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Murburn concept explains the acutely lethal effect of cyanide

View ORCID ProfileKelath Murali Manoj, Surjith Ramasamy, Abhinav Parashar, Vidhu Soman, Kannan Pakshirajan
doi: https://doi.org/10.1101/555888
Kelath Murali Manoj
*1Satyamjayatu: The Science & Ethics Foundation Snehatheeram, Kulappully, Shoranur-2 (PO), Kerala, India-679122.
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  • For correspondence: satyamjayatu@yahoo.com
Surjith Ramasamy
2Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India-781039
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Abhinav Parashar
3Department of Biotechnology, Vignan’s Foundation for Science, Technology & Research, Vadlamudi, Guntur, India-522213
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Vidhu Soman
4Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India-110016
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Kannan Pakshirajan
2Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India-781039
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Abstract

Cyanide (CN) toxicity is traditionally understood to result from its binding of hemeFe centers, thereby disrupting mitochondrial cytochrome oxidase function and oxygen utilization by other globin proteins. Recently, a diffusible reactive oxygen species (DROS) mediated reaction mechanism called murburn concept was proposed to explain mitochondrial ATP-synthesis and heat generation. Per this purview, it was theorized that CN ion-radical equilibrium dissipates the catalytically vital DROS into futile cycles, producing water. In the current study, a comparative quantitative assessment of the above two explanations is made for: (i) lethal dosage or concentrations of CN, (ii) thermodynamics and kinetics of the binding/reaction, and (iii) correlation of CN with the binding data and reaction chemistry of H2S/CO. The quantitative findings suggest that the hemeFe binding-based toxicity explanation is untenable. CN also inhibited the experimental in vitro DROS-mediated coupling of inorganic phosphate with ADP. Further, pH-dependent inhibition profiles of heme enzyme catalyzed oxidation of a phenolic (wherein an -OH group reacts with DROS to form water, quite akin to the murburn model of ATP synthesis) indicated that- (i) multiple competitive reactions in milieu controlled outcomes and (ii) low concentrations of CN cannot disrupt activity via a coordination (binding) of cyanide at the distal hemeFe. Therefore, the μM-level IC50 and the acutely lethal effect of CN on cellular respiration could be explained by the deleterious interaction of CN ion-radical equilibrium with DROS in matrix, disrupting mitochondrial ATP synthesis. This work supports the murburn explanation for cellular respiration.

Footnotes

  • The following changes have been made in the revision- 1. The manuscript (Abstract, Introduction, Results & Discussion, etc. sections) has been updated to include new data/results. 2. Correspondingly, author list has been updated with four more authors. 3. Three new figures have been incorporated. 4. Materials and Methods section has been moved towards the end. 5. Some contents have been moved to the Supplementary Information file appended at the end of the manuscript.

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Posted June 18, 2019.
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Murburn concept explains the acutely lethal effect of cyanide
Kelath Murali Manoj, Surjith Ramasamy, Abhinav Parashar, Vidhu Soman, Kannan Pakshirajan
bioRxiv 555888; doi: https://doi.org/10.1101/555888
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Murburn concept explains the acutely lethal effect of cyanide
Kelath Murali Manoj, Surjith Ramasamy, Abhinav Parashar, Vidhu Soman, Kannan Pakshirajan
bioRxiv 555888; doi: https://doi.org/10.1101/555888

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