloning of mammalian betaine-
RT homocysteine methyltransferase.";
RL J. Biol. Chem. 271:22831-22838(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Lung;
RX PubMed=10075673; DOI=10.1074/jbc.274.12.7816;
RA Park E.I., Garrow T.A.;
RT "Interaction between dietary methionine and methyl donor intake on rat
RT liver betaine-homocysteine methyltransferase gene expression and
RT organization of the human gene.";
RL J. Biol. Chem. 274:7816-7824(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP TISSUE SPECIFICITY.
RX PubMed=9281325; DOI=10.1006/abbi.1997.0246;
RA Sunden S.L.F., Renduchintala M.S., Park E.I., Miklasz S.D., Garrow T.A.;
RT "Betaine-homocysteine methyltransferase expression in porcine and human
RT tissues and chromosomal localization of the human gene.";
RL Arch. Biochem. Biophys. 345:171-174(1997).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND COFACTOR.
RC TISSUE=Liver;
RX PubMed=9681996; DOI=10.1006/abbi.1998.0757;
RA Millian N.S., Garrow T.A.;
RT "Human betaine-homocysteine methyltransferase is a zinc metalloenzyme.";
RL Arch. Biochem. Biophys. 356:93-98(1998).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, PATHWAY, AND MUTAGENESIS OF
RP ASN-216; CYS-217; ASP-220; CYS-299; CYS-300; GLU-303 AND HIS-306.
RX PubMed=10529246; DOI=10.1021/bi991003v;
RA Breksa A.P. III, Garrow T.A.;
RT "Recombinant human liver betaine-homocysteine S-methyltransferase:
RT identification of three cysteine residues critical for zinc binding.";
RL Biochemistry 38:13991-13998(1999).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (2.05 ANGSTROMS) IN COMPLEX WITH ZINC, AND SUBUNIT.
RX PubMed=12220488; DOI=10.1016/s0969-2126(02)00796-7;
RA Evans J.C., Huddler D.P., Jiracek J., Castro C., Millian N.S., Garrow T.A.,
RA Ludwig M.L.;
RT "Betaine-homocysteine methyltransferase: zinc in a distorted barrel.";
RL Structure 10:1159-1171(2002).
RN [9]
RP VARIANT GLN-239.
RX PubMed=12818402; DOI=10.1016/s0021-9150(03)00010-8;
RA Weisberg I.S., Park E., Ballman K.V., Berger P., Nunn M., Suh D.S.,
RA Breksa A.P., Garrow T.A., Rozen R.;
RT "Investigations of a common genetic variant in betaine-homocysteine
RT methyltransferase (BHMT) in coronary artery disease.";
RL Atherosclerosis 167:205-214(2003).
CC -!- FUNCTION: Involved in the regulation of homocysteine metabolism.
CC Converts betaine and homocysteine to dimethylglycine and methionine,
CC respectively. This reaction is also required for the irreversible
CC oxidation of choline. {ECO:0000269|PubMed:10529246,
CC ECO:0000269|PubMed:8798461, ECO:0000269|PubMed:9681996}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=glycine betaine + L-homocysteine = L-methionine + N,N-
CC dimethylglycine; Xref=Rhea:RHEA:22336, ChEBI:CHEBI:17750,
CC ChEBI:CHEBI:57844, ChEBI:CHEBI:58199, ChEBI:CHEBI:58251; EC=2.1.1.5;
CC Evidence={ECO:0000269|PubMed:10529246, ECO:0000269|PubMed:8798461,
CC ECO:0000269|PubMed:9681996};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22337;
CC Evidence={ECO:0000269|PubMed:10529246};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:10529246, ECO:0000269|PubMed:12220488,
CC ECO:0000269|PubMed:9681996};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:10529246,
CC ECO:0000269|PubMed:12220488};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2.2 mM for glycine betaine {ECO:0000269|PubMed:9681996};
CC KM=4 uM for L-homocysteine {ECO:0000269|PubMed:9681996};
CC -!- PATHWAY: Amine and polyamine degradation; betaine degradation;
CC sarcosine from betaine: step 1/2.
CC -!- PATHWAY: Amino-acid biosynthesis; L-methionine biosynthesis via de novo
CC pathway; L-methionine from L-homocysteine (BhmT route): step 1/1.
CC {ECO:0000269|PubMed:10529246}.
CC -!- SUBUNIT: Homotetramer. {ECO:0000269|PubMed:12220488}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:O09171}. Nucleus {ECO:0000250|UniProtKB:O09171}.
CC Note=Predominantly localized in the cytoplasm with a small fraction
CC detected in the nucleus. Translocates into the nucleus upon oxidative
CC stress. {ECO:0000250|UniProtKB:O09171}.
CC -!- TISSUE SPECIFICITY: Found exclusively in liver and kidney.
CC {ECO:0000269|PubMed:9281325}.
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DR EMBL; U50929; AAC50668.1; -; mRNA.
DR EMBL; AF118378; AAD22043.1; -; Genomic_DNA.
DR EMBL; AF118371; AAD22043.1; JOINED; Genomic_DNA.
DR EMBL; AF118372; AAD22043.1; JOINED; Genomic_DNA.
DR EMBL; AF118373; AAD22043.1; JOINED; Genomic_DNA.
DR EMBL; AF118374; AAD22043.1; JOINED; Genomic_DNA.
DR EMBL; AF118375; AAD22043.1; JOINED; Genomic_DNA.
DR EMBL; AF118376; AAD22043.1; JOINED; Genomic_DNA.
DR EMBL; AF118377; AAD22043.1; JOINED; Genomic_DNA.
DR EMBL; BC012616; AAH12616.1; -; mRNA.
DR CCDS; CCDS4046.1; -.
DR RefSeq; NP_001704.2; NM_001713.2.
DR PDB; 1LT7; X-ray; 2.15 A; A/B=1-406.
DR PDB; 1LT8; X-ray; 2.05 A; A/B=1-406.
DR PDB; 4M3P; X-ray; 1.90 A; A/B/C/D=1-406.
DR PDBsum; 1LT7; -.
DR PDBsum; 1LT8; -.
DR PDBsum; 4M3P; -.
DR AlphaFoldDB; Q93088; -.
DR SMR; Q93088; -.
DR BioGRID; 107104; 15.
DR IntAct; Q93088; 7.
DR MINT; Q93088; -.
DR STRING; 9606.ENSP00000274353; -.
DR BindingDB; Q93088; -.
DR ChEMBL; CHEMBL4328; -.
DR DrugBank; DB00134; Methionine.
DR DrugBank; DB02337; S-(D-Carboxybutyl)-L-Homocysteine.
DR GlyGen; Q93088; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q93088; -.
DR PhosphoSitePlus; Q93088; -.
DR BioMuta; BHMT; -.
DR DMDM; 145559446; -.
DR EPD; Q93088; -.
DR jPOST; Q93088; -.
DR MassIVE; Q93088; -.
DR PaxDb; Q93088; -.
DR PeptideAtlas; Q93088; -.
DR PRIDE; Q93088; -.
DR ProteomicsDB; 75719; -.
DR Antibodypedia; 12660; 474 antibodies from 39 providers.
DR DNASU; 635; -.
DR Ensembl; ENST00000274353.10; ENSP00000274353.5; ENSG00000145692.15.
DR GeneID; 635; -.
DR KEGG; hsa:635; -.
DR MANE-Select; ENST00000274353.10; ENSP00000274353.5; NM_001713.3; NP_001704.2.
DR CTD; 635; -.
DR DisGeNET; 635; -.
DR GeneCards; BHMT; -.
DR HGNC; HGNC:1047; BHMT.
DR HPA; ENSG00000145692; Group enriched (kidney, liver).
DR MIM; 602888; gene.
DR neXtProt; NX_Q93088; -.
DR OpenTargets; ENSG00000145692; -.
DR PharmGKB; PA25350; -.
DR VEuPathDB; HostDB:ENSG00000145692; -.
DR eggNOG; KOG1579; Eukaryota.
DR GeneTree; ENSGT00390000003122; -.
DR InParanoid; Q93088; -.
DR OMA; IATRWDI; -.
DR OrthoDB; 731388at2759; -.
DR PhylomeDB; Q93088; -.
DR TreeFam; TF329202; -.
DR BioCyc; MetaCyc:HS07273-MON; -.
DR BRENDA; 2.1.1.5; 2681.
DR PathwayCommons; Q93088; -.
DR Reactome; R-HSA-1614635; Sulfur amino acid metabolism.
DR Reactome; R-HSA-6798163; Choline catabolism.
DR SABIO-RK; Q93088; -.
DR SignaLink; Q93088; -.
DR SIGNOR; Q93088; -.
DR UniPathway; UPA00051; UER00083.
DR UniPathway; UPA00291; UER00432.
DR BioGRID-ORCS; 635; 14 hits in 1067 CRISPR screens.
DR ChiTaRS; BHMT; human.
DR EvolutionaryTrace; Q93088; -.
DR GenomeRNAi; 635; -.
DR Pharos; Q93088; Tchem.
DR PRO; PR:Q93088; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q93088; protein.
DR Bgee; ENSG00000145692; Expressed in nephron tubule and 115 other tissues.
DR ExpressionAtlas; Q93088; baseline and differential.
DR Genevisible; Q93088; HS.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0047150; F:betaine-homocysteine S-methyltransferase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0071266; P:'de novo' L-methionine biosynthetic process; IMP:UniProtKB.
DR GO; GO:0006579; P:amino-acid betaine catabolic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0006577; P:amino-acid betaine metabolic process; IDA:BHF-UCL.
DR GO; GO:0071267; P:L-methionine salvage; IDA:BHF-UCL.
DR GO; GO:0009086; P:methionine biosynthetic process; IBA:GO_Central.
DR GO; GO:0006479; P:protein methylation; NAS:UniProtKB.
DR GO; GO:0050666; P:regulation of homocysteine metabolic process; NAS:UniProtKB.
DR Gene3D; 3.20.20.330; -; 1.
DR InterPro; IPR017226; Betaine-hCys_S-MeTrfase_BHMT.
DR InterPro; IPR003726; HCY_dom.
DR InterPro; IPR036589; HCY_dom_sf.
DR Pfam; PF02574; S-methyl_trans; 1.
DR PIRSF; PIRSF037505; Betaine_HMT; 1.
DR SUPFAM; SSF82282; SSF82282; 1.
DR PROSITE; PS50970; HCY; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytoplasm; Metal-binding; Methyltransferase; Nucleus;
KW Phosphoprotein; Reference proteome; Transferase; Zinc.
FT CHAIN 1..406
FT /note="Betaine--homocysteine S-methyltransferase 1"
FT /id="PRO_0000114621"
FT DOMAIN 11..314
FT /note="Hcy-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT BINDING 217
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00333,
FT ECO:0000269|PubMed:12220488, ECO:0007744|PDB:1LT8"
FT BINDING 299
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00333,
FT ECO:0000269|PubMed:12220488, ECO:0007744|PDB:1LT8"
FT BINDING 300
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00333,
FT ECO:0000269|PubMed:12220488, ECO:0007744|PDB:1LT8"
FT MOD_RES 40
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:O35490"
FT MOD_RES 93
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:O35490"
FT MOD_RES 232
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:O35490"
FT MOD_RES 241
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:O35490"
FT MOD_RES 330
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O09171"
FT MOD_RES 340
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:O35490"
FT MOD_RES 377
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:O35490"
FT VARIANT 199
FT /note="G -> S (in dbSNP:rs59866108)"
FT /id="VAR_061345"
FT VARIANT 239
FT /note="R -> Q (may decrease risk for coronary artery
FT disease; dbSNP:rs3733890)"
FT /evidence="ECO:0000269|PubMed:12818402,
FT ECO:0000269|PubMed:8798461"
FT /id="VAR_015886"
FT MUTAGEN 216
FT /note="N->A,C: Decreases the catalytic efficiency."
FT /evidence="ECO:0000269|PubMed:10529246"
FT MUTAGEN 217
FT /note="C->A,S,H: Impairs zinc ion binding. Loss of
FT catalytic activity."
FT /evidence="ECO:0000269|PubMed:10529246"
FT MUTAGEN 220
FT /note="D->A: Has no significant effect on catalytic
FT activity."
FT MUTAGEN 299
FT /note="C->A,S: Impairs zinc ion binding. Loss of catalytic
FT activity."
FT /evidence="ECO:0000269|PubMed:10529246"
FT MUTAGEN 300
FT /note="C->A,S: Impairs zinc ion binding. Loss of catalytic
FT activity."
FT /evidence="ECO:0000269|PubMed:10529246"
FT MUTAGEN 303
FT /note="E->A: Has no significant effect on catalytic
FT activity."
FT /evidence="ECO:0000269|PubMed:10529246"
FT MUTAGEN 306
FT /note="H->A: Has no significant effect on catalytic
FT activity."
FT /evidence="ECO:0000269|PubMed:10529246"
FT HELIX 13..18
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 29..35
FT /evidence="ECO:0007829|PDB:4M3P"
FT TURN 41..43
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 48..51
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 53..66
FT /evidence="ECO:0007829|PDB:4M3P"
FT STRAND 69..72
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 97..111
FT /evidence="ECO:0007829|PDB:4M3P"
FT TURN 112..115
FT /evidence="ECO:0007829|PDB:4M3P"
FT STRAND 117..123
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 126..129
FT /evidence="ECO:0007829|PDB:1LT8"
FT HELIX 134..151
FT /evidence="ECO:0007829|PDB:4M3P"
FT STRAND 154..162
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 164..175
FT /evidence="ECO:0007829|PDB:4M3P"
FT STRAND 181..185
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 198..207
FT /evidence="ECO:0007829|PDB:4M3P"
FT STRAND 211..219
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 221..237
FT /evidence="ECO:0007829|PDB:4M3P"
FT STRAND 243..247
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 261..263
FT /evidence="ECO:0007829|PDB:4M3P"
FT TURN 265..269
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 272..274
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 278..290
FT /evidence="ECO:0007829|PDB:4M3P"
FT STRAND 293..296
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 304..313
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 315..318
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 323..327
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 330..335
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 341..344
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 349..354
FT /evidence="ECO:0007829|PDB:4M3P"
FT HELIX 377..400
FT /evidence="ECO:0007829|PDB:4M3P"
SQ SEQUENCE 406 AA; 44998 MW; 557855B8CEDD0D54 CRC64;
MPPVGGKKAK KGILERLNAG EIVIGDGGFV FALEKRGYVK AGPWTPEAAV EHPEAVRQLH
REFLRAGSNV MQTFTFYASE DKLENRGNYV LEKISGQEVN EAACDIARQV ADEGDALVAG
GVSQTPSYLS CKSETEVKKV FLQQLEVFMK KNVDFLIAEY FEHVEEAVWA VETLIASGKP
VAATMCIGPE GDLHGVPPGE CAVRLVKAGA SIIGVNCHFD PTISLKTVKL MKEGLEAARL
KAHLMSQPLA YHTPDCNKQG FIDLPEFPFG LEPRVATRWD IQKYAREAYN LGVRYIGGCC
GFEPYHIRAI AEELAPERGF LPPASEKHGS WGSGLDMHTK PWVRARARKE YWENLRIASG
RPYNPSMSKP DGWGVTKGTA ELMQQKEATT EQQLKELFEK QKFKSQ
