Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An overwhelming body of evidence has shown that IL-1 beta is a major mediator of inflammatory disease (Tocci and Schmidt, 1996). The discovery of ICE, a unique processing enzyme involved in the production of active IL-1 beta, has provided a new approach to specifically block the production of this potent cytokine. Consequently, the discovery and development of inhibitors against the enzyme could hold great promise therapeutically. Potent inhibitors of the enzyme would be useful in the treatment of a number of important inflammatory diseases and potentially in the management of leukemia (Arend, 1993b; Estrov and Talpaz, 1996). A number of key questions must be answered before the therapeutic potential of such inhibitors can be realized. The development of a pharmaceutically acceptable cysteine proteinase inhibitor will almost certainly involve new chemical strategies gauged at safely inactivating the enzyme. For such inhibitors, it will be necessary to achieve selectivity for ICE from among the growing number of ICE family members while retaining potency. It will also be important to establish the level of inhibition of IL-1 beta required to achieve therapeutic efficacy. The studies comparing IL-1 beta- and ICE-deficient mice suggest that complete abrogation of IL-1 beta is required to achieve efficacy in models of inflammation. It is not known if this is the case in humans. Understanding the source of the residual IL-1 beta produced in ICE-deficient mice will be important in order to ascertain if a similar mechanism could generate active IL-1 beta in patients receiving if a ICE inhibitor. As for ICE itself, a number of formidable questions remain regarding its regulation and mechanism of activation. Answering these questions experimentally will present a major challenge due to the extremely low levels of enzyme present in cells. Studies on other family members may provide easier access to some of these questions and provide clues that can be applied to ICE. The components of the pathway involved in IL-1 trafficking and secretion are unknown, as are the mechanisms of ICE activation and regulation. Clearly other cellular proteins that have yet to be discovered will be involved in each of these processes, opening up new avenues of research in this field.
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PMID:Structure and function of interleukin-1 beta converting enzyme. 919 77

Huntington disease (HD) is a progressive neurodegenerative disease that initially affects the striatum and leads to changes in behavior and loss of motor coordination. It is caused by an expansion in the polyglutamine repeat at the N terminus of huntingtin (HTT) that leads to aggregation of mutant HTT. The loss of wild-type function, in combination with the toxic gain of function mutation, initiates various cell death pathways. Wild-type and mutant HTT are regulated by different posttranslational modifications that can positively or negatively regulate their function or toxicity. In particular, we have previously shown that caspase cleavage of mutant HTT at amino acid position aspartate 586 (D586) by caspase-6 is critical for the pathogenesis of the disease in an HD mouse model. Herein, we describe the identification of a new caspase cleavage site at position D572 that is mediated by caspase-1. Inhibition of caspase-1 also appeared to decrease proteolysis at D586, likely by blocking the downstream activation of caspase-6 through caspase-1. Inhibition of caspase cleavage at D572 significantly decreased mutant HTT aggregation and significantly increased the turnover of soluble mutant HTT. This suggests that caspase-1 may be a viable target to inhibit caspase cleavage of mutant HTT at both D572 and D586 to promote mutant HTT clearance.-Martin, D. D. O., Schmidt, M. E., Nguyen, Y. T., Lazic, N., Hayden, M. R. Identification of a novel caspase cleavage site in huntingtin that regulates mutant huntingtin clearance.
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PMID:Identification of a novel caspase cleavage site in huntingtin that regulates mutant huntingtin clearance. 3042 59