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

Abstract

<jats:title>Abstract</jats:title><jats:p>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<jats:sub>50</jats:sub> (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<jats:sub>50</jats:sub>/Hill slopes analyses and comparison with ligands <jats:inline-formula><jats:alternatives><jats:tex-math>$\left( {\text{CO}}/{{{{\text{H}}_{2}}\text{S}}/{\text{N}_{3}^{\text{-}}}\;}\; \right)$</jats:tex-math></jats:alternatives></jats:inline-formula> 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.</jats:p>

The murburn precepts for photoreception

“…2. We have traced the historical precedence in literature (16)(17)(18)(19) and also demonstrated the theoretical, experimental and physiological viability of the proposal/fact that DROS (like superoxide) can sponsor non-specific phosphorylations in ambient redox metabolic environments (3,(20)(21)(22)(23)(24). Taking this account in the current context, the murburn model of signal transduction is ratified by the well-known phosphorylation of seven different ser/thr residues on rhodopsin (25,26).…”

In defense of the murburn explanation for aerobic respiration

“…Further, he critiques the protocols adopted and results obtained in our preliminary studies (13) and dismisses them as artifacts. The discerning reader must note that PJS does not cite our subsequent meticulous works with HPLC employing elaborate controls, which reproduced the results of our earlier studies and extended them to ratify the proposals with probes for cyanide inhibition (11). This attitude cannot be appreciated or respected.…”

“…oxidative phosphorylation (mOxPhos) (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Biophysical Chemistry has refused me and my collaborators a platform to present our rebuttals and surprisingly, continues to provide umbrella to the mock 'mOxPhos wars', which is ongoing with another off-shoot of the Mitchell-Boyer paradigm.…”

“…There is no effort at PJS's end to see that we had comprehensively debunked the "ETC-driven proton pumps generating a proton motive force (pmf; also seen as a trans-membrane potential or TMP), which drives rotary ATP synthesis (RAS)" or "ETC-driven chemiosmotic rotary ATP synthesis (ETC-CRAS)" paradigm. Our effort was commissioned highlighting the multitudes of limitations of individual components and the impossibility of their coming together as a comprehensive whole 'working machine unit' (2)(3)(4)(5)(7)(8)(9)(10)(11)(12)(13)(14)(15). People are entitled to their beliefs but considering the comprehensive treatment I have offered on the subject with my communications, it would take more than what PJS did for anyone to hold on to the ETC-CRAS view now.…”

“…that we have cited, which confirm ROS-assisted ATP synthesis in mitochondria and chloroplasts. Unfortunately, he chooses not to see such works or the myriads of theoretical and experimental supports from our own and others' papers, which we have cited to bolster the murburn explanation of mOxPhos (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)18). Most importantly, murburn explanation is the only standing rationale for cyanide toxicity towards several cellular physiologies (7,8,(43)(44)(45).…”