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| Class:Id | ReferenceGeneProduct:229348 |
|---|---|
| _chainChangeLog | chain:1-505 added on Sat February 7 2015 |
| _displayName | UniProt:Q9C0B1 FTO |
| _timestamp | 2025-02-21 20:09:10 |
| chain | chain:1-505 |
| checksum | 3498A92C6E6D81B1 |
| comment | 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:25452335, PubMed:26457839, PubMed:26458103, PubMed:28002401, PubMed:30197295). Specifically demethylates N(6)-methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes (PubMed:22002720, PubMed:25452335, PubMed:26457839, PubMed:26458103, PubMed:30197295). 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).CATALYTIC ACTIVITY a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-(N(6),2'-O-dimethyladenosine) in mRNA + 2-oxoglutarate + O2 = a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-(2'-O-methyladenosine) in mRNA + formaldehyde + succinate + CO2CATALYTIC ACTIVITY an N(6)-methyladenosine in mRNA + 2-oxoglutarate + O2 = an adenosine in mRNA + formaldehyde + succinate + CO2CATALYTIC ACTIVITY N(6)-methyladenosine in U6 snRNA + 2-oxoglutarate + O2 = adenosine in U6 snRNA + formaldehyde + succinate + CO2CATALYTIC ACTIVITY a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-(N(6),2'-O-dimethyladenosine) in U6 snRNA + 2-oxoglutarate + O2 = a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-(2'-O-methyladenosine) in U6 snRNA + formaldehyde + succinate + CO2CATALYTIC ACTIVITY an N(1)-methyladenosine in tRNA + 2-oxoglutarate + O2 = an adenosine in tRNA + formaldehyde + succinate + CO2COFACTOR Binds 1 Fe(2+) ion per subunit.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).BIOPHYSICOCHEMICAL PROPERTIES 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.SUBUNIT Monomer (By similarity). May also exist as homodimer (By similarity).INTERACTION 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).ALTERNATIVE PRODUCTS 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).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.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.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE Disease susceptibility is associated with variants 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).SIMILARITY Belongs to the fto family.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).SEQUENCE CAUTION Extended N-terminus. |
| created | [InstanceEdit:217385] Schmidt, EE, 2008-03-27 06:23:53 |
| description | recommendedName: fullName evidence="24"Alpha-ketoglutarate-dependent dioxygenase FTO alternativeName: fullName evidence="23"Fat mass and obesity-associated protein alternativeName: fullName evidence="24"U6 small nuclear RNA (2'-O-methyladenosine-N(6)-)-demethylase FTO ecNumber evidence="20"1.14.11.- alternativeName: fullName evidence="24"U6 small nuclear RNA N(6)-methyladenosine-demethylase FTO ecNumber evidence="20"1.14.11.- alternativeName: fullName evidence="24"mRNA (2'-O-methyladenosine-N(6)-)-demethylase FTO shortName evidence="24"m6A(m)-demethylase FTO ecNumber evidence="17 20"1.14.11.- alternativeName: fullName evidence="24"mRNA N(6)-methyladenosine demethylase FTO ecNumber evidence="10 13 20 25"1.14.11.53 alternativeName: fullName evidence="24"tRNA N1-methyl adenine demethylase FTO ecNumber evidence="20"1.14.11.- |
| geneName | FTO KIAA1752 |
| identifier | Q9C0B1 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Acetylation Alternative splicing Cytoplasm Dioxygenase Disease variant Iron Metal-binding Nucleus Obesity Oxidoreductase Phosphoprotein Proteomics identification Reference proteome Transferase |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 |
| name | FTO |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:8962231] ENSEMBL:ENSG00000140718 FTO [Homo sapiens] |
| secondaryIdentifier | FTO_HUMAN A2RUH1 B2RNS0 Q0P676 Q7Z785 |
| sequenceLength | 505 |
| species | [Species:48887] Homo sapiens |
| (isoformParent) | [ReferenceIsoform:229349] UniProt:Q9C0B1-2 FTO [Homo sapiens] [ReferenceIsoform:229350] UniProt:Q9C0B1-3 FTO [Homo sapiens] [ReferenceIsoform:229351] UniProt:Q9C0B1-4 FTO [Homo sapiens] [ReferenceIsoform:413600] UniProt:Q9C0B1-1 FTO [Homo sapiens] |
| (referenceEntity) | [EntityWithAccessionedSequence:8857715] FTO [nucleoplasm] [Homo sapiens] |
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