Regulatory Status Legend

Description

Caspases are cysteine proteases that play a central role in apoptosis. The caspase family was discovered by searching human cDNA libraries for sequences homologous to ced-3, a C. elegans death gene that is required for normal apoptosis during development. The first mammalian homolog of ced-3 to be identified was ICE (interleukin-1β-converting enzyme). Subsequent numerous human ced-3 homologues were rapidly identified which led to multiple names for many of the molecules. To achieve consistency, "caspase" was adopted as a root name for all family members. The name was selected based on two catalytic properties of these enzymes, the "c" reflects a cysteine protease mechanism and "aspase" refers to their unique ability to cleave after aspartic acid. There are at least 10 members, caspase-1 (ICE), caspase-2 (ICH-1), caspase-3 (CPP32, Yama, apopain), caspase-4 (TX, ICH-2, ICErel-II), caspase-5 (ICErel-III), caspase-6 (Mch2), caspase-7 (Mch3, ICE-LAP3, CMH-1), caspase-8 (MACH, FLICE, Mch5), caspase-9 (ICELAP6, Mch6), and caspase-10 (Mch4). Each caspase is synthesized as an inactive proenzyme that is processed by cleavage at asparte residues by another protease or by self-proteolysis. The processed forms consist of large (17-22 kDa) and small (10-12 kDa) subunits which associate to form an active enzyme. The activation of some of these caspases has been shown to occur during apoptosis.

Caspase-3, -6, -7, and -8 have been shown to play a role in apoptosis induced by the death receptors Fas and tumor necrosis factor receptor type 1 (TNFR1). One of their substrates is poly (ADP ribose) polymerase (PARP). PARP is an enzyme that is involved in DNA repair and genomic maintenance. Activated caspases 3, 6, 7 and 8 can all cleave PARP from its 116 kDa form to an 85 kDa residual fragment. The cleavage separates the DNA-binding domain in the N-terminus of PARP from its C-terminus catalytic domain, and results in loss of normal PARP function. The cleavage site in PARP is C-terminal to Asp-216.3 The upstream sequence of the PARP cleavage site, DEVD (Asp-Glu-Val-Asp), is utilized as a basis for highly specific caspase-3 substrates such as Ac(N-acetyl)-DEVD-AFC (7-amino-4-trifluoromethylcourmarin) and Ac(N-acetyl)-DEVD-AMC (7-amino-4-methylcoumarin) as well as the caspase-3 aldehyde inhibitor Ac-DEVD-CHO.