Inhibitor of apoptosis

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Apoptosis, or programmed cell death, is a highly regulated process used by many multi cellular organisms. Like any regulated process, apoptosis is subject to either activation or inhibition by a variety of chemical factors. Apoptosis can be triggered through two main pathways; extrinsic and intrinsic. The extrinsic pathway mostly involves extracellular signals triggering intracellular apoptosis mechanisms by binding to and sending signals from the outside of the cell. Intrinsic pathways involved internal cell signaling primarily through the mitochondria.[1] Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can oftentimes lead to cancer or other effects for the cell. Many of these inhibitors act to block caspases, a family of cysteine proteases that play an integral role in apoptosis. Some of these inhibitors include the Bcl-2 family, viral inhibitor crmA, and IAP's.


Bcl-2 is an oncogene that is part of the Bcl-2 family of proteins that can either inhibit or promote apoptosis. The Bcl-2 family is characterized by the Bcl-2 homologous domains BH1, BH2, BH3, and BH4, the combinations of which determine its role in the apoptosis process. Members of the family that inhibit apoptosis include Bcl-2 itself, Bcl-XL, and Bcl-w, which possess all four of the domains.[2] Studies have shown that the Bcl-2 oncogene may inhibit apoptosis in two ways; either by directly controlling the activation of caspases, or by disrupting the channels that allow proapoptotic factors from leaving the mitochondria. Regarding the activation a caspases, there exists a gene called ced-9 in C. elegans that protects against cell death that is a part of the Bcl-2 family. ced-9 encodes for a protein that is structurally similar to Bcl-2, that has been shown to function quite similarly in inhibiting apoptosis. In C. elegans, the ced-9 protein binds to another protein ced-4, a homolog of APAF-1 in humans, and prevents it from activating caspase ced-3, which is necessary for killing of the cell. [1]. In humans APAF-1 actually doesn't interact with Bcl-2; rather is activated by cytochrome c, the release of which from the mitochondria is regulated by Bcl-2. BAX and BAK are multidomain proapoptoic members of the Bcl-2 family that lie in the cytosol and the mitochondria, respectively. After several stimuli leading to cell death are activated, BAX also moves to the mitochondria where it carries out its functions there. Bcl-2 and Bcl-xl have been found to sequester BH3 domain molecules in the mitochondria, which prevents the activation of BAX and BAK. [2] (look up more)


crmA, or cytokine response modifier A, is a cowpox serpin that inhibits caspases 1, 6 and 8, forming complexes with these caspases that renders them unable to perform their apoptotic functions. [3] Cowpox is a orthopox virus that increases their chances of survival and infection by inhibition of specific caspases and preventing inflammatory responses and apoptosis. [4]. By inhibiting caspase 1, also known as interleukin 1Beta converting enzyme (ICE)crmA prevents cytokines interleukin 1B from being formed, preventing an inflammatory response. Caspase 8 initiates apoptosis by activating "executioner" caspases, numbered 3, 6, and 7, and inhibiting that crmA prevents the other caspases from ever being activated. Although free floating crmA is relatively unstable, it becomes incredibly stable after binding to caspase 1, forming an irreversible stable complex. [5] Serpins generally inhibit serine proteases by a suicide substrate inhibition mechanism, in which upon binding to the protein it is to inhibit, serine undergoes a drastic change in structure that is no longer reversible. A reactive center loop is bound to the central beta loop of the serine, trapping the enzyme in a state where it is no longer able to perform its catalytic functions. Studies have shown that an analogous method is used by crmA to inhibit the cysteine protease caspases. [6]

IAP inhibitors[edit]

The Inhibitors of apoptosis proteins (IAP) are a family of functionally and structurally related proteins that serve as endogenous inhibitors of programmed cell death (apoptosis). A common feature of all IAPs is the presence of a BIR (Baculovirus IAP Repeat, a ~70 amino acid domain) in one to three copies. The human IAP family consists of 8 members, and IAP homologs have been identified in numerous organisms.

The first members of the IAPs identified were from the baculovirus IAPs, Cp-IAP and Op-IAP, which bind to and inhibit caspases as a mechanism that contributes to its efficient infection and replication cycle in the host. Later, five more human IAPs were discovered which included XIAP, c-IAPl, C-IAP2, NAIP, Livin and Survivin.

The best characterized IAP is XIAP, which binds caspase-9, caspase-3 and caspase-7, thereby inhibiting their activation and preventing apoptosis. Also cIAP1 and cIAP2 have been shown to bind caspases, although how the IAPs inhibit apoptosis mechanistically at the molecular level is not completely understood.

Activity of XIAP is blocked by binding to DIABLO (Smac) and HTRA2 (Omi) proteins released from mitochondria after pro-apoptic stimuli.[3] Since the mid 2000s, significant progress has been made into the development of small molecule mimics of the endogenous IAP ligand Smac. One recent example published in 2013 describes the synthesis and testing of peptidomimetics whose structure is based on the AVPI tetrapeptide IAP binding motif present in the N-terminus of mature Smac. These peptidomimetic compounds were specifically noted for their exceptionally high level of binding to Livin, one of the important IAP family members yet to receive much attention from a drug discovery perspective.[4]

See also[edit]


  1. ^ Schwerk, Christian; Shulze-Osthoff, Klaus (1 July 2005). "Regulation of Apoptosis by Alternative Pre-mRNA Splicing". Molecular Cell. doi:10.1016/j.molcel.2005.05.026. PMID 15989960. 
  2. ^ Mayer, Oberbauer, Bernd, Rainer (1 June 2003). "Mitochondrial Regulation of Apoptosis". Physiology. doi:10.1152/nips.01433.2002. 
  3. ^ {{Takahashi, R, Deveraux, Q, Tamm, I, Welsh, K, Assa -Munt, N, Salvesen, GS and Reed, JC (1998). "A single BIR domain of XIAP sufficient for inhibiting caspases." J Biol Chem 273 (14): 7787-90. }}
  4. ^ Vamos, Mitchell; Welsh, Kate; Finlay, Darren; Lee, Pooi San; Mace, Peter; Snipas, Scott; Gonzalez, Monica; Ganji, Santhi; Ardecky, Robert; Riedl, Stefan; Salvesen, Guy; Vuori, Kristiina; Reed, John; Cosford, Nicholas (2013). "Expedient Synthesis of Highly Potent Antagonists of Inhibitor of Apoptosis Proteins (IAPs) with Unique Selectivity for ML-IAP". ACS Chemical Biology 8: 725–732. doi:10.1021/cb3005512. PMID 23323685. 

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