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Information on EC 1.14.11.54 - mRNA N1-methyladenine demethylase and Organism(s) Homo sapiens
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1.14.11.54 mRNA N1-methyladenine demethylaseIUBMB Comments
Contains iron(II). Catalyses oxidative demethylation of mRNA N1-methyladenine. The enzyme is also involved in alkylation repair in DNA .
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Word Map
- 1.14.11.54
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paraneoplastic
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pokeweed
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anti-yo
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anna-1
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cd45ra
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anti-il-6
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cell-restricted
- medicine
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
N1-methyladenine in mRNA
+
+
=
adenine in mRNA
+
+
+
Synonyms
pca-1, alkb homolog 3, prostate cancer antigen-1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ALKBH3
ALKBH3
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
mRNA-N1-methyladenine,2-oxoglutarate:oxygen oxidoreductase (formaldehyde-forming)
Contains iron(II). Catalyses oxidative demethylation of mRNA N1-methyladenine. The enzyme is also involved in alkylation repair in DNA [2].
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
5'-dAAAA-1-methyl-AYYAAA + 2-oxoglutarate + O2
5'-dAAAAAYYAAA + formaldehyde + succinate + CO2
-
-
-
?
N1-methyladenine in mRNA + 2-oxoglutarate + O2
adenine in mRNA + formaldehyde + succinate + CO2
N1-methyladenine in ssDNA + 2-oxoglutarate + O2
adenine in ssDNA + formaldehyde + succinate + CO2
-
-
-
?
N1-methyladenine in tRNA + 2-oxoglutarate + O2
adenine in tRNA + formaldehyde + succinate + CO2
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-
-
?
N3-methylcytidine in tRNA + 2-oxoglutarate + O2
cytidine in tRNA + formaldehyde + succinate + CO2
-
-
-
?
N1-methyladenine in mRNA + 2-oxoglutarate + O2
adenine in mRNA + formaldehyde + succinate + CO2
-
-
-
?
N1-methyladenine in mRNA + 2-oxoglutarate + O2
adenine in mRNA + formaldehyde + succinate + CO2
-
N1-methyladenine is prevalent in Homo sapiens mRNA, which shows an N1-methyladenine/adenine ratio of about 0.02%. Methylation of adenine in mRNA is reversible by ALKBH3. Recombinant ALKBH3 protein has robust demethylation activity against a synthetic RNA substrate containing a sitespecifically incorporated m1A modification
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-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
N1-methyladenine in mRNA + 2-oxoglutarate + O2
adenine in mRNA + formaldehyde + succinate + CO2
-
-
-
?
N1-methyladenine in ssDNA + 2-oxoglutarate + O2
adenine in ssDNA + formaldehyde + succinate + CO2
-
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
physiological function
1-methyladenine and 3-methylcytosine lesions in DNA/RNA contribute to the cytotoxicity of methylating agents. These lesions are directly reversed by ABH3 in humans
physiological function
ALKBH3 binds to transcription associated locations, such as places of promoter-proximal paused RNA polymerase II and enhancers. ALKBH3 strongly binds to the transcription initiation sites of a small number of highly active gene promoters characterized by high levels of transcriptional regulators, including transcription factors, the Mediator complex, cohesin, histone modifiers, and active histone marks. ALKBH3 does not directly influence the transcription of its target genes, but its depletion induces an upregulation of ALKBH3 non-bound inflammatory genes
physiological function
ALKBH3 is associated with the activating signal cointegrator complex ASCC. ALKBH3 is overexpressed in various cancers, and both ALKBH3 and ASCC are important for alkylation damage resistance in these tumor cell lines. ASCC3, the largest subunit of ASCC, encodes a 3'-5' DNA helicase, whose activity is crucial for the generation of single-stranded DNA upon which ALKBH3 preferentially functions for dealkylation. In cell lines that are dependent on ALKBH3 and ASCC3 for alkylation damage resistance, loss of ALKBH3 or ASCC3 leads to increased 3-methylcytosine and reduced cell proliferation. ALKBH3 catalytic activity is important for alkylation damage resistance
physiological function
human adenocarcinomas and squamous cell carcinomas of the lung show overexpression of Alkbh3 and the percentage of cells positive for Alkbh3 also correlates statistically to recurrence-free survival in adenocarcinoma. Knockdown of Alkbh3 by siRNA transfection induces expression of p21WAF1/Cip1 and p27Kip1 in the human lung adenocarcinoma cell line A-549, resulting in cell cycle arrest, senescence and strong suppression of cell growth in vitro. In vivo, peritoneal tumour growth and dissemination is inhibited in nude mice, previously inoculated with the A-549 cell line, by intraperitoneal injection of Alkbh3 siRNA plus atelocollagen
physiological function
-
N1-methyladenine in mRNA can be reversed by ALKBH3. Adenine methylation responds dynamically to stimuli, and hundreds of stress-induced N1-methyladenine sites can be identified. Knockout and overexpression of ALKBH3 in HEK-293T cells leads to an increased or decreased N1-methyladenine/adenine ratio in mRNA, respectively
physiological function
ALKBH3 is a 1-methyladenosine and 3-methylcytidine demethylase of tRNA. ALKBH3 can promote cancer cell proliferation, migration and invasion. The m1A demethylated tRNA is more sensitive to angiogenin cleavage, followed by generating tRNA-derived small RNAs around the anticodon regions. in ALKBH3-/- HeLa cells, m1A level of tRNA in cytoplasm, but not in nucleus, is remarkably higher than that of wild type cells. Deletion of ALKBH3 significantly increases the m1A levels of most target tRNAs such as tRNAGluCTC, tRNASeCTCA, tRNAGlyGCC, tRNAHisGTG, tRNASerGCT, tRNAGlnCTG, tRNAValCAC, tRNAArgCCT, tRNALeuCAA, tRNAGlyCCC, tRNAAlaCGC and tRNAeMetCAT. m1A levels of some targets, such as tRNALysCTT and tRNAAsnGTT, are not affected. m3C levels of target tRNA are significantly upregulated in Alkbh3-/- HeLa cells
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). ALKB3_HUMAN
286
0
33375
Swiss-Prot
Mitochondrion (Reliability: 3)
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
structure of the ABH3 catalytic core in complex with iron and 2-oxoglutarate at 1.5 A resolution. The ABH3 structure reveals the beta-strand jelly-roll fold that coordinates a catalytically active iron centre by a conserved His1-X-Asp/Glu-Xn-His2 motif. The structure shows a positively charged DNA/RNA binding groove and a flexible hairpin involved in nucleotide flipping and ss/ds-DNA discrimination, and reveals self-hydroxylation of an active site leucine
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
L177A
mutation at the active site, mutant lost its demethylation activity on m1A of tRNA in vitro and in vivo
R122A
mutant is defective in its DNA/RNA binding groove, mutant lost its demethylation activity on m1A of tRNA in vitro and in vivo
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
HisTrap affinity column chromatography, and Mono Q 5/50 GL anion ion exchange column chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
human adenocarcinomas and squamous cell carcinomas of the lung show overexpression of Alkbh3 and the percentage of cells positive for Alkbh3 also correlates statistically to recurrence-free survival in adenocarcinoma. Knockdown of Alkbh3 by siRNA transfection induces expression of p21WAF1/Cip1 and p27Kip1 in the human lung adenocarcinoma cell line A-549, resulting in cell cycle arrest, senescence and strong suppression of cell growth in vitro. In vivo, peritoneal tumour growth and dissemination is inhibited in nude mice, previously inoculated with the A-549 cell line, by intraperitoneal injection of Alkbh3 siRNA plus atelocollagen
medicine
ALKBH3 promoter CpG island hypermethylation is most frequent in Hodgkin lymphoma cell lines (44%; 4 of 9), followed by Burkitt lymphoma (38%; 5 of 13), other non-Hodgkin lymphoma cell lines (37%; 12 of 32), and anaplastic large cell lymphoma. ALKBH3 promoter hypermethylation is detected in detected in18% (14 of 80) of the primary Hodgkin lymphoma cases. ALKBH3 CpG island hypermethylation is associated with protein loss. ALKBH3 epigenetic silencing is also associated with COL1A2 and COL1A1 overexpression, whereas an unmethylated ALKBH3 CpG island is linked to the absence of collagen expression. ALKBH3 hypermethylation is associated with shorter overall survival in the studied Hodgkin lymphoma cohort
medicine
the alteration of ALKBH3 expression regulates the cytokine CSF-1 mRNA stability. Actions of cytokine CSF-1 lead to poor prognosis in ovarian and breast cancers. Demethylation of m1A by ALKBH3 increases the half-life of CSF-1 mRNA without affecting the translation efficiency. Overexpression of ALKBH3 increases CSF-1 expression and the degree of cancer cell invasiveness without affecting cell proliferation or migration
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Tasaki, M.; Shimada, K.; Kimura, H.; Tsujikawa, K.; Konishi, N.
ALKBH3, a human AlkB homologue, contributes to cell survival in human non-small-cell lung cancer
Br. J. Cancer
104
700-706
2011
Homo sapiens (Q96Q83)
Sundheim, O.; Vagbo, C.; Bjoras, M.; Sousa, M.; Talstad, V.; Aas, P.; Drablos, F.; Krokan, H.; Tainer, J.; Slupphaug, G.
Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage
EMBO J.
25
3389-3397
2006
Homo sapiens (Q96Q83)
Liefke, R.; Windhof-Jaidhauser, I.M.; Gaedcke, J.; Salinas-Riester, G.; Wu, F.; Ghadimi, M.; Dango, S.
The oxidative demethylase ALKBH3 marks hyperactive gene promoters in human cancer cells
Genome Med.
7
66
2015
Homo sapiens (Q96Q83)
Dango, S.; Mosammaparast, N.; Sowa, M.E.; Xiong, L.J.; Wu, F.; Park, K.; Rubin, M.; Gygi, S.; Harper, J.W.; Shi, Y.
DNA unwinding by ASCC3 helicase is coupled to ALKBH3-dependent DNA alkylation repair and cancer cell proliferation
Mol. Cell
44
373-384
2011
Homo sapiens (Q96Q83)
Li, X.; Xiong, X.; Wang, K.; Wang, L.; Shu, X.; Ma, S.; Yi, C.
Transcriptome-wide mapping reveals reversible and dynamic N(1)-methyladenosine methylome
Nat. Chem. Biol.
12
311-316
2016
Homo sapiens
Ueda, Y.; Kitae, K.; Ooshio, I.; Fusamae, Y.; Kawaguchi, M.; Jingushi, K.; Harada, K.; Hirata, K.; Tsujikawa, K.
A real-time PCR-based quantitative assay for 3-methylcytosine demethylase activity of ALKBH3
Biochem. Biophys. Rep.
5
476-481
2016
Homo sapiens (Q96Q83), Homo sapiens
Beharry, A.A.; Lacoste, S.; OConnor, T.R.; Kool, E.T.
Fluorescence monitoring of the oxidative repair of DNA alkylation damage by ALKBH3, a prostate cancer marker
J. Am. Chem. Soc.
138
3647-3650
2016
Homo sapiens (Q96Q83)
Woo, H.H.; Chambers, S.K.
Human ALKBH3-induced m1A demethylation increases the CSF-1 mRNA stability in breast and ovarian cancer cells
Biochim. Biophys. Acta Gene Regul. Mech.
1862
35-46
2019
Homo sapiens (Q96Q83)
Esteve-Puig, R.; Climent, F.; Pineyro, D.; Domingo-Domenech, E.; Davalos, V.; Encuentra, M.; Rea, A.; Espejo-Herrera, N.; Soler, M.; Lopez, M.; Ortiz-Barahona, V.; Tapia, G.; Navarro, J.; Cid, J.; Farre, L.; Villanueva, A.; Casanova, I.; Mangues, R.
Epigenetic loss of m1A RNA demethylase ALKBH3 in Hodgkin lymphoma targets collagen, conferring poor clinical outcome
Blood
137
994-999
2021
Homo sapiens (Q96Q83)
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Release 2023.1 (January 2023)
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