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Information on EC 1.14.11.51 - DNA N6-methyladenine demethylase
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1.14.11.51 DNA N6-methyladenine demethylaseIUBMB Comments
Contains iron(II). Catalyses oxidative demethylation of DNA N6-methyladenine, a prevalent modification in LINE-1 transposons, which are specifically enriched on the human X chromosome.
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Word Map
- 1.14.11.51
- dioxygenase
-
demethylation
- histone
-
2-oxoglutarate-dependent
-
abasic
-
alkbh7
-
eraser
The enzyme appears in viruses and cellular organisms
Reaction Schemes
N6-methyladenine in DNA
+
+
=
adenine in DNA
+
+
+
Synonyms
nmad-1, dna 6ma demethylase, 
more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ALKBH1
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
N6-methyladenine in DNA + 2-oxoglutarate + O2 = adenine in DNA + formaldehyde + succinate + CO2
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-
-
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SYSTEMATIC NAME
IUBMB Comments
DNA-N6-methyladenosine,2-oxoglutarate:oxygen oxidoreductase (formaldehyde-forming)
Contains iron(II). Catalyses oxidative demethylation of DNA N6-methyladenine, a prevalent modification in LINE-1 transposons, which are specifically enriched on the human X chromosome.
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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
N6-methyladenine in DNA + 2-oxoglutarate + O2
adenine in DNA + formaldehyde + succinate + CO2
additional information
?
-
ALKBH1 prefers bubbled or bulged DNAs as substrate. The middle N6-mA in the 3-nt bulge is efficiently demethylated compared to that in the 3-nt bubble (97% vs. 18% demethylation fraction) and the 1st and 3rd N6-mAs are more resistant to demethylation. N6-mAs deposited in the flexible region of hairpin (DNA stem loop), D-loop and R-loop are efficiently demethylated as in bubble and bulge, while those in cruciform and replication fork are less demethylated. m6rA in RNA hairpin, RNA-RNA bubble and RNA-DNA hybrid bubble can also be demethylated by ALKBH1, as well as 5-methylcytosine at anticodon loop and 1-methyladenosine
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-
-
N6-methyladenine in DNA + 2-oxoglutarate + O2
adenine in DNA + formaldehyde + succinate + CO2
-
-
-
-
?
N6-methyladenine in DNA + 2-oxoglutarate + O2
adenine in DNA + formaldehyde + succinate + CO2
-
-
-
-
?
N6-methyladenine in DNA + 2-oxoglutarate + O2
adenine in DNA + formaldehyde + succinate + CO2
-
-
-
-
?
N6-methyladenine in DNA + 2-oxoglutarate + O2
adenine in DNA + formaldehyde + succinate + CO2
-
-
-
?
N6-methyladenine in DNA + 2-oxoglutarate + O2
adenine in DNA + formaldehyde + succinate + CO2
-
-
-
?
N6-methyladenine in DNA + 2-oxoglutarate + O2
adenine in DNA + formaldehyde + succinate + CO2
the enzyme catalyses oxidative demethylation of DNA N6-methyladenine, a prevalent modification in LINE-1 transposons
-
-
?
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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
N6-methyladenine in DNA + 2-oxoglutarate + O2
adenine in DNA + formaldehyde + succinate + CO2
N6-methyladenine in DNA + 2-oxoglutarate + O2
adenine in DNA + formaldehyde + succinate + CO2
-
-
-
-
?
N6-methyladenine in DNA + 2-oxoglutarate + O2
adenine in DNA + formaldehyde + succinate + CO2
-
-
-
-
?
N6-methyladenine in DNA + 2-oxoglutarate + O2
adenine in DNA + formaldehyde + succinate + CO2
-
-
-
-
?
N6-methyladenine in DNA + 2-oxoglutarate + O2
adenine in DNA + formaldehyde + succinate + CO2
-
-
-
?
N6-methyladenine in DNA + 2-oxoglutarate + O2
adenine in DNA + formaldehyde + succinate + CO2
the enzyme catalyses oxidative demethylation of DNA N6-methyladenine, a prevalent modification in LINE-1 transposons
-
-
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
bifunctional apurinic/apyrimidinic sites lyase and m6A demethylase, cf. EC 4.2.99.18
UniProt
brenda
bifunctional apurinic/apyrimidinic sites lyase and m6A demethylase, cf. EC 4.2.99.18
SwissProt
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
ALKBH1 enhances proliferation and inhibits differentiation of C2C12 cells
brenda
N6-mA levels shows a steady increase, going along with a strong decrease of ALKBH1 during skeletal muscle development
brenda
additional information
-
gene is expressed during all embryonic development phases
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
N6-hydroxymethyladenine exists as an oxidized intermediate during N6-mA demethylation by ALKBH1
physiological function
malfunction
-
enzyme deletion accelerates the progressive fertility defect of spr-5 mutant worms
malfunction
-
enzyme-depleted mesenchymal stem cells exhibit a restricted capacity for bone formation in vivo
physiological function
the enzyme catalyses oxidative demethylation of DNA N6-methyladenine, a prevalent modification in LINE-1 transposons
physiological function
-
the enzyme promotes differentiation of early germ cells in fly ovary
physiological function
-
enzyme overexpression enhances osteoblastic differentiation of mesenchymal stem cells
physiological function
Alkbh1 expression in bone marrow mesenchymal stem cells declines during aging. Knockout of Alkbh1 promotes adipogenic differentiation of bone marrow mesenchymal stem cells while inhibits osteogenic differentiation. Bone marrow mesenchymal stem cells -specific Alkbh1 knockout mice exhibit reduced bone mass and increased marrow adiposity. Overexpression of Alkbh1 attenuates bone loss and marrow fat accumulation in aged mice
physiological function
ALKBH1 is critical for the myogenic differentiation of C2C12 cells. Overexpression of ALKBH1 reduces N6-mA levels, enhances proliferation and inhibits differentiation in C2C12 cells. ALKBH1 regulates a subset of genes and impairs multiple signaling required for muscle development
physiological function
ALKBH1 overexpression decreases hepatocellular carcinoma cell viability, induces apoptosis, and decreases migration and invasion
physiological function
knockdown of ALKBH1 inhibits adipogenic differentiation in both mesenchymal stem cells and 3T3-L1 preadipocytes, while overexpression of ALKBH1 leads to increased adipogenesis. Hypoxia-inducible factor HIF-1 signaling is a crucial downstream target of ALKBH1 activity. Depletion of ALKBH1 leads to hypermethylation of both HIF-1alpha and its downstream target GYS1
physiological function
-
RNAi knockdown of 6mA methyltransferase METTL4 and 6mA demethylase NMAD induce cell cycle arrest at G1 phase and also result in defects of chromosome alignments at metaphase
physiological function
the 6-methyl adenine demethylase activity is very low. The demethylase activity is less than half that of the apurinic/apyrimidinic lyase activity when ALKBH1 samples are assayed using identical buffer conditions. The two enzymatic activities are located in distinct but partially overlapping active sites for the two reactions
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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). ALKB1_HUMAN
389
0
43832
Swiss-Prot
other Location (Reliability: 5)
ALKB1_MOUSE
389
0
43746
Swiss-Prot
Mitochondrion (Reliability: 5)
ALKB4_HUMAN
302
0
33838
Swiss-Prot
other Location (Reliability: 1)
ALKB4_MOUSE
300
0
33394
Swiss-Prot
other Location (Reliability: 2)
DMAD_DROME
2860
0
306700
Swiss-Prot
other Location (Reliability: 2)
NMAD1_CAEEL
291
0
33292
Swiss-Prot
other Location (Reliability: 2)
A0A6J8BG71_MYTCO
385
0
44110
TrEMBL
other Location (Reliability: 2)
A0A6J8D5Y6_MYTCO
344
0
39228
TrEMBL
other Location (Reliability: 4)
A0A6J8EKK5_MYTCO
155
0
17872
TrEMBL
other Location (Reliability: 1)
A0A7R8H1C8_LEPSM
259
0
29888
TrEMBL
other Location (Reliability: 1)
A0A812CCK0_SEPPH
272
0
31283
TrEMBL
other Location (Reliability: 1)
A0A8M1P386_DANRE
188
0
21402
TrEMBL
other Location (Reliability: 3)
A0A6J8EMW8_MYTCO
238
0
27493
TrEMBL
other Location (Reliability: 1)
A0A8M1P7U9_DANRE
268
0
30712
TrEMBL
other Location (Reliability: 2)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
enzyme shows a stretch-out conformation of its Flip1 motif, explaining the observed preference of ALKBH1 for unpairing substrates, in which the flipped N6-mA is primed for catalysis. Structures of ALKBH1 bound to a 21-mer bulged DNA show the need of both flanking duplexes and a flipped base for recognition and catalysis
structure to 3.1 A resolution. The N-terminal domain of the protein forms close contacts with the core catalytic domain and might be responsible for the recognition of nucleic acid substrates. H231, D233 and H287 are ligands of the catalytic iron metal
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C118A
m6A demethylase activity similar to wild-type, about 25% decrease in apurinic/apyrimidinic lyase activity
C118A/C129A
about 50% decrease in m6A demethylase activity, about 20% decrease in apurinic/apyrimidinic lyase activity
C129A
about 90% decrease in m6A demethylase activity, about 30% decrease in apurinic/apyrimidinic lyase activity
D233A
H113A/C118A/C129A/H134A
no residual m6A demethylase activity, about 55% decrease in apurinic/apyrimidinic lyase activity
H231A
H287A
K133A
about 50% decrease in m6A demethylase activity, about 45% decrease in apurinic/apyrimidinic lyase activity
R338A
residue plays an important role in substrate recognition and catalysis
R344A
mutation in highly conserved residue, strong decrease in demethylation ability
Y184A
mutation in highly conserved residue, strong decrease in demethylation ability
K158A
mutation of basic residue of Flip1 region, abolishes N6-mA demethylation activity of ALKBH1
R159A
mutation of basic residue of Flip1 region, abolishes N6-mA demethylation activity of ALKBH1
R160A
mutation of basic residue of Flip1 region, abolishes N6-mA demethylation activity of ALKBH1
R167A
mutation of basic residue of Flip1 region, abolishes N6-mA demethylation activity of ALKBH1
R169A
mutation of basic residue of Flip1 region, abolishes N6-mA demethylation activity of ALKBH1
D233A
no residual m6A demethylase activity, about 30% decrease in apurinic/apyrimidinic lyase activity
D233A
residue plays an important role in substrate recognition and catalysis
H231A
no residual m6A demethylase activity, about 20% decrease in apurinic/apyrimidinic lyase activity
H231A
residue plays an important role in substrate recognition and catalysis
H287A
no residual m6A demethylase activity, about 25% decrease in apurinic/apyrimidinic lyase activity
H287A
residue plays an important role in substrate recognition and catalysis
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
enzyme expression in human mesenchymal stem cells is upregulated during osteogenic induction
-
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
development of assay method using a methylation-sensitive restriction endonuclease
medicine
medicine
ALKBH1 overexpression decreases hepatocellular carcinoma cell viability, induces apoptosis, and decreases migration and invasion. 23779 gain-of-6 mA regions and 11240 loss-of-6 mA regions are differentially identified in hepatocellular carcinoma tissues. The differential gain and loss of 6 mA regions are considerably enriched in intergenic regions. 7% of the differential 6 mA modifications are associated with tumors, with 60 associated with oncogenes and 57 with tumor suppressor genes, and 17 are common to oncogenes and TSGs
medicine
during the progression of vascular calcification in a model of chronic kidney disease, increased ALKBH1 expression is linked to decreased 6mA levels
medicine
expression levels of ALKBH1 in lung cancer tissues and cells are up regulated. The invasion and migration abilities of lung cancer cells are significantly suppressed in vitro upon the silencing of ALKBH1 while they are significantly promoted upon its overexpression
medicine
in patients with chronic kidney disease, leukocyte 6mA levels are significantly reduced as the severity of vascular calcification increases. Decreased 6mA demethylation results from the upregulation of ALKBH1. ALKBH1 overexpression aggravates whereas its depletion blunts vascular calcification progression and osteogenic reprogramming in vivo and in vitro
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Wu, T.P.; Wang, T.; Seetin, M.G.; Lai, Y.; Zhu, S.; Lin, K.; Liu, Y.; Byrum, S.D.; Mackintosh, S.G.; Zhong, M.; Tackett, A.; Wang, G.; Hon, L.S.; Fang, G.; Swenberg, J.A.; Xiao, A.Z.
DNA methylation on N-adenine in mammalian embryonic stem cells
Nature
532
329-333
2016
Mus musculus (P0CB42)
brenda
Zhang, G.; Huang, H.; Liu, D.; Cheng, Y.; Liu, X.; Zhang, W.; Yin, R.; Zhang, D.; Zhang, P.; Liu, J.; Li, C.; Liu, B.; Luo, Y.; Zhu, Y.; Zhang, N.; He, S.; He, C.; Wang, H.; Chen, D.
N6-methyladenine DNA modification in Drosophila
Cell
161
893-906
2015
Drosophila melanogaster
brenda
Ye, F.; Zhang, L.; Jin, L.; Zheng, M.; Jiang, H.; Luo, C.
Repair of methyl lesions in RNA by oxidative demethylation
MedChemComm
5
1797-1803
2014
Homo sapiens (Q13686)
-
brenda
Zhou, C.; Liu, Y.; Li, X.; Zou, J.; Zou, S.
DNA N6-methyladenine demethylase ALKBH1 enhances osteogenic differentiation of human MSCs
Bone Res.
4
16033
2016
Homo sapiens
brenda
Greer, E.L.; Blanco, M.A.; Gu, L.; Sendinc, E.; Liu, J.; Aristizabal-Corrales, D.; Hsu, C.H.; Aravind, L.; He, C.; Shi, Y.
DNA methylation on N6-adenine in C. elegans
Cell
161
868-878
2015
Caenorhabditis elegans
brenda
Li, H.; Zhang, Y.; Guo, Y.; Liu, R.; Yu, Q.; Gong, L.; Liu, Z.; Xie, W.; Wang, C.
ALKBH1 promotes lung cancer by regulating m6A RNA demethylation
Biochem. Pharmacol.
189
114284
2021
Mus musculus (P0CB42), Homo sapiens (Q13686)
brenda
Mueller, T.A.; Tobar, M.A.; Perian, M.N.; Hausinger, R.P.
Biochemical characterization of AP lyase and m(6)A demethylase activities of human AlkB homologue 1 (ALKBH1)
Biochemistry
56
1899-1910
2017
Homo sapiens (Q13686)
brenda
Wang, X.; Li, Z.; Zhang, Q.; Li, B.; Lu, C.; Li, W.; Cheng, T.; Xia, Q.; Zhao, P.
DNA methylation on N6-adenine in lepidopteran Bombyx mori
Biochim. Biophys. Acta Gene Regul. Mech.
1861
815-825
2018
Bombyx mori
brenda
Cai, G.P.; Liu, Y.L.; Luo, L.P.; Xiao, Y.; Jiang, T.J.; Yuan, J.; Wang, M.
Alkbh1-mediated DNA N6-methyladenine modification regulates bone marrow mesenchymal stem cell fate during skeletal aging
Cell Prolif.
55
e13178
2022
Mus musculus (P0CB42)
brenda
Zhang, M.; Yang, S.; Nelakanti, R.; Zhao, W.; Liu, G.; Li, Z.; Liu, X.; Wu, T.; Xiao, A.; Li, H.
Mammalian ALKBH1 serves as an N6-mA demethylase of unpairing DNA
Cell Res.
30
197-210
2020
Mus musculus (P0CB42)
brenda
Diao, L.; Xie, S.; Yu, P.; Sun, Y.; Yang, F.; Tan, Y.; Tao, S.; Hou, Y.; Zheng, L.; Xiao, Z.; Zhang, Q.
N6-methyladenine demethylase ALKBH1 inhibits the differentiation of skeletal muscle
Exp. Cell Res.
400
112492
2021
Mus musculus (P0CB42)
brenda
Lin, Q.; Chen, J.W.; Yin, H.; Li, M.A.; Zhou, C.R.; Hao, T.F.; Pan, T.; Wu, C.; Li, Z.R.; Zhu, D.; Wang, H.F.; Huang, M.S.
DNA N6-methyladenine involvement and regulation of hepatocellular carcinoma development
Genomics
114
110265
2022
Homo sapiens (Q13686)
brenda
Liu, Y.; Chen, Y.; Wang, Y.; Jiang, S.; Lin, W.; Wu, Y.; Li, Q.; Guo, Y.; Liu, W.; Yuan, Q.
DNA demethylase ALKBH1 promotes adipogenic differentiation via regulation of HIF-1 signaling
J. Biol. Chem.
298
101499
2022
Homo sapiens (Q13686)
brenda
Ouyang, L.; Su, X.; Li, W.; Tang, L.; Zhang, M.; Zhu, Y.; Xie, C.; Zhang, P.; Chen, J.; Huang, H.
ALKBH1-demethylated DNA N6-methyladenine modification triggers vascular calcification via osteogenic reprogramming in chronic kidney disease
J. Clin. Invest.
131
e146985
2021
Mus musculus (P0CB42), Homo sapiens (Q13686)
brenda
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Release 2023.1 (January 2023)
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