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Alpha-ketoglutarate-dependent dioxygenase FTO (EC 1.14.11.-) (Fat mass and obesity-associated protein)

 FTO_HUMAN               Reviewed;         505 AA.
Q9C0B1; A2RUH1; B2RNS0; Q0P676; Q7Z785;
01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
29-MAY-2007, sequence version 3.
05-DEC-2018, entry version 125.
RecName: Full=Alpha-ketoglutarate-dependent dioxygenase FTO {ECO:0000305};
AltName: Full=Fat mass and obesity-associated protein {ECO:0000303|PubMed:17496892};
AltName: Full=U6 small nuclear RNA (2'-O-methyladenosine-N(6)-)-demethylase FTO {ECO:0000305};
EC=1.14.11.- {ECO:0000269|PubMed:30197295};
AltName: Full=U6 small nuclear RNA N(6)-methyladenosine-demethylase FTO {ECO:0000305};
EC=1.14.11.- {ECO:0000269|PubMed:30197295};
AltName: Full=mRNA (2'-O-methyladenosine-N(6)-)-demethylase FTO {ECO:0000305};
Short=m6A(m)-demethylase FTO {ECO:0000305};
EC=1.14.11.- {ECO:0000269|PubMed:28002401, ECO:0000269|PubMed:30197295};
AltName: Full=mRNA N(6)-methyladenosine demethylase FTO {ECO:0000305};
EC=1.14.11.53 {ECO:0000269|PubMed:25452335, ECO:0000269|PubMed:26457839, ECO:0000269|PubMed:30197295, ECO:0000305|PubMed:22002720};
AltName: Full=tRNA N1-methyl adenine demethylase FTO {ECO:0000305};
EC=1.14.11.- {ECO:0000269|PubMed:30197295};
Name=FTO {ECO:0000303|PubMed:17496892, ECO:0000312|HGNC:HGNC:24678};
Synonyms=KIAA1752 {ECO:0000303|PubMed:11214970};
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
TISSUE=Brain;
PubMed=11214970; DOI=10.1093/dnares/7.6.347;
Nagase T., Kikuno R., Hattori A., Kondo Y., Okumura K., Ohara O.;
"Prediction of the coding sequences of unidentified human genes. XIX.
The complete sequences of 100 new cDNA clones from brain which code
for large proteins in vitro.";
DNA Res. 7:347-355(2000).
[2]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
TISSUE=Brain;
PubMed=15616553; DOI=10.1038/nature03187;
Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
Rubin E.M., Pennacchio L.A.;
"The sequence and analysis of duplication-rich human chromosome 16.";
Nature 432:988-994(2004).
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3 AND 4).
TISSUE=Cervix, Eye, and Lung;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[4]
POLYMORPHISM, AND TISSUE SPECIFICITY.
PubMed=17496892; DOI=10.1038/ng2048;
Dina C., Meyre D., Gallina S., Durand E., Korner A., Jacobson P.,
Carlsson L.M.S., Kiess W., Vatin V., Lecoeur C., Delplanque J.,
Vaillant E., Pattou F., Ruiz J., Weill J., Levy-Marchal C., Horber F.,
Potoczna N., Hercberg S., Le Stunff C., Bougneres P., Kovacs P.,
Marre M., Balkau B., Cauchi S., Chevre J.-C., Froguel P.;
"Variation in FTO contributes to childhood obesity and severe adult
obesity.";
Nat. Genet. 39:724-726(2007).
[5]
POLYMORPHISM, AND TISSUE SPECIFICITY.
PubMed=17434869; DOI=10.1126/science.1141634;
Frayling T.M., Timpson N.J., Weedon M.N., Zeggini E., Freathy R.M.,
Lindgren C.M., Perry J.R., Elliott K.S., Lango H., Rayner N.W.,
Shields B., Harries L.W., Barrett J.C., Ellard S., Groves C.J.,
Knight B., Patch A.M., Ness A.R., Ebrahim S., Lawlor D.A., Ring S.M.,
Ben-Shlomo Y., Jarvelin M.-R., Sovio U., Bennett A.J., Melzer D.,
Ferrucci L., Loos R.J., Barroso I., Wareham N.J., Karpe F., Owen K.R.,
Cardon L.R., Walker M., Hitman G.A., Palmer C.N., Doney A.S.,
Morris A.D., Davey-Smith G., Hattersley A.T., McCarthy M.I.;
"A common variant in the FTO gene is associated with body mass index
and predisposes to childhood and adult obesity.";
Science 316:889-894(2007).
[6]
FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
PubMed=18775698; DOI=10.1016/j.febslet.2008.08.019;
Jia G., Yang C.G., Yang S., Jian X., Yi C., Zhou Z., He C.;
"Oxidative demethylation of 3-methylthymine and 3-methyluracil in
single-stranded DNA and RNA by mouse and human FTO.";
FEBS Lett. 582:3313-3319(2008).
[7]
ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-216, AND IDENTIFICATION BY
MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=19608861; DOI=10.1126/science.1175371;
Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
Walther T.C., Olsen J.V., Mann M.;
"Lysine acetylation targets protein complexes and co-regulates major
cellular functions.";
Science 325:834-840(2009).
[8]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21269460; DOI=10.1186/1752-0509-5-17;
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
"Initial characterization of the human central proteome.";
BMC Syst. Biol. 5:17-17(2011).
[9]
FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF 231-HIS--ASP-233, AND
CHARACTERIZATION OF VARIANT GDFD GLN-316.
PubMed=22002720; DOI=10.1038/nchembio.687;
Jia G., Fu Y., Zhao X., Dai Q., Zheng G., Yang Y., Yi C., Lindahl T.,
Pan T., Yang Y.G., He C.;
"N6-methyladenosine in nuclear RNA is a major substrate of the
obesity-associated FTO.";
Nat. Chem. Biol. 7:885-887(2011).
[10]
POLYMORPHISM, AND INVOLVEMENT IN BMIQ14.
PubMed=22982992; DOI=10.1038/nature11401;
Yang J., Loos R.J., Powell J.E., Medland S.E., Speliotes E.K.,
Chasman D.I., Rose L.M., Thorleifsson G., Steinthorsdottir V.,
Maegi R., Waite L., Smith A.V., Yerges-Armstrong L.M., Monda K.L.,
Hadley D., Mahajan A., Li G., Kapur K., Vitart V., Huffman J.E.,
Wang S.R., Palmer C., Esko T., Fischer K., Zhao J.H., Demirkan A.,
Isaacs A., Feitosa M.F., Luan J., Heard-Costa N.L., White C.,
Jackson A.U., Preuss M., Ziegler A., Eriksson J., Kutalik Z., Frau F.,
Nolte I.M., Van Vliet-Ostaptchouk J.V., Hottenga J.J., Jacobs K.B.,
Verweij N., Goel A., Medina-Gomez C., Estrada K., Bragg-Gresham J.L.,
Sanna S., Sidore C., Tyrer J., Teumer A., Prokopenko I., Mangino M.,
Lindgren C.M., Assimes T.L., Shuldiner A.R., Hui J., Beilby J.P.,
McArdle W.L., Hall P., Haritunians T., Zgaga L., Kolcic I.,
Polasek O., Zemunik T., Oostra B.A., Junttila M.J., Groenberg H.,
Schreiber S., Peters A., Hicks A.A., Stephens J., Foad N.S.,
Laitinen J., Pouta A., Kaakinen M., Willemsen G., Vink J.M.,
Wild S.H., Navis G., Asselbergs F.W., Homuth G., John U.,
Iribarren C., Harris T., Launer L., Gudnason V., O'Connell J.R.,
Boerwinkle E., Cadby G., Palmer L.J., James A.L., Musk A.W.,
Ingelsson E., Psaty B.M., Beckmann J.S., Waeber G., Vollenweider P.,
Hayward C., Wright A.F., Rudan I., Groop L.C., Metspalu A., Khaw K.T.,
van Duijn C.M., Borecki I.B., Province M.A., Wareham N.J.,
Tardif J.C., Huikuri H.V., Cupples L.A., Atwood L.D., Fox C.S.,
Boehnke M., Collins F.S., Mohlke K.L., Erdmann J., Schunkert H.,
Hengstenberg C., Stark K., Lorentzon M., Ohlsson C., Cusi D.,
Staessen J.A., Van der Klauw M.M., Pramstaller P.P., Kathiresan S.,
Jolley J.D., Ripatti S., Jarvelin M.R., de Geus E.J., Boomsma D.I.,
Penninx B., Wilson J.F., Campbell H., Chanock S.J., van der Harst P.,
Hamsten A., Watkins H., Hofman A., Witteman J.C., Zillikens M.C.,
Uitterlinden A.G., Rivadeneira F., Zillikens M.C., Kiemeney L.A.,
Vermeulen S.H., Abecasis G.R., Schlessinger D., Schipf S.,
Stumvoll M., Toenjes A., Spector T.D., North K.E., Lettre G.,
McCarthy M.I., Berndt S.I., Heath A.C., Madden P.A., Nyholt D.R.,
Montgomery G.W., Martin N.G., McKnight B., Strachan D.P., Hill W.G.,
Snieder H., Ridker P.M., Thorsteinsdottir U., Stefansson K.,
Frayling T.M., Hirschhorn J.N., Goddard M.E., Visscher P.M.;
"FTO genotype is associated with phenotypic variability of body mass
index.";
Nature 490:267-272(2012).
[11]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-4, AND IDENTIFICATION BY
MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma, and Erythroleukemia;
PubMed=23186163; DOI=10.1021/pr300630k;
Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
Mohammed S.;
"Toward a comprehensive characterization of a human cancer cell
phosphoproteome.";
J. Proteome Res. 12:260-271(2013).
[12]
INVOLVEMENT IN OBESITY.
PubMed=24646999; DOI=10.1038/nature13138;
Smemo S., Tena J.J., Kim K.H., Gamazon E.R., Sakabe N.J.,
Gomez-Marin C., Aneas I., Credidio F.L., Sobreira D.R.,
Wasserman N.F., Lee J.H., Puviindran V., Tam D., Shen M., Son J.E.,
Vakili N.A., Sung H.K., Naranjo S., Acemel R.D., Manzanares M.,
Nagy A., Cox N.J., Hui C.C., Gomez-Skarmeta J.L., Nobrega M.A.;
"Obesity-associated variants within FTO form long-range functional
connections with IRX3.";
Nature 507:371-375(2014).
[13]
FUNCTION, AND INVOLVEMENT IN OBESITY.
PubMed=26287746; DOI=10.1056/NEJMoa1502214;
Claussnitzer M., Dankel S.N., Kim K.H., Quon G., Meuleman W.,
Haugen C., Glunk V., Sousa I.S., Beaudry J.L., Puviindran V.,
Abdennur N.A., Liu J., Svensson P.A., Hsu Y.H., Drucker D.J.,
Mellgren G., Hui C.C., Hauner H., Kellis M.;
"FTO obesity variant circuitry and adipocyte browning in humans.";
N. Engl. J. Med. 373:895-907(2015).
[14]
FUNCTION, AND SUBCELLULAR LOCATION.
PubMed=26458103; DOI=10.1038/nature15377;
Zhou J., Wan J., Gao X., Zhang X., Jaffrey S.R., Qian S.B.;
"Dynamic m(6)A mRNA methylation directs translational control of heat
shock response.";
Nature 526:591-594(2015).
[15]
FUNCTION, AND TISSUE SPECIFICITY.
PubMed=28017614; DOI=10.1016/j.ccell.2016.11.017;
Li Z., Weng H., Su R., Weng X., Zuo Z., Li C., Huang H.,
Nachtergaele S., Dong L., Hu C., Qin X., Tang L., Wang Y., Hong G.M.,
Huang H., Wang X., Chen P., Gurbuxani S., Arnovitz S., Li Y., Li S.,
Strong J., Neilly M.B., Larson R.A., Jiang X., Zhang P., Jin J.,
He C., Chen J.;
"FTO plays an oncogenic role in acute myeloid leukemia as a N6-
methyladenosine RNA demethylase.";
Cancer Cell 31:127-141(2017).
[16]
FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND
SUBCELLULAR LOCATION.
PubMed=28002401; DOI=10.1038/nature21022;
Mauer J., Luo X., Blanjoie A., Jiao X., Grozhik A.V., Patil D.P.,
Linder B., Pickering B.F., Vasseur J.J., Chen Q., Gross S.S.,
Elemento O., Debart F., Kiledjian M., Jaffrey S.R.;
"Reversible methylation of m6Am in the 5' cap controls mRNA
stability.";
Nature 541:371-375(2017).
[17]
FUNCTION, AND ACTIVITY REGULATION.
PubMed=29249359; DOI=10.1016/j.cell.2017.11.031;
Su R., Dong L., Li C., Nachtergaele S., Wunderlich M., Qing Y.,
Deng X., Wang Y., Weng X., Hu C., Yu M., Skibbe J., Dai Q., Zou D.,
Wu T., Yu K., Weng H., Huang H., Ferchen K., Qin X., Zhang B., Qi J.,
Sasaki A.T., Plas D.R., Bradner J.E., Wei M., Marcucci G., Jiang X.,
Mulloy J.C., Jin J., He C., Chen J.;
"R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA
signaling.";
Cell 172:90-105(2018).
[18]
FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
PubMed=30197295; DOI=10.1016/j.molcel.2018.08.011;
Wei J., Liu F., Lu Z., Fei Q., Ai Y., He P.C., Shi H., Cui X., Su R.,
Klungland A., Jia G., Chen J., He C.;
"Differential m6A, m6Am, and m1A demethylation mediated by FTO in the
cell nucleus and cytoplasm.";
Mol. Cell 71:973-985(2018).
[19]
X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 32-505 IN COMPLEX WITH IRON
IONS; N-OXALYLGLYCINE AND 3-METHYLTHYMIDINE, CATALYTIC ACTIVITY,
FUNCTION, COFACTOR, ACTIVITY REGULATION, MUTAGENESIS OF ARG-96;
TYR-108; PHE-114; GLU-234 AND CYS-392, CIRCULAR DICHROISM, AND DOMAIN.
PubMed=20376003; DOI=10.1038/nature08921;
Han Z., Niu T., Chang J., Lei X., Zhao M., Wang Q., Cheng W., Wang J.,
Feng Y., Chai J.;
"Crystal structure of the FTO protein reveals basis for its substrate
specificity.";
Nature 464:1205-1209(2010).
[20] {ECO:0000244|PDB:4IDZ, ECO:0000244|PDB:4IE0, ECO:0000244|PDB:4IE4, ECO:0000244|PDB:4IE5, ECO:0000244|PDB:4IE6, ECO:0000244|PDB:4IE7}
X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 32-505 IN COMPLEX WITH ZINC.
PubMed=23547775; DOI=10.1021/jm400193d;
Aik W., Demetriades M., Hamdan M.K., Bagg E.A., Yeoh K.K., Lejeune C.,
Zhang Z., McDonough M.A., Schofield C.J.;
"Structural basis for inhibition of the fat mass and obesity
associated protein (FTO).";
J. Med. Chem. 56:3680-3688(2013).
[21] {ECO:0000244|PDB:4CXW, ECO:0000244|PDB:4CXX, ECO:0000244|PDB:4CXY}
X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF 32-505 IN COMPLEX WITH ZINC,
FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
PubMed=28553460; DOI=10.1039/c4sc02554g;
Toh J.D.W., Sun L., Lau L.Z.M., Tan J., Low J.J.A., Tang C.W.Q.,
Cheong E.J.Y., Tan M.J.H., Chen Y., Hong W., Gao Y.G., Woon E.C.Y.;
"A strategy based on nucleotide specificity leads to a subfamily-
selective and cell-active inhibitor of N6-methyladenosine demethylase
FTO.";
Chem. Sci. 6:112-122(2015).
[22] {ECO:0000244|PDB:4ZS2, ECO:0000244|PDB:4ZS3}
X-RAY CRYSTALLOGRAPHY (2.16 ANGSTROMS) OF 32-505 IN COMPLEX WITH
2-OXOGLUTARATE AND MANGANESE, FUNCTION, CATALYTIC ACTIVITY, AND
ACTIVITY REGULATION.
PubMed=26457839; DOI=10.1021/jacs.5b06690;
Wang T., Hong T., Huang Y., Su H., Wu F., Chen Y., Wei L., Huang W.,
Hua X., Xia Y., Xu J., Gan J., Yuan B., Feng Y., Zhang X., Yang C.G.,
Zhou X.;
"Fluorescein derivatives as bifunctional molecules for the
simultaneous inhibiting and labeling of FTO protein.";
J. Am. Chem. Soc. 137:13736-13739(2015).
[23] {ECO:0000244|PDB:4QKN}
X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 32-503 IN COMPLEX WITH
MANGANESE AND N-OXALYLGLYCINE, FUNCTION, CATALYTIC ACTIVITY, AND
ACTIVITY REGULATION.
PubMed=25452335; DOI=10.1093/nar/gku1276;
Huang Y., Yan J., Li Q., Li J., Gong S., Zhou H., Gan J., Jiang H.,
Jia G.F., Luo C., Yang C.G.;
"Meclofenamic acid selectively inhibits FTO demethylation of m6A over
ALKBH5.";
Nucleic Acids Res. 43:373-384(2015).
[24]
VARIANT GDFD GLN-316, AND CHARACTERIZATION OF VARIANT GDFD GLN-316.
PubMed=19559399; DOI=10.1016/j.ajhg.2009.06.002;
Boissel S., Reish O., Proulx K., Kawagoe-Takaki H., Sedgwick B.,
Yeo G.S., Meyre D., Golzio C., Molinari F., Kadhom N., Etchevers H.C.,
Saudek V., Farooqi I.S., Froguel P., Lindahl T., O'Rahilly S.,
Munnich A., Colleaux L.;
"Loss-of-function mutation in the dioxygenase-encoding FTO gene causes
severe growth retardation and multiple malformations.";
Am. J. Hum. Genet. 85:106-111(2009).
[25]
VARIANT GDFD GLN-322.
PubMed=26697951; DOI=10.1002/ajmg.a.37515;
Rohena L., Lawson M., Guzman E., Ganapathi M., Cho M.T.,
Haverfield E., Anyane-Yeboa K.;
"FTO variant associated with malformation syndrome.";
Am. J. Med. Genet. A 170:1023-1028(2016).
[26]
VARIANT PRO-271.
PubMed=26740239; DOI=10.1038/jhg.2015.160;
Caglayan A.O., Tueysuez B., Coskun S., Quon J., Harmanci A.S.,
Baranoski J.F., Baran B., Erson-Omay E.Z., Henegariu O., Mane S.M.,
Bilguevar K., Yasuno K., Guenel M.;
"A patient with a novel homozygous missense mutation in FTO and
concomitant nonsense mutation in CETP.";
J. Hum. Genet. 61:395-403(2016).
[27]
VARIANT GDFD PHE-319, AND CHARACTERIZATION OF VARIANT GDFD PHE-319.
PubMed=26378117; DOI=10.1136/jmedgenet-2015-103399;
Daoud H., Zhang D., McMurray F., Yu A., Luco S.M., Vanstone J.,
Jarinova O., Carson N., Wickens J., Shishodia S., Choi H.,
McDonough M.A., Schofield C.J., Harper M.E., Dyment D.A., Armour C.M.;
"Identification of a pathogenic FTO mutation by next-generation
sequencing in a newborn with growth retardation and developmental
delay.";
J. Med. Genet. 53:200-207(2016).
-!- FUNCTION: RNA demethylase that mediates oxidative demethylation of
different RNA species, such as mRNAs, tRNAs and snRNAs, and acts
as a regulator of fat mass, adipogenesis and energy homeostasis
(PubMed:22002720, PubMed:26458103, PubMed:28002401,
PubMed:30197295, PubMed:26457839, PubMed:25452335). Specifically
demethylates N(6)-methyladenosine (m6A) RNA, the most prevalent
internal modification of messenger RNA (mRNA) in higher eukaryotes
(PubMed:22002720, PubMed:26458103, PubMed:30197295,
PubMed:26457839, PubMed:25452335). M6A demethylation by FTO
affects mRNA expression and stability (PubMed:30197295). Also able
to demethylate m6A in U6 small nuclear RNA (snRNA)
(PubMed:30197295). Mediates demethylation of N(6),2'-O-
dimethyladenosine cap (m6A(m)), by demethylating the N(6)-
methyladenosine at the second transcribed position of mRNAs and U6
snRNA (PubMed:28002401, PubMed:30197295). Demethylation of m6A(m)
in the 5'-cap by FTO affects mRNA stability by promoting
susceptibility to decapping (PubMed:28002401). Also acts as a tRNA
demethylase by removing N(1)-methyladenine from various tRNAs
(PubMed:30197295). Has no activity towards 1-methylguanine
(PubMed:20376003). Has no detectable activity towards double-
stranded DNA (PubMed:20376003). Also able to repair alkylated DNA
and RNA by oxidative demethylation: demethylates single-stranded
RNA containing 3-methyluracil, single-stranded DNA containing 3-
methylthymine and has low demethylase activity towards single-
stranded DNA containing 1-methyladenine or 3-methylcytosine
(PubMed:18775698, PubMed:20376003). Ability to repair alkylated
DNA and RNA is however unsure in vivo (PubMed:18775698,
PubMed:20376003). Involved in the regulation of fat mass,
adipogenesis and body weight, thereby contributing to the
regulation of body size and body fat accumulation
(PubMed:18775698, PubMed:20376003). Involved in the regulation of
thermogenesis and the control of adipocyte differentiation into
brown or white fat cells (PubMed:26287746). Regulates activity of
the dopaminergic midbrain circuitry via its ability to demethylate
m6A in mRNAs (By similarity). Plays an oncogenic role in a number
of acute myeloid leukemias by enhancing leukemic oncogene-mediated
cell transformation: acts by mediating m6A demethylation of target
transcripts such as MYC, CEBPA, ASB2 and RARA, leading to promote
their expression (PubMed:28017614, PubMed:29249359).
{ECO:0000250|UniProtKB:Q8BGW1, ECO:0000269|PubMed:18775698,
ECO:0000269|PubMed:20376003, ECO:0000269|PubMed:22002720,
ECO:0000269|PubMed:25452335, ECO:0000269|PubMed:26287746,
ECO:0000269|PubMed:26457839, ECO:0000269|PubMed:26458103,
ECO:0000269|PubMed:28002401, ECO:0000269|PubMed:28017614,
ECO:0000269|PubMed:29249359, ECO:0000269|PubMed:30197295}.
-!- CATALYTIC ACTIVITY:
Reaction=2-oxoglutarate + a 5'-(N(7)-methyl 5'-
triphosphoguanosine)-(N(7),2'-O-dimethyladenosine 5'-phosphate)-
[mRNA] + O2 = a 5'-(N(7)-methyl 5'-triphosphoguanosine)-(2'-O-
methyladenosine 5'-phosphate)-[mRNA] + CO2 + formaldehyde +
succinate; Xref=Rhea:RHEA:57896, Rhea:RHEA-COMP:11518,
Rhea:RHEA-COMP:11519, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526,
ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031,
ChEBI:CHEBI:85958, ChEBI:CHEBI:85959;
Evidence={ECO:0000269|PubMed:28002401,
ECO:0000269|PubMed:30197295};
-!- CATALYTIC ACTIVITY:
Reaction=2-oxoglutarate + N(6)-methyladenosine in mRNA + O2 =
adenosine in mRNA + CO2 + formaldehyde + succinate;
Xref=Rhea:RHEA:49520, Rhea:RHEA-COMP:12414, Rhea:RHEA-
COMP:12417, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526,
ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031,
ChEBI:CHEBI:74411, ChEBI:CHEBI:74449; EC=1.14.11.53;
Evidence={ECO:0000269|PubMed:25452335,
ECO:0000269|PubMed:26457839, ECO:0000269|PubMed:30197295,
ECO:0000305|PubMed:22002720};
-!- CATALYTIC ACTIVITY:
Reaction=2-oxoglutarate + N(6)-methyladenosine in U6 snRNA + O2 =
adenosine in U6 snRNA + CO2 + formaldehyde + succinate;
Xref=Rhea:RHEA:57900, Rhea:RHEA-COMP:13573, Rhea:RHEA-
COMP:13574, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526,
ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031,
ChEBI:CHEBI:74411, ChEBI:CHEBI:74449;
Evidence={ECO:0000269|PubMed:30197295};
-!- CATALYTIC ACTIVITY:
Reaction=2-oxoglutarate + a 5'-(N(7)-methyl 5'-
triphosphoguanosine)-(N(7),2'-O-dimethyladenosine 5'-phosphate)
in U6 snRNA + O2 = a 5'-(N(7)-methyl 5'-triphosphoguanosine)-
(2'-O-methyladenosine 5'-phosphate) in U6 snRNA + CO2 +
formaldehyde + succinate; Xref=Rhea:RHEA:57904, Rhea:RHEA-
COMP:15030, Rhea:RHEA-COMP:15031, ChEBI:CHEBI:15379,
ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842,
ChEBI:CHEBI:30031, ChEBI:CHEBI:85958, ChEBI:CHEBI:85959;
Evidence={ECO:0000269|PubMed:30197295};
-!- CATALYTIC ACTIVITY:
Reaction=2-oxoglutarate + N(1)-methyladenosine in tRNA + O2 =
adenosine in tRNA + CO2 + formaldehyde + succinate;
Xref=Rhea:RHEA:54576, Rhea:RHEA-COMP:10242, Rhea:RHEA-
COMP:12312, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526,
ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031,
ChEBI:CHEBI:74411, ChEBI:CHEBI:74491;
Evidence={ECO:0000269|PubMed:30197295};
-!- COFACTOR:
Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
Evidence={ECO:0000269|PubMed:20376003};
Note=Binds 1 Fe(2+) ion per subunit.
{ECO:0000269|PubMed:20376003};
-!- ACTIVITY REGULATION: Activated by ascorbate (By similarity).
Inhibited by N-oxalylglycine, fumarate and succinate (By
similarity). RNA N(6)-methyladenosine demethylase activity is
inhibited by fluorescein derivatives (PubMed:26457839). RNA N(6)-
methyladenosine demethylase activity is selectively inhibited by
meclofenamic acid; inhibition is specific to FTO and meclofenamic
acid does not inhibit ALKBH5 (PubMed:25452335). Specifically
inhibited by R-2-hydroxyglutarate (R-2HG), an oncometabolite that
also exerts a broad antileukemic activity (PubMed:29249359).
Inhibition by R-2HG leads to increased level of N(6)-
methyladenosine-containing transcripts, leading to down-regulate
expression of MYC and CEBPA transcripts (PubMed:29249359).
{ECO:0000250|UniProtKB:Q8BGW1, ECO:0000269|PubMed:25452335,
ECO:0000269|PubMed:26457839, ECO:0000269|PubMed:29249359}.
-!- BIOPHYSICOCHEMICAL PROPERTIES:
Kinetic parameters:
KM=1.34 uM for m(7)Gppp(m6A(m))CA mRNA
{ECO:0000269|PubMed:28002401};
KM=16.09 uM for for m(7)Gppp(m6ACA mRNA
{ECO:0000269|PubMed:28002401};
KM=9.29 uM for GG(m6A)CU mRNA {ECO:0000269|PubMed:28002401};
KM=6.4 uM for m(7)GpppAC(m6) mRNA {ECO:0000269|PubMed:28002401};
Note=Kcat is 8.78 min(-1) for m(7)Gppp(m6A(m))CA mRNA. Kcat is
7.77 min(-1) for m(7)Gppp(m6A)CA mRNA. Kcat is 0.54 min(-1) for
GG(m6A)CU mRNA. Kcat is 0.46 min(-1) for m(7)GpppAC(m6) mRNA.
{ECO:0000269|PubMed:28002401};
pH dependence:
Optimum pH is 5.5-6. {ECO:0000269|PubMed:18775698};
-!- SUBUNIT: Monomer (By similarity). May also exist as homodimer (By
similarity). {ECO:0000250|UniProtKB:Q8BGW1}.
-!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:22002720,
ECO:0000269|PubMed:26458103, ECO:0000269|PubMed:28002401,
ECO:0000269|PubMed:30197295}. Nucleus speckle
{ECO:0000269|PubMed:22002720}. Cytoplasm
{ECO:0000269|PubMed:30197295}. Note=Localizes mainly in the
nucleus, where it is able to demethylate N(6)-methyladenosine
(m6A) and N(6),2'-O-dimethyladenosine cap (m6A(m)) in U6 small
nuclear RNA (snRNA), N(1)-methyladenine from tRNAs and internal
m6A in mRNAs (PubMed:30197295). In the cytoplasm, mediates
demethylation of m6A and m6A(m) in mRNAs and N(1)-methyladenine
from tRNAs (PubMed:30197295). {ECO:0000269|PubMed:30197295}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=4;
Name=1;
IsoId=Q9C0B1-1; Sequence=Displayed;
Name=2;
IsoId=Q9C0B1-2; Sequence=VSP_025004, VSP_025005;
Note=No experimental confirmation available.;
Name=3;
IsoId=Q9C0B1-3; Sequence=VSP_025002, VSP_025006;
Note=No experimental confirmation available.;
Name=4;
IsoId=Q9C0B1-4; Sequence=VSP_025003;
Note=No experimental confirmation available.;
-!- TISSUE SPECIFICITY: Ubiquitously expressed, with relatively high
expression in adrenal glands and brain; especially in hypothalamus
and pituitary (PubMed:17434869, PubMed:17496892). Highly expressed
in highly expressed in acute myeloid leukemias (AML) with
t(11;11)(q23;23) with KMT2A/MLL1 rearrangements,
t(15;17)(q21;q21)/PML-RARA, FLT3-ITD, and/or NPM1 mutations
(PubMed:28017614). {ECO:0000269|PubMed:17434869,
ECO:0000269|PubMed:17496892, ECO:0000269|PubMed:28017614}.
-!- DOMAIN: The 3D-structure of the Fe2OG dioxygenase domain is
similar to that of the Fe2OG dioxygenase domain found in the
bacterial DNA repair dioxygenase alkB and its mammalian orthologs,
but sequence similarity is very low. As a consequence, the domain
is not detected by protein signature databases.
{ECO:0000269|PubMed:20376003}.
-!- POLYMORPHISM: Genetic variations at the FTO locus define the body
mass index quantitative trait locus 14 (BMIQ14) [MIM:612460].
Variance in body mass index is a susceptibility factor for
obesity. {ECO:0000269|PubMed:17434869,
ECO:0000269|PubMed:17496892, ECO:0000269|PubMed:22982992}.
-!- DISEASE: Growth retardation, developmental delay, and facial
dysmorphism (GDFD) [MIM:612938]: A severe polymalformation
syndrome characterized by postnatal growth retardation,
microcephaly, severe psychomotor delay, functional brain deficits
and characteristic facial dysmorphism. In some patients,
structural brain malformations, cardiac defects, genital
anomalies, and cleft palate are observed. Early death occurs by
the age of 3 years. {ECO:0000269|PubMed:19559399,
ECO:0000269|PubMed:22002720, ECO:0000269|PubMed:26378117,
ECO:0000269|PubMed:26697951}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized
by an increase of body weight beyond the limitation of skeletal
and physical requirements, as the result of excessive accumulation
of body fat. {ECO:0000269|PubMed:24646999,
ECO:0000269|PubMed:26287746}. Note=Disease susceptibility is
associated with variations affecting the gene represented in this
entry. It is unclear whether variations associated with obesity
directly affect FTO function or alter the expression of adjacent
genes such as IRX3, rather than FTO itself (PubMed:24646999,
PubMed:26287746). A pathogenic intronic FTO variation (rs1421085)
disrupts an evolutionarily conserved motif for ARID5B binding
(PubMed:26287746). Loss of ARID5B binding results in
overexpression of two genes distal to FTO, IRX3 and IRX5. IRX3 and
IRX5 overexpression shifts pre-adipocytes differentiation from
brown to white fat cells, resulting in increased lipid storage and
loss of mitochondrial thermogenesis (PubMed:26287746).
{ECO:0000269|PubMed:24646999, ECO:0000269|PubMed:26287746}.
-!- SIMILARITY: Belongs to the fto family. {ECO:0000305}.
-!- CAUTION: According to a report, mainly mediates demethylation of
N(6),2'-O-dimethyladenosine cap (m6A(m)), by demethylating the
N(6)-methyladenosine adjacent to mRNA cap, whereas it has low
activity toward internal N(6)-methyladenosine (m6A) in mRNAs
(PubMed:28002401). According to a second report, has strong
activity toward internal N(6)-methyladenosine (m6A) in mRNAs and
is able to demethylate different RNA species, such as tRNA, mRNA
or small nuclear RNA (snRNA), depending on the context and
subcellular location (PubMed:30197295).
{ECO:0000269|PubMed:28002401, ECO:0000269|PubMed:30197295}.
-!- SEQUENCE CAUTION:
Sequence=BAB21843.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305};
-----------------------------------------------------------------------
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EMBL; AB051539; BAB21843.1; ALT_INIT; mRNA.
EMBL; AC007347; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; AC007496; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; AC007909; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; BC003583; AAH03583.1; -; mRNA.
EMBL; BC030798; AAH30798.1; -; mRNA.
EMBL; BC132892; AAI32893.1; -; mRNA.
EMBL; BC137091; AAI37092.1; -; mRNA.
CCDS; CCDS32448.1; -. [Q9C0B1-1]
RefSeq; NP_001073901.1; NM_001080432.2. [Q9C0B1-1]
UniGene; Hs.528833; -.
PDB; 3LFM; X-ray; 2.50 A; A=32-505.
PDB; 4CXW; X-ray; 3.10 A; A=32-505.
PDB; 4CXX; X-ray; 2.76 A; A=32-505.
PDB; 4CXY; X-ray; 2.65 A; A=32-505.
PDB; 4IDZ; X-ray; 2.46 A; A=32-505.
PDB; 4IE0; X-ray; 2.53 A; A=32-505.
PDB; 4IE4; X-ray; 2.50 A; A=32-505.
PDB; 4IE5; X-ray; 1.95 A; A=32-505.
PDB; 4IE6; X-ray; 2.50 A; A=32-505.
PDB; 4IE7; X-ray; 2.60 A; A=32-505.
PDB; 4QHO; X-ray; 2.37 A; A=32-505.
PDB; 4QKN; X-ray; 2.20 A; A=32-503.
PDB; 4ZS2; X-ray; 2.16 A; A=32-505.
PDB; 4ZS3; X-ray; 2.45 A; A=32-505.
PDB; 5DAB; X-ray; 2.10 A; A=32-505.
PDB; 5F8P; X-ray; 2.20 A; A=32-502.
PDBsum; 3LFM; -.
PDBsum; 4CXW; -.
PDBsum; 4CXX; -.
PDBsum; 4CXY; -.
PDBsum; 4IDZ; -.
PDBsum; 4IE0; -.
PDBsum; 4IE4; -.
PDBsum; 4IE5; -.
PDBsum; 4IE6; -.
PDBsum; 4IE7; -.
PDBsum; 4QHO; -.
PDBsum; 4QKN; -.
PDBsum; 4ZS2; -.
PDBsum; 4ZS3; -.
PDBsum; 5DAB; -.
PDBsum; 5F8P; -.
ProteinModelPortal; Q9C0B1; -.
SMR; Q9C0B1; -.
BioGrid; 122520; 28.
IntAct; Q9C0B1; 9.
STRING; 9606.ENSP00000418823; -.
BindingDB; Q9C0B1; -.
ChEMBL; CHEMBL2331065; -.
iPTMnet; Q9C0B1; -.
PhosphoSitePlus; Q9C0B1; -.
BioMuta; FTO; -.
DMDM; 148841515; -.
EPD; Q9C0B1; -.
MaxQB; Q9C0B1; -.
PaxDb; Q9C0B1; -.
PeptideAtlas; Q9C0B1; -.
PRIDE; Q9C0B1; -.
ProteomicsDB; 79982; -.
ProteomicsDB; 79983; -. [Q9C0B1-2]
ProteomicsDB; 79984; -. [Q9C0B1-3]
ProteomicsDB; 79985; -. [Q9C0B1-4]
DNASU; 79068; -.
Ensembl; ENST00000431610; ENSP00000415636; ENSG00000140718. [Q9C0B1-4]
Ensembl; ENST00000460382; ENSP00000417422; ENSG00000140718. [Q9C0B1-4]
Ensembl; ENST00000463855; ENSP00000417843; ENSG00000140718. [Q9C0B1-2]
Ensembl; ENST00000471389; ENSP00000418823; ENSG00000140718. [Q9C0B1-1]
GeneID; 79068; -.
KEGG; hsa:79068; -.
UCSC; uc002ehr.4; human. [Q9C0B1-1]
CTD; 79068; -.
DisGeNET; 79068; -.
EuPathDB; HostDB:ENSG00000140718.18; -.
GeneCards; FTO; -.
H-InvDB; HIX0013037; -.
H-InvDB; HIX0134382; -.
H-InvDB; HIX0204005; -.
HGNC; HGNC:24678; FTO.
HPA; CAB017123; -.
HPA; HPA041086; -.
HPA; HPA068695; -.
MalaCards; FTO; -.
MIM; 601665; phenotype.
MIM; 610966; gene.
MIM; 612460; phenotype.
MIM; 612938; phenotype.
neXtProt; NX_Q9C0B1; -.
OpenTargets; ENSG00000140718; -.
Orphanet; 210144; Lethal polymalformative syndrome, Boissel type.
PharmGKB; PA152208656; -.
eggNOG; ENOG410IJ5C; Eukaryota.
eggNOG; ENOG4111PKJ; LUCA.
GeneTree; ENSGT00390000017730; -.
HOGENOM; HOG000273870; -.
HOVERGEN; HBG101847; -.
InParanoid; Q9C0B1; -.
KO; K19469; -.
OrthoDB; EOG091G08LA; -.
PhylomeDB; Q9C0B1; -.
TreeFam; TF333296; -.
Reactome; R-HSA-73943; Reversal of alkylation damage by DNA dioxygenases.
ChiTaRS; FTO; human.
GeneWiki; FTO_gene; -.
GenomeRNAi; 79068; -.
PRO; PR:Q9C0B1; -.
Proteomes; UP000005640; Chromosome 16.
Bgee; ENSG00000140718; Expressed in 236 organ(s), highest expression level in forebrain.
CleanEx; HS_FTO; -.
ExpressionAtlas; Q9C0B1; baseline and differential.
Genevisible; Q9C0B1; HS.
GO; GO:0016607; C:nuclear speck; IDA:UniProtKB.
GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
GO; GO:0005634; C:nucleus; IDA:UniProtKB.
GO; GO:0043734; F:DNA-N1-methyladenine dioxygenase activity; IDA:UniProtKB.
GO; GO:0008198; F:ferrous iron binding; IDA:UniProtKB.
GO; GO:0035516; F:oxidative DNA demethylase activity; IDA:UniProtKB.
GO; GO:0035515; F:oxidative RNA demethylase activity; IDA:UniProtKB.
GO; GO:1990931; F:RNA N6-methyladenosine dioxygenase activity; IMP:UniProtKB.
GO; GO:0060612; P:adipose tissue development; IEA:Ensembl.
GO; GO:0006307; P:DNA dealkylation involved in DNA repair; IDA:UniProtKB.
GO; GO:0080111; P:DNA demethylation; IDA:BHF-UCL.
GO; GO:0070989; P:oxidative demethylation; IDA:BHF-UCL.
GO; GO:0035552; P:oxidative single-stranded DNA demethylation; IDA:UniProtKB.
GO; GO:0035553; P:oxidative single-stranded RNA demethylation; IDA:UniProtKB.
GO; GO:0090335; P:regulation of brown fat cell differentiation; IMP:UniProtKB.
GO; GO:0010883; P:regulation of lipid storage; IMP:UniProtKB.
GO; GO:0040014; P:regulation of multicellular organism growth; IEA:Ensembl.
GO; GO:0044065; P:regulation of respiratory system process; IEA:Ensembl.
GO; GO:0070350; P:regulation of white fat cell proliferation; IEA:Ensembl.
GO; GO:0042245; P:RNA repair; IDA:BHF-UCL.
GO; GO:0001659; P:temperature homeostasis; IEA:Ensembl.
Gene3D; 1.20.58.1470; -; 1.
Gene3D; 2.60.120.590; -; 1.
InterPro; IPR037151; AlkB-like_sf.
InterPro; IPR032868; FTO.
InterPro; IPR024366; FTO_C.
InterPro; IPR038413; FTO_C_sf.
InterPro; IPR024367; FTO_cat_dom.
PANTHER; PTHR31291; PTHR31291; 1.
Pfam; PF12934; FTO_CTD; 1.
Pfam; PF12933; FTO_NTD; 1.
SMART; SM01223; FTO_NTD; 1.
1: Evidence at protein level;
3D-structure; Acetylation; Alternative splicing; Complete proteome;
Cytoplasm; Dioxygenase; Disease mutation; Iron; Metal-binding;
Nucleus; Obesity; Oxidoreductase; Phosphoprotein; Polymorphism;
Reference proteome; Transferase.
CHAIN 1 505 Alpha-ketoglutarate-dependent dioxygenase
FTO.
/FTId=PRO_0000286163.
REGION 32 327 Fe2OG dioxygenase domain.
{ECO:0000269|PubMed:20376003}.
REGION 213 224 Loop L1; predicted to block binding of
double-stranded DNA or RNA.
{ECO:0000269|PubMed:20376003}.
REGION 231 234 Substrate binding. {ECO:0000244|PDB:3LFM,
ECO:0000269|PubMed:20376003}.
REGION 316 318 Alpha-ketoglutarate binding.
{ECO:0000244|PDB:3LFM,
ECO:0000244|PDB:4QKN,
ECO:0000244|PDB:4ZS2,
ECO:0000244|PDB:4ZS3,
ECO:0000269|PubMed:20376003,
ECO:0000269|PubMed:25452335,
ECO:0000269|PubMed:26457839}.
METAL 231 231 Iron; catalytic. {ECO:0000244|PDB:3LFM,
ECO:0000244|PDB:4CXW,
ECO:0000244|PDB:4CXX,
ECO:0000244|PDB:4CXY,
ECO:0000244|PDB:4IDZ,
ECO:0000244|PDB:4IE0,
ECO:0000244|PDB:4IE4,
ECO:0000244|PDB:4IE5,
ECO:0000244|PDB:4IE6,
ECO:0000244|PDB:4IE7,
ECO:0000244|PDB:4QKN,
ECO:0000244|PDB:4ZS2,
ECO:0000244|PDB:4ZS3,
ECO:0000269|PubMed:20376003,
ECO:0000269|PubMed:25452335,
ECO:0000305|PubMed:23547775,
ECO:0000305|PubMed:25452335,
ECO:0000305|PubMed:26457839,
ECO:0000305|PubMed:28553460}.
METAL 233 233 Iron; catalytic. {ECO:0000244|PDB:3LFM,
ECO:0000244|PDB:4CXW,
ECO:0000244|PDB:4CXX,
ECO:0000244|PDB:4CXY,
ECO:0000244|PDB:4IDZ,
ECO:0000244|PDB:4IE0,
ECO:0000244|PDB:4IE4,
ECO:0000244|PDB:4IE5,
ECO:0000244|PDB:4IE6,
ECO:0000244|PDB:4IE7,
ECO:0000244|PDB:4QKN,
ECO:0000244|PDB:4ZS2,
ECO:0000244|PDB:4ZS3,
ECO:0000269|PubMed:20376003,
ECO:0000305|PubMed:23547775,
ECO:0000305|PubMed:25452335,
ECO:0000305|PubMed:26457839,
ECO:0000305|PubMed:28553460}.
METAL 307 307 Iron; catalytic. {ECO:0000244|PDB:3LFM,
ECO:0000244|PDB:4CXW,
ECO:0000244|PDB:4CXX,
ECO:0000244|PDB:4CXY,
ECO:0000244|PDB:4IDZ,
ECO:0000244|PDB:4IE0,
ECO:0000244|PDB:4IE4,
ECO:0000244|PDB:4IE5,
ECO:0000244|PDB:4IE6,
ECO:0000244|PDB:4IE7,
ECO:0000244|PDB:4QKN,
ECO:0000244|PDB:4ZS2,
ECO:0000244|PDB:4ZS3,
ECO:0000269|PubMed:20376003,
ECO:0000305|PubMed:23547775,
ECO:0000305|PubMed:25452335,
ECO:0000305|PubMed:26457839,
ECO:0000305|PubMed:28553460}.
BINDING 96 96 Substrate. {ECO:0000244|PDB:3LFM,
ECO:0000269|PubMed:20376003}.
BINDING 108 108 Substrate. {ECO:0000244|PDB:3LFM,
ECO:0000269|PubMed:20376003}.
BINDING 205 205 Alpha-ketoglutarate.
{ECO:0000244|PDB:3LFM,
ECO:0000244|PDB:4QKN,
ECO:0000269|PubMed:20376003,
ECO:0000269|PubMed:25452335}.
BINDING 295 295 Alpha-ketoglutarate.
{ECO:0000244|PDB:3LFM,
ECO:0000244|PDB:4QKN,
ECO:0000244|PDB:4ZS2,
ECO:0000244|PDB:4ZS3,
ECO:0000269|PubMed:20376003,
ECO:0000269|PubMed:25452335,
ECO:0000269|PubMed:26457839}.
BINDING 320 320 Alpha-ketoglutarate.
{ECO:0000244|PDB:3LFM,
ECO:0000269|PubMed:20376003}.
BINDING 322 322 Alpha-ketoglutarate.
{ECO:0000244|PDB:3LFM,
ECO:0000244|PDB:4QKN,
ECO:0000244|PDB:4ZS2,
ECO:0000269|PubMed:20376003,
ECO:0000269|PubMed:25452335,
ECO:0000269|PubMed:26457839}.
MOD_RES 4 4 Phosphothreonine.
{ECO:0000244|PubMed:23186163}.
MOD_RES 216 216 N6-acetyllysine.
{ECO:0000244|PubMed:19608861}.
VAR_SEQ 1 445 Missing (in isoform 3).
{ECO:0000303|PubMed:15489334}.
/FTId=VSP_025002.
VAR_SEQ 1 399 Missing (in isoform 4).
{ECO:0000303|PubMed:15489334}.
/FTId=VSP_025003.
VAR_SEQ 1 378 Missing (in isoform 2).
{ECO:0000303|PubMed:15489334}.
/FTId=VSP_025004.
VAR_SEQ 379 413 LRQFWFQGNRYRKCTDWWCQPMAQLEALWKKMEGV -> ME
WRKVSECNSVEPCREVKKWPYRCIHHGKNFSRM (in
isoform 2).
{ECO:0000303|PubMed:15489334}.
/FTId=VSP_025005.
VAR_SEQ 446 455 QNLRREWHAR -> MACQGREECW (in isoform 3).
{ECO:0000303|PubMed:15489334}.
/FTId=VSP_025006.
VARIANT 271 271 H -> P (found in a patient with
microcephaly, developmental delay,
behavioral abnormalities, dysmorphic
facial features, hypotonia and other
various phenotypic abnormalities; unknown
pathological significance).
{ECO:0000269|PubMed:26740239}.
/FTId=VAR_076423.
VARIANT 316 316 R -> Q (in GDFD; has no residual normal
activity, impaired ability to demethylate
N(6)-methyladenosine RNAs (m6A) RNAs;
dbSNP:rs121918214).
{ECO:0000269|PubMed:19559399,
ECO:0000269|PubMed:22002720}.
/FTId=VAR_063252.
VARIANT 319 319 S -> F (in GDFD; reduced enzyme activity;
dbSNP:rs781028867).
{ECO:0000269|PubMed:26378117}.
/FTId=VAR_075468.
VARIANT 322 322 R -> Q (in GDFD; dbSNP:rs745616565).
{ECO:0000269|PubMed:26697951}.
/FTId=VAR_075469.
VARIANT 405 405 A -> V (in dbSNP:rs16952624).
/FTId=VAR_032078.
MUTAGEN 96 96 R->M,W: Almost abolishes enzyme activity.
{ECO:0000269|PubMed:20376003}.
MUTAGEN 108 108 Y->A: Abolishes enzyme activity.
{ECO:0000269|PubMed:20376003}.
MUTAGEN 114 114 F->D: Perturbs interaction between N-
terminal and C-terminal domains and
strongly reduces enzyme activity.
{ECO:0000269|PubMed:20376003}.
MUTAGEN 231 233 HHD->AHA: Abolishes ability to
demethylate N(6)-methyladenosine RNAs
(m6A) RNAs.
{ECO:0000269|PubMed:22002720}.
MUTAGEN 234 234 E->P: Abolishes enzyme activity.
Abolishes ability to demethylate N(6)-
methyladenosine RNAs (m6A) RNAs; when
associated with Q-322.
{ECO:0000269|PubMed:20376003}.
MUTAGEN 392 392 C->D: Perturbs interaction between N-
terminal and C-terminal domains and
strongly reduces enzyme activity.
{ECO:0000269|PubMed:20376003}.
CONFLICT 316 316 R -> W (in Ref. 1; BAB21843 and 3;
AAH03583/AAH30798/AAI32893).
{ECO:0000305}.
STRAND 35 37 {ECO:0000244|PDB:4QKN}.
HELIX 38 45 {ECO:0000244|PDB:4IE5}.
STRAND 49 52 {ECO:0000244|PDB:4IE5}.
HELIX 54 56 {ECO:0000244|PDB:4IE5}.
HELIX 59 74 {ECO:0000244|PDB:4IE5}.
STRAND 79 85 {ECO:0000244|PDB:4IE5}.
STRAND 88 101 {ECO:0000244|PDB:4IE5}.
STRAND 104 108 {ECO:0000244|PDB:4IE5}.
STRAND 111 114 {ECO:0000244|PDB:4IE5}.
HELIX 130 162 {ECO:0000244|PDB:4IE5}.
HELIX 190 196 {ECO:0000244|PDB:4IE5}.
STRAND 201 207 {ECO:0000244|PDB:4IE5}.
TURN 209 211 {ECO:0000244|PDB:4IE5}.
STRAND 212 214 {ECO:0000244|PDB:3LFM}.
STRAND 219 221 {ECO:0000244|PDB:4IE5}.
STRAND 225 231 {ECO:0000244|PDB:4IE5}.
STRAND 242 248 {ECO:0000244|PDB:4IE5}.
STRAND 271 276 {ECO:0000244|PDB:4IE5}.
STRAND 280 282 {ECO:0000244|PDB:4IE5}.
STRAND 284 288 {ECO:0000244|PDB:4IE5}.
STRAND 293 297 {ECO:0000244|PDB:4IE5}.
HELIX 301 304 {ECO:0000244|PDB:4IE5}.
STRAND 305 310 {ECO:0000244|PDB:4IE5}.
STRAND 316 322 {ECO:0000244|PDB:4IE5}.
STRAND 327 330 {ECO:0000244|PDB:5F8P}.
HELIX 331 342 {ECO:0000244|PDB:4IE5}.
HELIX 361 377 {ECO:0000244|PDB:4IE5}.
HELIX 379 384 {ECO:0000244|PDB:4IE5}.
TURN 385 387 {ECO:0000244|PDB:4IE5}.
HELIX 389 391 {ECO:0000244|PDB:4IE5}.
HELIX 397 422 {ECO:0000244|PDB:4IE5}.
STRAND 423 426 {ECO:0000244|PDB:4IDZ}.
HELIX 428 457 {ECO:0000244|PDB:4IE5}.
HELIX 459 463 {ECO:0000244|PDB:4IE5}.
HELIX 466 468 {ECO:0000244|PDB:4IE5}.
STRAND 482 485 {ECO:0000244|PDB:5DAB}.
HELIX 490 500 {ECO:0000244|PDB:4IE5}.
SEQUENCE 505 AA; 58282 MW; 3498A92C6E6D81B1 CRC64;
MKRTPTAEER EREAKKLRLL EELEDTWLPY LTPKDDEFYQ QWQLKYPKLI LREASSVSEE
LHKEVQEAFL TLHKHGCLFR DLVRIQGKDL LTPVSRILIG NPGCTYKYLN TRLFTVPWPV
KGSNIKHTEA EIAAACETFL KLNDYLQIET IQALEELAAK EKANEDAVPL CMSADFPRVG
MGSSYNGQDE VDIKSRAAYN VTLLNFMDPQ KMPYLKEEPY FGMGKMAVSW HHDENLVDRS
AVAVYSYSCE GPEEESEDDS HLEGRDPDIW HVGFKISWDI ETPGLAIPLH QGDCYFMLDD
LNATHQHCVL AGSQPRFSST HRVAECSTGT LDYILQRCQL ALQNVCDDVD NDDVSLKSFE
PAVLKQGEEI HNEVEFEWLR QFWFQGNRYR KCTDWWCQPM AQLEALWKKM EGVTNAVLHE
VKREGLPVEQ RNEILTAILA SLTARQNLRR EWHARCQSRI ARTLPADQKP ECRPYWEKDD
ASMPLPFDLT DIVSELRGQL LEAKP


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