Molecules that modulate Apaf‐1 activity

Abstract

Programmed cell death, apoptosis, is a highly regulated cellular pathway, responsible for the elimination of cells in the organism that are no longer needed or extensively damaged. Defects in the regulation of apoptosis could be at the molecular basis of different diseases, either when it is insufficient or excessive. The formation of the macromolecular complex, apoptosome, is a key event in this pathway, which has also been defined as the intrinsic apoptosis pathway. The apoptosome is a holoenzyme multiprotein complex formed by cytochrome c-activated apoptotic protease-activating factor (Apaf-1), dATP, and procaspase-9. Recent studies have produced a wealth of information about the regulation and functions of Apaf-1, but additional studies aimed at elucidating its role as a signaling device at the crosstalk between different signaling pathways are needed to take advantage for the development of modulators of apoptosis pathways and possible therapeutic applications.

Polypeptide Modulators of Caspase Recruitment Domain (CARD)-CARD-mediated Protein-Protein Interactions

“…Recombinant WD40 repeat-depleted Apaf-1 (Apaf-1 1-591) and recombinant PC9 were produced to set up the apoptosome in vitro reconstitution assay (29). Apaf-1 1-591 is able to promote the processing and activation of PC9 as followed by the release of the fluorophore afc from caspase-9-specific peptide substrate Ac-LEHD-afc (37). We tested the ability of the recombinant CARDs to inhibit the Apaf-1 1-591-mediated PC9 activation.…”

“…The isolated recombinant Apaf-1 CARD has been reported to be able to activate PC9 (37,38). PC9 was preincubated with the different CARDs at increasing concentrations.…”

Chemical Modulation of Peptoids: Synthesis and Conformational Studies on Partially Constrained Derivatives

“…In this context, programmed cell-death mechanisms (apoptosis) constitute an example of the pivotal interest in controlling different pathologies. [19] We previously reported that a medium-throughput screening of a positional-scanning combinatorial library of N-alkylglycine trimers [20] allowed the identification of peptoid 1 a (Scheme 1) as an inhibitor of the apoptosomedependent activation of procaspase-9. [21] In this context, we also identified peptoids as pharmacological inhibitors of noncanonical polyubiquitylation; these compounds compete with ubiquitin E2 variant (UEV) for its interaction with UBC13 and inhibit its enzymatic activity.…”

Bisdemethoxycurcumin attenuates gastric adenocarcinoma growth by inducing mitochondrial dysfunction

“…Cyt c is an essential component of the electron transport chain, capable of undergoing oxidation and reduction, which transfers electrons between Complexes III (Coenzyme Q-Cyt c reductase) and IV (Cyt c oxidase), indicating its significance in cancers (20). Cyt c is also involved in the initiation of apoptosis, by binding to Apaf-1 (21). This study revealed increased levels of Cyt c and caspase-3 following treatment with BDMC, compared with the control groups.…”