Acute toxicity of cyanide in aerobic respiration: Theoretical and experimental support for murburn explanation

• Published in: Biomolecular concepts Vol. 11; no. 1; pp. 32 - 56
• Main Authors: Manoj, Kelath Murali, Ramasamy, Surjith, Parashar, Abhinav, Gideon, Daniel Andrew, Soman, Vidhu, Jacob, Vivian David, Pakshirajan, Kannan
• Format: Journal Article
• Language: English
• Published: Berlin De Gruyter 17.03.2020; Walter de Gruyter GmbH
• Subjects: Acute toxicity; Aerobic respiration; ATP-synthesis; Catalase; Chlorine; cyanide-poisoning; cytochrome oxidase; diffusible reactive oxygen species (DROS); Electron transfer; Free energy; Haloperoxidase; Heme proteins; hemoglobin; Hydrogen cyanide; Mitochondria; murburn concept; Oxidation; Oxidative phosphorylation; Phosphorylation; Reactive oxygen species; Superoxide
• ISSN: 1868-5021; 1868-5021; 1868-503X
• DOI: 10.1515/bmc-2020-0004

The inefficiency of cyanide/HCN (CN) binding with heme proteins (under physiological regimes) is demonstrated with an assessment of thermodynamics, kinetics, and inhibition constants. The acute onset of toxicity and CN’s mg/Kg LD (μM lethal concentration) suggests that the classical hemeFe binding-based inhibition rationale is untenable to account for the toxicity of CN. In vitro mechanistic probing of CN-mediated inhibition of hemeFe reductionist systems was explored as a murburn model for mitochondrial oxidative phosphorylation (mOxPhos). The effect of CN in haloperoxidase catalyzed chlorine moiety transfer to small organics was considered as an analogous probe for phosphate group transfer in mOxPhos. Similarly, inclusion of CN in peroxidase-catalase mediated one-electron oxidation of small organics was used to explore electron transfer outcomes in mOxPhos, leading to water formation. The free energy correlations from a Hammett study and IC /Hill slopes analyses and comparison with ligands provide insights into the involvement of diffusible radicals and proton-equilibriums, explaining analogous outcomes in mOxPhos chemistry. Further, we demonstrate that superoxide (diffusible reactive oxygen species, DROS) enables in vitro ATP synthesis from ADP+phosphate, and show that this reaction is inhibited by CN. Therefore, practically instantaneous CN ion-radical interactions with DROS in matrix catalytically disrupt mOxPhos, explaining the acute lethal effect of CN.