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)

Aurintricarboxylic acid (ATA) is an endonuclease inhibitor which has been shown to block apoptotic cell death. We have now demonstrated that ATA is also an inhibitor of the Ca(2+)-activated neutral protease (calpain), a class of cytosolic enzyme that may also be activated during apoptosis. The two major calpain isoforms (mu- and m-calpain) were both inhibited by ATA with IC50's of 22 microM and 10 microM, respectively. The autolysis of purified mu-calpain was prevented by ATA in a concentration-dependent manner. Using casein zymography, it was found that the inhibition of mu-calpain by ATA was reversible. Finally, in a fetal rat cerebrocortical culture model of excitotoxicity, pre- and post-treatment of ATA (50 microM) reduced N-methyl-D-aspartate (NMDA)-induced spectrin breakdown and neuronal death, while application of ATA concurrent to NMDA challenge alone had no effect. This pattern of protection could not be explained by simple NMDA receptor antagonism. We thus propose that the neuroprotective effect of ATA could be in part due to its ability to inhibit calpain.
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PMID:Aurintricarboxylic acid is an inhibitor of mu- and m-calpain. 766 33

A dysregulation in the 2',5'-oligoadenylate (2-5A)-dependent RNase L antiviral pathway has been detected in peripheral blood mononuclear cells (PBMC) of chronic fatigue syndrome (CFS) patients, which is characterized by upregulated 2-5A synthetase and RNase L activities, as well as by the presence of a low molecular weight (LMW) 2-5A-binding protein of 37-kDa related to RNase L. This truncated protein has been shown to originate from proteolytic cleavage of the native 83-kDa RNase L by m-calpain and human leukocyte elastase (HLE). We investigated the possible role of 2-5A oligomers in the proteolytic action toward the endonuclease and show that incubation of CFS PBMC extracts with 2-5A trimer and tetramer, but not with the dimer, results in a significant protection of the native 83-kDa RNase L against cleavage by endogenous and purified proteases. Similar results are obtained with a purified recombinant RNase L. An analysis of the size of 2-5A oligomers produced by the catalytic activity of the 2-5A synthetase present in PBMC extracts further shows that samples containing the 37-kDa RNase L preferentially produce 2-5A dimers instead of higher oligomers. Taken together, our results indicate that homodimerization of RNase L by 2-5A oligomers higher than the dimer prevents its cleavage by proteolytic enzymes. The presence of the truncated 37-kDa RNase L in PBMC extracts is therefore likely to result, not only from the abnormal activation of inflammatory proteases, but also from a dysregulation in 2-5A synthetase induction or activation towards the preferential production of 2-5A dimers.
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PMID:2',5'-Oligoadenylate size is critical to protect RNase L against proteolytic cleavage in chronic fatigue syndrome. 1592 78