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Literature summary for 4.2.99.18 extracted from

  • Tell, G.; Quadrifoglio, F.; Tiribelli, C.; Kelley, M.R.
    The Many Functions of APE1/Ref-1: Not Only a DNA Repair Enzyme (2008), Antioxid. Redox Signal., 11, 601-619.
    View publication on PubMedView publication on EuropePMC

Activating Compound

Activating Compound Comment Organism Structure
cockayne syndrome B protein cockayne syndrome B protein potentiates the APE1 activity on fully paired AP-DNA but much more on bubble AP-DNA, suggesting a role for this protein in the transcription-repair pathway Homo sapiens
additional information APE1 functional activation is a consequence of different stimuli (UV light, hypoxia, ischemia/reperfusion, hypxic-ischemic insult, Helicobacter pylori infection, reactive oxygen species, atherosclerotic plaque, TSH, CD40 triggering, P2Y triggering, cysteamine-induced duodenal ulceration, Pb asbestos, intracellular Ca2+) that generate both physiological and toxic oxidative stress conditions or increase the intracellular cAMP levels leading to different outcomes Homo sapiens
additional information expression is altered in several metabolic and proliferative disorders such as in tumors and aging Homo sapiens
additional information functional triggering of membrane-bound receptors (such as those for thyrotropin, CD40L, ATP, interleukin-2) can lead to APE1 functional activation through intracellular generation of sublethal doses of reactive oxygen species Homo sapiens

Application

Application Comment Organism
drug development strategies to modulate the proteolytic removal of the APE1 n-terminus will constitute a possible good candidate target for future drug development Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
3-[5-(2,3-dimethoxy-6-methyl-1,4-benzoquinoyl)]-2-nonyl-2-propionic acid E3330 specifically blocking the APE1 redox but not DNA activity, an equilibrium constant (KD) of 1.6 nM is obtained for the binding of E3330 to APE1. E3330 is also shown to block the ability of APE1 to reduce NF-kappaB, thus interfering with the redox activity of APE1 Homo sapiens
RPA proteins RPA proteins are able to suppress the APE1 endonuclease activity in ssDNA of a replicative fork but not in a transcription bubble or in dsDNA Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
cytoplasm cytoplasmic localization of APE1in fibroblasts, spermatocytes, thyrocytes, lymphocytes, hepatocytes, and hippocampal cells is associated with high metabolic or proliferative rates and may be related to a cell cycle-dependent expression Homo sapiens 5737
-
mitochondrion APE1 protein is also localized within mitochondria in different cell types, mitochondrial localization of APE1 is associated to a potential role in DNA repair of oxidized bases in the mitochondrial genome Homo sapiens 5739
-
additional information expression and subcellular localization are altered in several metabolic and proliferative disorders such as in tumors and aging Homo sapiens
-
-
nucleus APE1 subcellular distribution, in different mammalian cell types, is mainly nuclear and is critical in controlling cellular proliferative rate Homo sapiens 5634
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Molecular Weight [Da]

Molecular Weight [Da] Molecular Weight Maximum [Da] Comment Organism
37000
-
canonical APE1 protein Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
AP-DNA Homo sapiens Base excision repair pathway, enzyme cleaves the 5'-phosphodiester bond, generating 3'-OH and 5'-dRP termini fragments of DNA
-
?
additional information Homo sapiens APE1 has been identified as a protein capable of nuclear redox activity, inducing the DNA binding activity of several transcription factors, such as activator protein-1, nuclear factor-kappaB, Myb, polyoma virus enhancer-binding protein-2, HLF, nuclear factor-Y, early growth response protein-1, hypoxia inducible factor-1alpha, ATF/CREB family, p53, and Pax proteins. In each case, this effect is accomplished by maintaining the cysteine residues of the transcription factors in the reduced state. ?
-
?
additional information Homo sapiens APE1 is directly responsible for the control of the intracellular ROS levels through its inhibitory effect on Rac1, the regulatory subunit of a membrane nonphagocytic NADPH oxidase system. ?
-
?
additional information Homo sapiens multifunctional protein possessing both DNA repair and transcriptional regulatory activities, has a pleiotropic role in controlling cellular response to oxidative stress. APE1 is the main apurinic/apyrimidinic endonuclease in eukaryotic cells, playing a central role in the DNA base excision repair pathway of all DNA lesions (uracil, alkylated and oxidized, and abasic sites), including single-strand breaks, and has also co-transcriptional activity by modulating genes expression directly regulated by either ubiquitous and tissue specific transcription factors. It controls the intracellular redox state by inhibiting the reactive oxygen species production ?
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens P27695 human sequence
-

Posttranslational Modification

Posttranslational Modification Comment Organism
acetylation Lys6 and Lys7 residues Homo sapiens
phosphoprotein several different phosphorylation sites are scattered throughout the molecule, these potential phosphorylation sites include consensus sequences for casein kinase I and II, for protein kinase C, and for glycogen synthase kinase 3 Homo sapiens
proteolytic modification Proteolysis occurring at residue Lys31, this post-translational regulation of APE1 protein is responsible for enhanced cell death mediated by granzyme A and granzyme K. Truncated APE1 looses its AP-endonuclease activity and acquire a nonspecific DNAse function. Homo sapiens
S-nitrosation 2 of the 7 Cys residues (Cys93 and Cys310) of APE1 undergoes S-nitrosation in response to nitric oxide stimulation, leading to nucleus to cytoplasm relocalization of the protein in a CRM1-independent process, possibly as a consequence of demasking a putative nuclear export signal Homo sapiens
sumoylation high probability, putative sumoylation site, which contains a canonical sumoylation K-X-D/E motif, addition of a small ubiquitin-like modifier (SUMO) molecule to the target protein accounts for an increase of 12 kDa of the apparent molecular mass of the target protein. The effects of posttranslational modification by SUMO to compete for target lysines enhance or inhibit interactions with other proteins (or other binding partners such as DNA) or induce conformational changes. Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
central nervous system APE1 is highly expressed in selected regions of the central nervous system Homo sapiens
-
cerebellar cortex increased nuclear expression of APE1 in neuronal and glial cells in both familial and sporadic Alzheimer Homo sapiens
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hippocampus a reduction in APE1 expression, followed by an increase in the apoptotic rate, occurs in the hippocampus after a hypoxic-ischemic injury, patients with Alzheimer show an increased expression of APE1 levels in senile plaques and plaque-like structures Homo sapiens
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spinal cord reduction in APE1 expression after ischemia Homo sapiens
-

Specific Activity [micromol/min/mg]

Specific Activity Minimum [µmol/min/mg] Specific Activity Maximum [µmol/min/mg] Comment Organism
additional information
-
The necessity of APE1 for cellular survival and its frequent overexpression in tumor cells strongly suggest a fundamental role of this protein in preventing cell death and in controlling cellular proliferation. Homo sapiens
additional information
-
The regulatory functions of the different APE1 activities can be fine-tuned and implemented via three different mechanisms: increase in APE1 level after transcriptional activation, relocalization of APE1 from the cytoplasm to the nucleus, and modulation of the posttranslational modifications of APE1, such as acetylation and phosphorylation. Homo sapiens

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
AP-DNA Base excision repair pathway, enzyme cleaves the 5'-phosphodiester bond, generating 3'-OH and 5'-dRP termini Homo sapiens fragments of DNA
-
?
additional information APE1 has been identified as a protein capable of nuclear redox activity, inducing the DNA binding activity of several transcription factors, such as activator protein-1, nuclear factor-kappaB, Myb, polyoma virus enhancer-binding protein-2, HLF, nuclear factor-Y, early growth response protein-1, hypoxia inducible factor-1alpha, ATF/CREB family, p53, and Pax proteins. In each case, this effect is accomplished by maintaining the cysteine residues of the transcription factors in the reduced state. Homo sapiens ?
-
?
additional information APE1 is directly responsible for the control of the intracellular ROS levels through its inhibitory effect on Rac1, the regulatory subunit of a membrane nonphagocytic NADPH oxidase system. Homo sapiens ?
-
?
additional information multifunctional protein possessing both DNA repair and transcriptional regulatory activities, has a pleiotropic role in controlling cellular response to oxidative stress. APE1 is the main apurinic/apyrimidinic endonuclease in eukaryotic cells, playing a central role in the DNA base excision repair pathway of all DNA lesions (uracil, alkylated and oxidized, and abasic sites), including single-strand breaks, and has also co-transcriptional activity by modulating genes expression directly regulated by either ubiquitous and tissue specific transcription factors. It controls the intracellular redox state by inhibiting the reactive oxygen species production Homo sapiens ?
-
?

Subunits

Subunits Comment Organism
More These two biological activities are located in two functionally distinct domains. The n-terminus, containing the nuclear localization signal region, is principally devoted to the redox activity, through Cys65, while the c-terminus exerts the enzymatic activity on the abasic sites of DNA. Homo sapiens

Synonyms

Synonyms Comment Organism
AP endonuclease
-
Homo sapiens
APE1
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Homo sapiens
APE1/Ref-1
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Homo sapiens
apurinic/apyrimidinic endonuclease
-
Homo sapiens
HAP1
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Homo sapiens