ID AS3MT_HUMAN Reviewed; 375 AA. AC Q9HBK9; A6NP79; Q0VDK3; Q0VDK4; Q5PZ02; DT 04-JAN-2005, integrated into UniProtKB/Swiss-Prot. DT 14-OCT-2008, sequence version 3. DT 27-MAR-2024, entry version 167. DE RecName: Full=Arsenite methyltransferase; DE EC=2.1.1.137 {ECO:0000269|PubMed:16407288, ECO:0000269|PubMed:25997655}; DE AltName: Full=Methylarsonite methyltransferase; DE AltName: Full=S-adenosyl-L-methionine:arsenic(III) methyltransferase; GN Name=AS3MT; Synonyms=CYT19; 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] (ISOFORM 1), CATALYTIC ACTIVITY, RP BIOPHYSICOCHEMICAL PROPERTIES, AND VARIANTS TRP-173; THR-287 AND ILE-306. RX PubMed=16407288; DOI=10.1074/jbc.m512227200; RA Wood T.C., Salavagionne O.E., Mukherjee B., Wang L., Klumpp A.F., RA Thomae B.A., Eckloff B.W., Schaid D.J., Wieben E.D., Weinshilboum R.M.; RT "Human arsenic methyltransferase (AS3MT) pharmacogenetics: gene RT resequencing and functional genomics studies."; RL J. Biol. Chem. 281:7364-7373(2006). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Adrenal tumor; RA Xiao H., Song H., Gao G., Ren S., Chen Z., Han Z.; RL Submitted (JAN-2000) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Yu L., Kalla K., Guthrie E., Vidrine A., Klimecki W.T.; RL Submitted (DEC-2004) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-367 (ISOFORM 1). 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 [7] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [8] RP ALTERNATIVE SPLICING. RX PubMed=22005461; DOI=10.1016/j.bbrc.2011.10.008; RA Sumi D., Fukushima K., Miyataka H., Himeno S.; RT "Alternative splicing variants of human arsenic (+3 oxidation state) RT methyltransferase."; RL Biochem. Biophys. Res. Commun. 415:48-53(2011). RN [9] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-335, AND IDENTIFICATION BY RP 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 [10] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=25997655; DOI=10.1093/toxsci/kfv101; RA Zhang H., Ge Y., He P., Chen X., Carina A., Qiu Y., Aga D.S., Ren X.; RT "Interactive effects of N6AMT1 and As3MT in arsenic biomethylation."; RL Toxicol. Sci. 146:354-362(2015). RN [11] RP VARIANT THR-287. RX PubMed=18334919; DOI=10.1097/fpc.0b013e3282f7f46b; RA Hernandez A., Xamena N., Sekaran C., Tokunaga H., Sampayo-Reyes A., RA Quinteros D., Creus A., Marcos R.; RT "High arsenic metabolic efficiency in AS3MT287Thr allele carriers."; RL Pharmacogenet. Genomics 18:349-355(2008). CC -!- FUNCTION: Catalyzes the transfer of a methyl group from AdoMet to CC trivalent arsenicals producing methylated and dimethylated arsenicals CC (PubMed:16407288, PubMed:25997655). It methylates arsenite to form CC methylarsonate, Me-AsO(3)H(2), which is reduced by methylarsonate CC reductase to methylarsonite, Me-As(OH)2 (PubMed:16407288, CC PubMed:25997655). Methylarsonite is also a substrate and it is CC converted into the much less toxic compound dimethylarsinate CC (cacodylate), Me(2)As(O)-OH (PubMed:16407288, PubMed:25997655). CC {ECO:0000269|PubMed:16407288, ECO:0000269|PubMed:25997655}. CC -!- CATALYTIC ACTIVITY: CC Reaction=[thioredoxin]-dithiol + arsenic triglutathione + 2 H2O + S- CC adenosyl-L-methionine = [thioredoxin]-disulfide + 3 glutathione + CC H(+) + methylarsonous acid + S-adenosyl-L-homocysteine; CC Xref=Rhea:RHEA:69460, Rhea:RHEA-COMP:10698, Rhea:RHEA-COMP:10700, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:17826, CC ChEBI:CHEBI:29950, ChEBI:CHEBI:50058, ChEBI:CHEBI:57856, CC ChEBI:CHEBI:57925, ChEBI:CHEBI:59789, ChEBI:CHEBI:183640; CC EC=2.1.1.137; Evidence={ECO:0000269|PubMed:16407288, CC ECO:0000269|PubMed:25997655}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2 [thioredoxin]-dithiol + arsenic triglutathione + H2O + 2 S- CC adenosyl-L-methionine = 2 [thioredoxin]-disulfide + dimethylarsinous CC acid + 3 glutathione + 2 H(+) + 2 S-adenosyl-L-homocysteine; CC Xref=Rhea:RHEA:69464, Rhea:RHEA-COMP:10698, Rhea:RHEA-COMP:10700, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:23808, CC ChEBI:CHEBI:29950, ChEBI:CHEBI:50058, ChEBI:CHEBI:57856, CC ChEBI:CHEBI:57925, ChEBI:CHEBI:59789, ChEBI:CHEBI:183640; CC EC=2.1.1.137; Evidence={ECO:0000269|PubMed:16407288, CC ECO:0000269|PubMed:25997655}; CC -!- CATALYTIC ACTIVITY: CC Reaction=3 [thioredoxin]-dithiol + arsenic triglutathione + 3 S- CC adenosyl-L-methionine = 3 [thioredoxin]-disulfide + 3 glutathione + 3 CC H(+) + 3 S-adenosyl-L-homocysteine + trimethylarsine; CC Xref=Rhea:RHEA:69432, Rhea:RHEA-COMP:10698, Rhea:RHEA-COMP:10700, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:27130, ChEBI:CHEBI:29950, CC ChEBI:CHEBI:50058, ChEBI:CHEBI:57856, ChEBI:CHEBI:57925, CC ChEBI:CHEBI:59789, ChEBI:CHEBI:183640; EC=2.1.1.137; CC Evidence={ECO:0000269|PubMed:16407288, ECO:0000269|PubMed:25997655}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=4.6 uM for sodium arsenite {ECO:0000269|PubMed:16407288}; CC KM=11.8 uM for AdoMet {ECO:0000269|PubMed:16407288}; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol CC {ECO:0000250|UniProtKB:Q8VHT6}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Comment=An isoform missing exon 3 is produced with a premature stop CC codon at AA 23 and is targeted to nonsense-mediated mRNA decay CC (NMD).; CC Name=1; CC IsoId=Q9HBK9-1; Sequence=Displayed; CC Name=2; Synonyms=31.1 kDa, delta4,5; CC IsoId=Q9HBK9-2; Sequence=VSP_053494; CC -!- MISCELLANEOUS: [Isoform 2]: Devoid of methyltransferase activity. CC {ECO:0000305}. CC -!- SIMILARITY: Belongs to the methyltransferase superfamily. Arsenite CC methyltransferase family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAG09731.1; Type=Frameshift; Evidence={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; AF226730; AAG09731.1; ALT_FRAME; mRNA. DR EMBL; AY817668; AAV68045.1; -; Genomic_DNA. DR EMBL; AL358790; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471066; EAW49668.1; -; Genomic_DNA. DR EMBL; BC119637; AAI19638.1; -; mRNA. DR EMBL; BC119638; AAI19639.2; -; mRNA. DR CCDS; CCDS41567.1; -. [Q9HBK9-1] DR RefSeq; NP_065733.2; NM_020682.3. [Q9HBK9-1] DR AlphaFoldDB; Q9HBK9; -. DR SMR; Q9HBK9; -. DR BioGRID; 121513; 10. DR IntAct; Q9HBK9; 2. DR STRING; 9606.ENSP00000358896; -. DR BindingDB; Q9HBK9; -. DR ChEMBL; CHEMBL4295950; -. DR DrugBank; DB00118; Ademetionine. DR GlyGen; Q9HBK9; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q9HBK9; -. DR PhosphoSitePlus; Q9HBK9; -. DR BioMuta; AS3MT; -. DR DMDM; 209572762; -. DR EPD; Q9HBK9; -. DR jPOST; Q9HBK9; -. DR MassIVE; Q9HBK9; -. DR MaxQB; Q9HBK9; -. DR PaxDb; 9606-ENSP00000358896; -. DR PeptideAtlas; Q9HBK9; -. DR ProteomicsDB; 81567; -. [Q9HBK9-1] DR Pumba; Q9HBK9; -. DR Antibodypedia; 2804; 165 antibodies from 32 providers. DR DNASU; 57412; -. DR Ensembl; ENST00000369880.8; ENSP00000358896.3; ENSG00000214435.9. [Q9HBK9-1] DR GeneID; 57412; -. DR KEGG; hsa:57412; -. DR MANE-Select; ENST00000369880.8; ENSP00000358896.3; NM_020682.4; NP_065733.2. DR UCSC; uc001kwk.4; human. [Q9HBK9-1] DR AGR; HGNC:17452; -. DR CTD; 57412; -. DR DisGeNET; 57412; -. DR GeneCards; AS3MT; -. DR HGNC; HGNC:17452; AS3MT. DR HPA; ENSG00000214435; Tissue enhanced (adrenal). DR MIM; 611806; gene. DR neXtProt; NX_Q9HBK9; -. DR OpenTargets; ENSG00000214435; -. DR PharmGKB; PA134896392; -. DR VEuPathDB; HostDB:ENSG00000214435; -. DR eggNOG; ENOG502QQD6; Eukaryota. DR GeneTree; ENSGT00390000001742; -. DR InParanoid; Q9HBK9; -. DR OMA; EPACEDY; -. DR OrthoDB; 3685828at2759; -. DR PhylomeDB; Q9HBK9; -. DR TreeFam; TF343797; -. DR BioCyc; MetaCyc:HS01822-MONOMER; -. DR BRENDA; 2.1.1.137; 2681. DR PathwayCommons; Q9HBK9; -. DR Reactome; R-HSA-156581; Methylation. DR SABIO-RK; Q9HBK9; -. DR SignaLink; Q9HBK9; -. DR BioGRID-ORCS; 57412; 8 hits in 1159 CRISPR screens. DR GeneWiki; AS3MT; -. DR GenomeRNAi; 57412; -. DR Pharos; Q9HBK9; Tbio. DR PRO; PR:Q9HBK9; -. DR Proteomes; UP000005640; Chromosome 10. DR RNAct; Q9HBK9; Protein. DR Bgee; ENSG00000214435; Expressed in right adrenal gland and 99 other cell types or tissues. DR ExpressionAtlas; Q9HBK9; baseline and differential. DR GO; GO:0005829; C:cytosol; ISS:UniProtKB. DR GO; GO:0030791; F:arsenite methyltransferase activity; IDA:UniProtKB. DR GO; GO:0030792; F:methylarsonite methyltransferase activity; IDA:UniProtKB. DR GO; GO:0018872; P:arsonoacetate metabolic process; IDA:UniProtKB. DR GO; GO:0032259; P:methylation; IDA:UniProtKB. DR GO; GO:0009404; P:toxin metabolic process; IDA:UniProtKB. DR CDD; cd02440; AdoMet_MTases; 1. DR Gene3D; 3.40.5.100; -; 1. DR Gene3D; 3.40.50.150; Vaccinia Virus protein VP39; 1. DR InterPro; IPR026669; Arsenite_MeTrfase-like. DR InterPro; IPR025714; Methyltranfer_dom. DR InterPro; IPR029063; SAM-dependent_MTases_sf. DR PANTHER; PTHR43675; ARSENITE METHYLTRANSFERASE; 1. DR PANTHER; PTHR43675:SF8; ARSENITE METHYLTRANSFERASE; 1. DR Pfam; PF13847; Methyltransf_31; 1. DR SUPFAM; SSF53335; S-adenosyl-L-methionine-dependent methyltransferases; 1. DR Genevisible; Q9HBK9; HS. PE 1: Evidence at protein level; KW Alternative splicing; Cytoplasm; Methyltransferase; Phosphoprotein; KW Reference proteome; S-adenosyl-L-methionine; Transferase. FT CHAIN 1..375 FT /note="Arsenite methyltransferase" FT /id="PRO_0000204447" FT MOD_RES 335 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT VAR_SEQ 58..153 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000305" FT /id="VSP_053494" FT VARIANT 173 FT /note="R -> W (frequency in African-Americans 0.008; not FT detected in Caucasian-Americans; enzyme activity is 31% of FT wild-type; dbSNP:rs35232887)" FT /evidence="ECO:0000269|PubMed:16407288" FT /id="VAR_027392" FT VARIANT 287 FT /note="M -> T (frequency in African-Americans 0.108 and FT Caucasian-Americans 0.100; enzyme activity is 350% of FT wild-type; dbSNP:rs11191439)" FT /evidence="ECO:0000269|PubMed:16407288, FT ECO:0000269|PubMed:18334919" FT /id="VAR_027393" FT VARIANT 306 FT /note="T -> I (frequency in Caucasian-Americans 0.008; not FT detected in African-Americans; dbSNP:rs34556438)" FT /evidence="ECO:0000269|PubMed:16407288" FT /id="VAR_027394" FT CONFLICT 125 FT /note="Q -> R (in Ref. 6; AAI19638)" FT /evidence="ECO:0000305" FT CONFLICT 132 FT /note="I -> F (in Ref. 2; AAG09731)" FT /evidence="ECO:0000305" FT CONFLICT 135 FT /note="Y -> N (in Ref. 2; AAG09731)" FT /evidence="ECO:0000305" FT CONFLICT 140 FT /note="G -> A (in Ref. 2; AAG09731)" FT /evidence="ECO:0000305" SQ SEQUENCE 375 AA; 41748 MW; 2E0C758A8597AE33 CRC64; MAALRDAEIQ KDVQTYYGQV LKRSADLQTN GCVTTARPVP KHIREALQNV HEEVALRYYG CGLVIPEHLE NCWILDLGSG SGRDCYVLSQ LVGEKGHVTG IDMTKGQVEV AEKYLDYHME KYGFQASNVT FIHGYIEKLG EAGIKNESHD IVVSNCVINL VPDKQQVLQE AYRVLKHGGE LYFSDVYTSL ELPEEIRTHK VLWGECLGGA LYWKELAVLA QKIGFCPPRL VTANLITIQN KELERVIGDC RFVSATFRLF KHSKTGPTKR CQVIYNGGIT GHEKELMFDA NFTFKEGEIV EVDEETAAIL KNSRFAQDFL IRPIGEKLPT SGGCSALELK DIITDPFKLA EESDSMKSRC VPDAAGGCCG TKKSC //