Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.30.2 (endonuclease)
 18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have isolated and characterized several overlapping clones from two human genomic libraries constructed in cosmid and bacteriophage vectors. They span about 80 kbp and include the entire human cytosolic aldehyde dehydrogenase (ALDH1) gene. Restriction endonuclease mapping, Southern blotting with cDNA and specific oligonucleotide probes, and DNA sequencing were performed to analyze the cloned genomic DNA. The ALDH1 gene is about 53 kbp long and is divided into 13 exons which encode 501 amino acid residues. Primer extension results defined the transcription initiation site to 53 bp upstream from the A of the initiation codon ATG. The promoter region of the gene contains an ATA box and a CCAAT box, which are located 32 and 74 bp upstream, respectively, from the transcription initiation site. The possible functional domains of the protein encoded by exons are discussed. A similar intron-exon organization between the genes of cytosolic ALDH1 and its mitochondrial ALDH2 isozyme in which both enzymes are encoded by 13 exons and 9 of the 12 introns interrupt the coding sequence at homologous positions was observed. This is consistent with the model that the two isozyme genes evolved after the duplication of a common ancestor gene.
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PMID:Genomic structure of the human cytosolic aldehyde dehydrogenase gene. 259 67

Although chemotherapy-induced peripheral neuropathy (CIPN) affects approximately 5-60% of cancer patients, there are currently no treatments available in part due to the fact that the underlying causes of CIPN are not well understood. One contributing factor in CIPN may be persistence of DNA lesions resulting from treatment with platinum-based agents such as cisplatin. In support of this hypothesis, overexpression of the base excision repair (BER) enzyme, apurinic/apyrimidinic endonuclease 1 (APE1), reduces DNA damage and protects cultured sensory neurons treated with cisplatin. Here, we address stimulation of APE1's endonuclease through a small molecule, nicorandil, as a means of mimicking the beneficial effects observed for overexpression of APE1. Nicorandil, was identified through high-throughput screening of small molecule libraries and found to stimulate APE1 endonuclease activity by increasing catalytic efficiency approximately 2-fold. This stimulation is primarily due to an increase in kcat. To prevent metabolism of nicorandil, an approved drug in Europe for the treatment of angina, cultured sensory neurons were pretreated with nicorandil and daidzin, an aldehyde dehydrogenase 2 inhibitor, resulting in decreased DNA damage but not altered transmitter release by cisplatin. This finding suggests that activation of APE1 by nicorandil in cisplatin-treated cultured sensory neurons does not imbalance the BER pathway in contrast to overexpression of the kinetically faster R177A APE1. Taken together, our results suggest that APE1 activators can be used to reduce DNA damage induced by cisplatin in cultured sensory neurons, although further studies will be required to fully assess their protective effects.
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PMID:Small molecule activation of apurinic/apyrimidinic endonuclease 1 reduces DNA damage induced by cisplatin in cultured sensory neurons. 2707 77