Alpha-ketoglutarate-dependent dioxygenase FTO

UniProt Q9C0B1 Organism Homo sapiens Gene FTO, KIAA1752 EC 1.14.11.-, 1.14.11.53

Also known as: FTO, KIAA1752

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. Specifically demethylates N(6)-methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. M6A demethylation by FTO affects mRNA expression and stability. Also able to demethylate m6A in U6 small nuclear RNA (snRNA). 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. Demethylation of m6A(m) in the 5'-cap by FTO affects mRNA stability by promoting susceptibility to decapping. Also acts as a tRNA demethylase by removing N(1)-methyladenine from various tRNAs. Has no activity towards 1-methylguanine. Has no detectable activity towards double-stranded DNA. 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. Ability to repair alkylated DNA and RNA is however unsure in vivo. Involved in the regulation of fat mass, adipogenesis and body weight, thereby contributing to the regulation of body size and body fat accumulation. Involved in the regulation of thermogenesis and the control of adipocyte differentiation into brown or white fat cells. 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.

Classification

Family (Pfam): PF12934 FTO_CTD, PF12933 FTO_NTD
InterPro: AlkB-like_sf, FTO, FTO_C, FTO_C_sf, FTO_cat_dom
Functional cluster: S-Adenosylmethionine Synthases & related

Experimental structures · PDB · 28

3LFM X-ray 2.50A
4CXW X-ray 3.10A
4CXX X-ray 2.76A
4CXY X-ray 2.65A
4IDZ X-ray 2.46A
4IE0 X-ray 2.53A
4IE4 X-ray 2.50A
4IE5 X-ray 1.95A
4IE6 X-ray 2.50A
4IE7 X-ray 2.60A
4QHO X-ray 2.37A
4QKN X-ray 2.20A
… and 16 more

A predicted model is available from AlphaFold.

Gene Ontology · 22

Disease associations

inherited obesity MONDO:0019182
OMIM:612460 RAW:OMIM_612460
lethal polymalformative syndrome, Boissel type MONDO:0013050

Drugs targeting this protein · 1

BISANTRENE inhibitor

Related proteins · sequence + function similarity

Co-cited proteins · studied together in the literature

Alpha-ketoglutarate-dependent dioxygenase FTO 3 shared papers
E3 ubiquitin-protein ligase TRIM37 1 shared papers
Probable E3 ubiquitin-protein ligase DTX2 1 shared papers
Protein fantom 1 shared papers
Iroquois-class homeodomain protein IRX-3 1 shared papers
m7GpppN-mRNA hydrolase 1 shared papers
YTH domain-containing family protein 3 1 shared papers
N(6)-adenosine-methyltransferase non-catalytic subunit METTL14 1 shared papers
Pre-mRNA-splicing regulator WTAP 1 shared papers
YTH domain-containing family protein 2 1 shared papers
N(6)-adenosine-methyltransferase catalytic subunit METTL3 1 shared papers

Literature · 28 cited papers

Targeting DTX2/UFD1-mediated FTO degradation to regulate antitumor immunity. Proc. Natl. Acad. Sci. U.S.A. · 2024
Differential m6A, m6Am, and m1A demethylation mediated by FTO in the cell nucleus and cytoplasm. Mol. Cell · 2018
R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA signaling. Cell · 2018
A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N6-methyladenosine demethylase FTO. Chem. Sci. · 2015
FTO plays an oncogenic role in acute myeloid leukemia as a N6-methyladenosine RNA demethylase. Cancer Cell · 2017
Reversible methylation of m6Am in the 5' cap controls mRNA stability. Nature · 2017
A patient with a novel homozygous missense mutation in FTO and concomitant nonsense mutation in CETP. J. Hum. Genet. · 2016
FTO variant associated with malformation syndrome. Am. J. Med. Genet. A · 2016
Dynamic m(6)A mRNA methylation directs translational control of heat shock response. Nature · 2015
Fluorescein derivatives as bifunctional molecules for the simultaneous inhibiting and labeling of FTO protein. J. Am. Chem. Soc. · 2015
Identification of a pathogenic FTO mutation by next-generation sequencing in a newborn with growth retardation and developmental delay. J. Med. Genet. · 2016
FTO obesity variant circuitry and adipocyte browning in humans. N. Engl. J. Med. · 2015
… and 16 more in the literature graph

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