The Bioinorganic Chemistry of Apoptosis: Potential Inhibitory Zinc Binding Sites in Caspase‐3

Abstract

Zn 2+ inhibits the action of several of the caspases and thus may act as a regulator of apoptosis. Reversal of this inhibition is one possible approach for the development of apoptosis-based therapies. Few studies describe the molecular details of the Zn 2+ -caspase interaction, the understanding of which is essential for the success of any therapeutic strategies. Enzyme kinetics and biophysical studies have shown that the inhibition is of mixed type with prominent (ca. 60 % of inhibition) uncompetitive characteristics and an IC 50 of 0.8 mm under the conditions used. Fluorescence-based techniques confirmed that, during inhibition in the sub-micromolar range, substrate binding remains unaffected. A new zinc binding site composed of the catalytic histidine and a nearby methionine residue, rather than the catalytic histidine and cysteine dyad, is proposed based on the experimental observations. DFT models were used to demonstrate that the proposed site could be the preferred inhibitory zinc binding site.

Development of nsP2 protease based cell free high throughput screening assay for evaluation of inhibitors against emerging Chikungunya virus

“…Similar zinc coordination sites are observed in the crystal structures of caspase-3 and mammalian NOS regulator dimethylarginine dimethylaminohydrolase. In caspase-3, the residues Cys163 and His121 along with two water molecules stabilize the Zn ion in the active site 36 . In the structure of the mammalian NOS regulator dimethylarginine dimethylaminohydrolase, the Cys273 and His172 along with two water molecules stabilize the Zn ion in the active site with Asp78 residue showing coordination with water molecules 37 .…”

What is the protective effect of metformin on rat ovary against ischemia‐reperfusion injury?

“…Caspase‐3 has a role in the apoptotic cascade, and it is mostly used to measure cell apoptosis . In this study, we evaluated the tissue caspase‐3 activity in the study groups, and we observed the highest levels in the torsion/detorsion + saline group (group 3).…”

“…Caspase-3 has a role in the apoptotic cascade, and it is mostly used to measure cell apoptosis. 42 In this study, we evaluated the tissue caspase-3 activity in the study groups, and we observed the highest levels in the torsion/detorsion + saline group (group 3). High-dose metformin administration after IRI enhanced the tissue caspase-3 activity, but we could not demonstrate the same effect for low-dose metformin administration.…”

Influence of Intracellular Zinc on Cultures of Rat Cardiac Neural Crest Cells

“…As reported by others (Chimienti et al, 2001;Corniola et al, 2008;Bozym et al, 2010;Pang et al, 2012Pang et al, , 2013Strand et al, 2013), cleaved capase-3 (active caspase) was increased significantly in TPEN-treated cNCC. Zn is an endogenous inhibitor of CC3; removal of Zn from procaspase inhibitory binding sites results in the auto-proteolytic cleavage transformation of the zymogen into an active effector capase3 (Peterson et al, 2009;Daniel et al, 2014). This inhibition requires the maintenance of relatively high intracellular (nM) Zn ion concentrations (Maret et al, 1999;Maret, 2011).…”