{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q6P6C2","secondaryAccessions":["B4DVJ4","D3DXC6","Q9NXD6"],"uniProtkbId":"ALKB5_HUMAN","entryAudit":{"firstPublicDate":"2006-05-30","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2012-10-03","entryVersion":172,"sequenceVersion":2},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"24616105"}],"value":"RNA demethylase ALKBH5"},"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24616105"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"34048572"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36944332"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37257451"}],"value":"1.14.11.53"}]},"alternativeNames":[{"fullName":{"value":"Alkylated DNA repair protein alkB homolog 5"}},{"fullName":{"value":"Alpha-ketoglutarate-dependent dioxygenase alkB homolog 5"}}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"23177736"},{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:25996"}],"value":"ALKBH5"},"synonyms":[{"value":"ABH5"},{"value":"OFOXD1"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q3TSG4"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21264265"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23177736"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24489119"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24616105"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24778178"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"34048572"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36944332"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37257451"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37369679"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37474102"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"40793791"}],"value":"Dioxygenase that specifically demethylates N(6)-methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes (PubMed:23177736, PubMed:24489119, PubMed:24616105, PubMed:24778178, PubMed:34048572, PubMed:36944332, PubMed:37257451, PubMed:37369679, PubMed:40793791). Demethylates RNA by oxidative demethylation, which requires molecular oxygen, alpha-ketoglutarate and iron (PubMed:21264265, PubMed:23177736, PubMed:24489119, PubMed:24616105, PubMed:24778178). Demethylation of m6A mRNA affects mRNA processing, translation and export (PubMed:23177736, PubMed:34048572, PubMed:36944332, PubMed:37257451). Can also demethylate N(6)-methyladenosine in single-stranded DNA (in vitro) (PubMed:24616105). Required for the late meiotic and haploid phases of spermatogenesis by mediating m6A demethylation in spermatocytes and round spermatids: m6A demethylation of target transcripts is required for correct splicing and the production of longer 3'-UTR mRNAs in male germ cells (By similarity). Involved in paraspeckle assembly, a nuclear membraneless organelle, by undergoing liquid-liquid phase separation (PubMed:37369679, PubMed:37474102). Paraspeckle assembly is coupled with m6A demethylation of RNAs, such as NEAT1 non-coding RNA (PubMed:37474102). Also acts as a negative regulator of T-cell development: inhibits gamma-delta T-cell proliferation via demethylation of JAG1 and NOTCH2 transcripts (By similarity). Inhibits regulatory T-cell (Treg) recruitment by mediating demethylation and destabilization of CCL28 mRNAs (By similarity)"}],"commentType":"FUNCTION"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"an N(6)-methyladenosine in mRNA + 2-oxoglutarate + O2 = an adenosine in mRNA + formaldehyde + succinate + CO2","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:49520"},{"database":"Rhea","id":"RHEA-COMP:12414"},{"database":"Rhea","id":"RHEA-COMP:12417"},{"database":"ChEBI","id":"CHEBI:15379"},{"database":"ChEBI","id":"CHEBI:16526"},{"database":"ChEBI","id":"CHEBI:16810"},{"database":"ChEBI","id":"CHEBI:16842"},{"database":"ChEBI","id":"CHEBI:30031"},{"database":"ChEBI","id":"CHEBI:74411"},{"database":"ChEBI","id":"CHEBI:74449"}],"ecNumber":"1.14.11.53","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24616105"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"34048572"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36944332"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37257451"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:49521"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24616105"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"34048572"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36944332"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37257451"}]}]},{"commentType":"COFACTOR","cofactors":[{"name":"Fe(2+)","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24489119"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24616105"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24778178"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35333330"}],"cofactorCrossReference":{"database":"ChEBI","id":"CHEBI:29033"}}],"note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"24489119"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"24616105"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"24778178"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"35333330"}],"value":"Binds 1 Fe(2+) ion per subunit."}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"34048572"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37257451"}],"value":"RNA demethylase activity is inhibited following sumoylation (PubMed:34048572, PubMed:37257451). Inhibition is relieved following desumoylation (PubMed:34048572, PubMed:37257451)"}],"commentType":"ACTIVITY REGULATION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24778178"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37257451"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37369679"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"40793791"}],"value":"Monomer (PubMed:24778178). Interacts with RBM33; promoting desumoylation by SENP1 and recruitment to N(6)-methyladenosine-containing mRNAs (PubMed:37257451). Interacts (when acetylated by KAT8) with PSPC1; interaction facilitates recognition of N(6)-methyladenosine (m6A) mRNA (PubMed:37369679). Interacts with DDX54; this interaction down-regulates the interferon antiviral response (PubMed:40793791)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37474102"}],"value":"Promotes formation and localizes to paraspeckles, a nuclear membraneless organelle"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21264265"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23177736"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37474102"}],"value":"Nucleus speckle","id":"SL-0186"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"40793791"}],"value":"Nucleus, nucleoplasm","id":"SL-0190"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"2"},"isoformIds":["Q6P6C2-2"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"1"},"isoformIds":["Q6P6C2-1"],"sequenceIds":["VSP_019130"],"isoformSequenceStatus":"Described"},{"name":{"value":"3"},"isoformIds":["Q6P6C2-3"],"sequenceIds":["VSP_044226"],"isoformSequenceStatus":"Described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17979886"}],"value":"Widely expressed, with highest expression in lung, followed by testis, pancreas, spleen and ovary"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21264265"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22761421"}],"value":"By hypoxia, directly activated by HIF1A. Expression is regulated by PRMT7"}],"commentType":"INDUCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37474102"}],"value":"The C-terminal disordered region undergoes liquid-liquid phase separation (LLPS) for the formation of paraspeckle membraneless compartment"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"34048572"}],"value":"Phosphorylated at Ser-87 and Ser-325 in response to reactive oxygen species (ROS), promoting sumoylation and inactivation"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37369679"}],"value":"Acetylated by KAT8 at Lys-235, promoting interaction with PSPC1, thereby facilitating recognition of N(6)-methyladenosine (m6A) mRNA by ALKBH5 (PubMed:37369679). Deacetylated at Lys-235 by HDAC7 (PubMed:37369679)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"34048572"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37257451"}],"value":"Sumoylated at Lys-86 and Lys-321 by PIAS4 following phosphorylation at Ser-87 and Ser-325 in response to reactive oxygen species (ROS), inhibiting the RNA demethylase activity (PubMed:34048572, PubMed:37257451). Desumoylated by SENP1; relieving RNA demethylase inhibition, leading to N(6)-methyladenosine-containing mRNAs demethylation (PubMed:34048572, PubMed:37257451)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37454738"}],"value":"Ubiquitinated at Lys-57 via 'Lys-48'-linked polyubiquitin chain, leading to its degradation by the proteasome (PubMed:37454738). Deubiquitinated at Lys-57 by USP9X, promoting its stabilizazion (PubMed:37454738)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the alkB family"}],"commentType":"SIMILARITY"},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"BAA91078.1","note":"Truncated N-terminus.","evidences":[{"evidenceCode":"ECO:0000305"}]}],"features":[{"type":"Initiator methionine","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":1,"modifier":"EXACT"}},"description":"Removed","evidences":[{"evidenceCode":"ECO:0007744","source":"PubMed","id":"19413330"},{"evidenceCode":"ECO:0007744","source":"PubMed","id":"22814378"}]},{"type":"Chain","location":{"start":{"value":2,"modifier":"EXACT"},"end":{"value":394,"modifier":"EXACT"}},"description":"RNA demethylase 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