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Information on EC 3.2.2.21 - DNA-3-methyladenine glycosylase II and Organism(s) Homo sapiens and UniProt Accession P29372
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3.2.2.21 DNA-3-methyladenine glycosylase IIIUBMB Comments
Involved in the removal of alkylated bases from DNA in Escherichia coli (cf. EC 2.1.1.63 methylated-DNA---[protein]-cysteine S-methyltransferase).
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Word Map
- 3.2.2.21
- glycosylases
- endonuclease
- 8-oxoguanine
- strand
- guanine
- thymine
- mismatch
-
abasic
- pyrimidine
- uracil
- duplex
-
8-oxog
-
excises
- cytosine
-
alkyladenine
- mispairs
-
mutyh
- 7,8-dihydro-8-oxoguanine
- formamidopyrimidine
- hypoxanthine
- 7-methylguanine
- ape1
- 5-methylcytosine
- 1,n6-ethenoadenine
-
undamaged
- 8-hydroxyguanine
- 8-oxo-7,8-dihydroguanine
-
formamidopyrimidine-dna
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nucleobase
-
transversions
-
apurinic
-
uracil-dna
-
n-glycosidic
-
ser326cys
-
etheno
-
mutyh-associated
-
unrepaired
-
mismatch-specific
-
8-oxo-7,8-dihydro-2'-deoxyguanosine
-
base-excision
- 5-hydroxymethyluracil
-
apyrimidinic
-
8-oxoguanine-dna
-
premutagenic
-
alkylation-induced
- ap-endonuclease
-
thymine-dna
- medicine
-
miscoding
-
extrahelical
-
methylmethane
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
dna glycosylase, n-methylpurine-dna glycosylase, 3-methyladenine dna glycosylase ii, 3-methyladenine-dna glycosylase ii, alka protein, alkylpurine-dna-n-glycosylase, tagii, alka1, mag1 protein, helix-hairpin-helix dna glycosylase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
3-methyladenine-DNA glycosidase II
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-
-
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3-methyladenine-DNA glycosylase II
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-
-
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AlkA
-
-
-
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deoxyribonucleate 3-methyladenine glycosidase II
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-
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DNA-3-methyladenine glycosidase II
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-
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TagII
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-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of N-glycosyl bond
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-
-
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SYSTEMATIC NAME
IUBMB Comments
alkylated-DNA glycohydrolase (releasing methyladenine and methylguanine)
Involved in the removal of alkylated bases from DNA in Escherichia coli (cf. EC 2.1.1.63 methylated-DNA---[protein]-cysteine S-methyltransferase).
CAS REGISTRY NUMBER
COMMENTARY
89287-38-7
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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
duplex oligonucleotide substrate containing ethenoadenine + H2O
ethenoadenine + oligonucleotide
-
-
-
?
1,N6-ethenoadenine residues in alkylated DNA + H2O
ethenoadenine + DNA
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-
-
-
?
alkylated DNA + H2O
3-methyladenine + 7-methylguanine + ?
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-
ratio of 3-methyladenine/7-methylguanine is 29:1 for wild-type enzyme, 24:1 for mutant enzyme N169S and 26:1 for mutant enzyme N169A, no production of 7-methylguanine is detected with mutant enzyme N169D
-
?
alkylated DNA + H2O
3-methyladenine + 7-methylguanine + hypoxanthine + DNA
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-
-
-
?
alkylated DNA + H2O
3-methyladenine + 7-methylguanine + O2-methylthymine + O2-methylcytosine + DNA
alkylated DNA + H2O
3-methyladenine + 7-methylguanine + O2-methylthymine + O2-methylcytosine + DNA
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-
-
-
?
alkylated DNA + H2O
3-methyladenine + 7-methylguanine + O2-methylthymine + O2-methylcytosine + DNA
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short-patch base excision repair pathway, repair of alkylation and oxidative DNA damage
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-
?
additional information
?
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removes N-alkylpurine damage, unrepaired DNA damage leads to carcinogenesis, cell death, and aging, also releases 1,N6-ethenoadenine
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-
?
additional information
?
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removes N-alkylpurine damage, unrepaired DNA damage leads to carcinogenesis, cell death, and aging, also releases 1,N6-ethenoadenine
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-
?
additional information
?
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removes also hypoxanthine and 1,N6-ethenoadenine
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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
alkylated DNA + H2O
3-methyladenine + 7-methylguanine + O2-methylthymine + O2-methylcytosine + DNA
alkylated DNA + H2O
3-methyladenine + 7-methylguanine + O2-methylthymine + O2-methylcytosine + DNA
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-
-
-
?
alkylated DNA + H2O
3-methyladenine + 7-methylguanine + O2-methylthymine + O2-methylcytosine + DNA
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short-patch base excision repair pathway, repair of alkylation and oxidative DNA damage
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-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Cd2+
inhibitory above 0.05 mM. Reduced catalytic activity in presence of Zn2+ is not due to altered binding of substrate
Ni2+
inhibitory above 0.05 mM, but to lesser extent than Cd2+ or Zn2+. Reduced catalytic activity in presence of Zn2+ is not due to altered binding of substrate
Zn2+
enzyme active site has a potential binding site for Zn2+. Reduced catalytic activity in presence of Zn2+ is not due to altered binding of substrate
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000024
1,N6-ethenoadenine residues in alkylated DNA
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pH 7.5, 37°C, excision of 1, N6-ethenoadenine
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000833
1,N6-ethenoadenine residues in alkylated DNA
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pH 7.5, 37°C, excision of1, N6-ethenoadenine
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
the crude extract shows a specific activity of 80 IU/mg, the 125fold purified enzyme displays a specific activity of 10000 IU/mg, one international unit (IU) is defined as the activity, which cleaves 50% of 0.5 pmole of double stranded DNA oligo substrate containing a hypoxanthine lesion in 10 min at 37°C
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pI VALUE
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
alkyladenine DNA glycosylase protects an abasic site on one strand of a DNA duplex from cross-linking with an amine on the opposing strand by binding tightly to the abasic site and sequestering it. AAG protects an abasic site opposite T, the product of its canonical glycosylase reaction, by a factor of about 10fold
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). 3MG_HUMAN
298
0
32869
Swiss-Prot
other Location (Reliability: 4)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
molecular dynamics simulations show that neutral substrates form a common DNA-protein hydrogen bond, which results in a consistent active site conformation that maximizes pi-pi interactions between the aromatic residues and the nucleobase required for catalysis. The exocyclic amino groups of the natural purines clash with active site residues, which leads to catalytically incompetent DNA-enzyme complexes due to significant reorganization of active site water. Water resides between the A nucleobase and the active site aromatic amino acids required for catalysis, while a shift in the position of the general base (E125) repositions water away from G. The methyl substituents in cationic purine lesions (3-methyladenine and 7-methyladenine) exhibit repulsion with active site residues
quantum mechanis study of alkyladenine DNA glycosylase AAG bound to DNA containing hypoxanthine, guanine or 7-methylguanine. Subtle differences in protein-DNA contacts upon binding different substrates within the flexible AAG active site can significantly affect the deglycosylation reaction. AAG excises hypoxanthine in a concerted mechanism that is facilitated through correct alignment of the E125 general base due to hydrogen bonding with a neighboring aromatic amino acid Y127. Hypoxanthine departure is further stabilized by pi-pi interactions with aromatic amino acids and hydrogen bonds with active site water. Guanine is not excised since the additional exocyclic amino group leads to misalignment of the general base due to disruption of the key E125-Y127 hydrogen bond, the catalytically unfavorable placement of water within the active site, and weakened pi-contacts between aromatic amino acids and the nucleobase. 7-methylguanine does not occupy the same position within the AAG active site as guanine due to steric clashes with the additional N7 methyl group
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
N169A
-
ratio of 3-methyladenine/7-methylguanine is 29:1 for wild-type enzyme and 26:1 for mutant enzyme N169A, 30fold lower activity than wild-type enzyme. Expression of the N169A in Saccharomyces cerevisiae during methyl methanesulfonate exposure results in greater sensitivity, greater mutation induction following exposure to methyl methanesulfonate and more strand breaks in vivo
N169D
-
ratio of 3-methyladenine/7-methylguanine is 29:1 for wild-type enzyme, 100fold lower production of 3-methyladeine and no production of 7-methylguanine is detected with mutant enzyme N169D. When expressed in Saccharomyces cerevisiae, the N169D variant provides better protection against methyl methanesulfonate toxicity than wild-type enzyme. Fewer strand breaks in vivo are seen in the presence of the N169D variant following exposure to methyl methanesulfonate
N169S
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ratio of 3-methyladenine/7-methylguanine is 29:1 for wild-type enzyme and 24:1 for mutant enzyme N169S, 30fold lower activity than wild-type enzyme. Expression of the N169S in Saccharomyces cerevisiae during methyl methanesulfonate exposure results in greater sensitivity, greater mutation induction following exposure to methyl methanesulfonate and more strand breaks in vivo
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
50
-
the purified full-length MPG is stable at high temperature, at 50 °C 30 min of incubation inactivate the protein by 30%
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
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overexpression of MPG can result in increased kill of tumor cells using lower doses of harmful alkylating agents such as temozolomide and cross-linking agents such as cisplatin, use of lower doses of chemotherapeutic agents, which will decrease the emergence of drug-resistant tumor cells and decrease the need fro stem-cell support, leading to an increased patient response and a better quality of life for the patient
medicine
-
MPG overexpression is paradoxically associated with increased suspectibility to DNA damage, up-regulation of this gene may suggest a functional role in breast carcinogenesis, animal models using transgenic mice overexpressing the enzyme are being developed to determine the in vivo role of MPG in breast carcinogenesis
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Cerda, S.R.; Turk, P.W.; Thor, A.D.; Weitzman, S.A.
Altered expression of the DNA repair protein, N-methylpurine-DNA glycosylase (MPG) in breast cancer
FEBS Lett.
431
12-18
1998
Homo sapiens
Je, K.H.; Son, J.K.; O'Connor, T.R.; Lee, C.S.
Hepsulfam induced DNA adducts and its excision repair by bacterial and mammalian 3-methyladenine DNA glycosylases
Mol. Cells
8
691-697
1998
Escherichia coli, Homo sapiens, Rattus norvegicus
Wyatt, M.D.; Allan, J.M.; Lau, A.Y.; Ellenberger, T.E.; Samson, L.D.
3-Methyladenine DNA glycosylases: structure, function, and biological importance
Bioessays
21
668-676
1999
Arabidopsis thaliana, Saccharomyces cerevisiae, Escherichia coli, Homo sapiens, Mus musculus, Rattus norvegicus, Schizosaccharomyces pombe
Roy, R.; Biswas, T.; Lee, J.C.; Mitra, S.
Mutation of a unique aspartate residue abolishes the catalytic activity but not substrate binding of the mouse N-methylpurine-DNA glycosylase (MPG)
J. Biol. Chem.
275
4278-4282
2000
Homo sapiens, Mus musculus
Saparbaev, M.; Langouet, S.; Privezentzev, C.V.; Guengerich, F.P.; Cai, H.; Elder, R.H.; Laval, J.
1,N(2)-ethenoguanine, a mutagenic DNA adduct, is a primary substrate of Escherichia coli mismatch-specific uracil-DNA glycosylase and human alkylpurine-DNA-N-glycosylase
J. Biol. Chem.
277
26987-26993
2002
Homo sapiens
Fishel, M.L.; Seo, Y.R.; Smith, M.L.; Kelley, M.R.
Imbalancing the DNA base excision repair pathway in the mitochondria; targeting and overexpressing N-methylpurine DNA glycosylase in mitochondria leads to enhanced cell killing
Cancer Res.
63
608-615
2003
Homo sapiens
Wozniak, K.; Blasiak, J.
Nickel impairs the repair of UV- and MNNG-damaged DNA
Cell. Mol. Biol. Lett.
9
83-94
2004
Homo sapiens
Connor, E.E.; Wilson, J.J.; Wyatt, M.D.
Effects of substrate specificity on initiating the base excision repair of N-methylpurines by variant human 3-methyladenine DNA glycosylases
Chem. Res. Toxicol.
18
87-94
2005
Homo sapiens
Wang, P.; Guliaev, A.B.; Hang, B.
Metal inhibition of human N-methylpurine-DNA glycosylase activity in base excision repair
Toxicol. Lett.
166
237-247
2006
Homo sapiens (P29372), Homo sapiens
Adhikari, S.; Manthena, P.V.; Uren, A.; Roy, R.
Expression, purification and characterization of codon-optimized human N-methylpurine-DNA glycosylase from Escherichia coli
Protein Expr. Purif.
58
257-262
2008
Homo sapiens
Admiraal, S.J.; O'Brien, P.J.
Base excision repair enzymes protect abasic sites in duplex DNA from interstrand cross-links
Biochemistry
54
1849-1857
2015
Escherichia coli, Homo sapiens (P29372), Homo sapiens
Lenz, S.A.P.; Wetmore, S.D.
Evaluating the substrate selectivity of alkyladenine DNA glycosylase the synergistic interplay of active site flexibility and water reorganization
Biochemistry
55
798-808
2016
Homo sapiens (P29372), Homo sapiens
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