Target Information
Target General Information | Top | |||||
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Target ID |
T13348
(Former ID: TTDR00967)
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Target Name |
AP endonuclease 1 (APEX1)
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Synonyms |
Redox factor-1; REF1; REF-1; HAP1; DNA-(apurinic or apyrimidinic site) lyase; Apurinic-apyrimidinic endonuclease 1; APX; APEX nuclease; APEX; APEN; APE1; APE-1; APE
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Gene Name |
APEX1
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 2 Target-related Diseases | + | ||||
1 | Retinopathy [ICD-11: 9B71] | |||||
2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
Function |
Multifunctional protein that plays a central role in the cellular response to oxidative stress. The two major activities of APEX1 are DNA repair and redox regulation of transcriptional factors. Functions as a apurinic/apyrimidinic (AP) endodeoxyribonuclease in the DNA base excision repair (BER) pathway of DNA lesions induced by oxidative and alkylating agents. Initiates repair of AP sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone immediately adjacent to the damage, generating a single-strand break with 5'-deoxyribose phosphate and 3'-hydroxyl ends. Does also incise at AP sites in the DNA strand of DNA/RNA hybrids, single-stranded DNA regions of R-loop structures, and single-stranded RNA molecules. Has a 3'-5' exoribonuclease activity on mismatched deoxyribonucleotides at the 3' termini of nicked or gapped DNA molecules during short-patch BER. Possesses a DNA 3' phosphodiesterase activity capable of removing lesions (such as phosphoglycolate) blocking the 3' side of DNA strand breaks. May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation. Acts as a loading factor for POLB onto non-incised AP sites in DNA and stimulates the 5'-terminal deoxyribose 5'-phosphate (dRp) excision activity of POLB. Plays a role in the protection from granzymes-mediated cellular repair leading to cell death. Also involved in the DNA cleavage step of class switch recombination (CSR). On the other hand, APEX1 also exerts reversible nuclear redox activity to regulate DNA binding affinity and transcriptional activity of transcriptional factors by controlling the redox status of their DNA-binding domain, such as the FOS/JUN AP-1 complex after exposure to IR. Involved in calcium-dependent down-regulation of parathyroid hormone (PTH) expression by binding to negative calcium response elements (nCaREs). Together with HNRNPL or the dimer XRCC5/XRCC6, associates with nCaRE, acting as an activator of transcriptional repression. Stimulates the YBX1-mediated MDR1 promoter activity, when acetylated at Lys-6 and Lys-7, leading to drug resistance. Acts also as an endoribonuclease involved in the control of single-stranded RNA metabolism. Plays a role in regulating MYC mRNA turnover by preferentially cleaving in between UA and CA dinucleotides of the MYC coding region determinant (CRD). In association with NMD1, plays a role in the rRNA quality control process during cell cycle progression. Associates, together with YBX1, on the MDR1 promoter. Together with NPM1, associates with rRNA. Binds DNA and RNA.
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BioChemical Class |
Alpha-carbonic anhydrase
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UniProt ID | ||||||
EC Number |
EC 3.1.-.-
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Sequence |
MPKRGKKGAVAEDGDELRTEPEAKKSKTAAKKNDKEAAGEGPALYEDPPDQKTSPSGKPA
TLKICSWNVDGLRAWIKKKGLDWVKEEAPDILCLQETKCSENKLPAELQELPGLSHQYWS APSDKEGYSGVGLLSRQCPLKVSYGIGDEEHDQEGRVIVAEFDSFVLVTAYVPNAGRGLV RLEYRQRWDEAFRKFLKGLASRKPLVLCGDLNVAHEEIDLRNPKGNKKNAGFTPQERQGF GELLQAVPLADSFRHLYPNTPYAYTFWTYMMNARSKNVGWRLDYFLLSHSLLPALCDSKI RSKALGSDHCPITLYLAL Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T39M81 |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
1 | APX3330 | Drug Info | Phase 2 | Diabetic retinopathy | [2] | |
2 | APX-3330 | Drug Info | Phase 1 | Solid tumour/cancer | [3] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 5 Inhibitor drugs | + | ||||
1 | APX3330 | Drug Info | [4] | |||
2 | APX-3330 | Drug Info | [1] | |||
3 | 1,3-bis(1,3-benzothiazol-2-ylthio)acetone | Drug Info | [5] | |||
4 | 3-benzofuran-2-yl-2-benzothiazol-2-yl-3-oxo-propanenitrile | Drug Info | [5] | |||
5 | 5-fluoro-1H-indole-2-carboxylic acid | Drug Info | [5] |
Chemical Structure based Activity Landscape of Target | Top |
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Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-interacting Proteins |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
1 | Base excision repair | |||||
PID Pathway | [+] 1 PID Pathways | + | ||||
1 | HIF-2-alpha transcription factor network | |||||
WikiPathways | [+] 3 WikiPathways | + | ||||
1 | Spinal Cord Injury | |||||
2 | TSH signaling pathway | |||||
3 | Base Excision Repair |
References | Top | |||||
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REF 1 | Inhibition of APE1/Ref-1 redox activity with APX3330 blocks retinal angiogenesis in vitro and in vivo. Vision Res. 2011 Jan;51(1):93-100. | |||||
REF 2 | ClinicalTrials.gov (NCT04692688) Study of the Safety and Efficacy of APX3330 in Diabetic Retinopathy (ZETA-1). U.S. National Institutes of Health. | |||||
REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 4 | Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic. NPJ Precis Oncol. 2017;1:19. | |||||
REF 5 | Development and evaluation of human AP endonuclease inhibitors in melanoma and glioma cell lines. Br J Cancer. 2011 Feb 15;104(4):653-63. |
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