1,721,059 research outputs found
Supplementary_Information_for_Dose_Response_Mar_2018_revision_Final - Murburn Concept: A Molecular Explanation for Hormetic and Idiosyncratic Dose Responses
No full textSupplementary_Information_for_Dose_Response_Mar_2018_revision_Final for Murburn Concept: A Molecular Explanation for Hormetic and Idiosyncratic Dose Responses by Abhinav Parashar, Daniel Andrew Gideon, and Kelath Murali Manoj in Dose-Response</p
Oxidation or dehydrogenation of alpha-hydroxy acids in bioenergetic metabolism: A murburn perspective
No full textGlycolate, lactate, malate, hydroxyglutarate and isocitrate are key alpha-hydroxyacyl metabolic intermediates found in the tissues/cells/organelles of diverse life forms. They are respectively oxidized to glyoxylate, pyruvate, oxaloacetate, ketoglutarate and oxalosuccinate in cell bioenergetic metabolism. These molecules form key junction points for divergent pathways of two to six carbon-backboned molecules (of various classes of biomolecules like carbohydrates, amino acids, etc.). The oxido-reduction of the alpha-hydroxyacyl species is traditionally believed to be carried out by reversible (de)hydrogenases, employing nicotinamide cofactors. Herein, I propose that while the reductive pathway can be mediated in a facile manner by the (de)hydrogenases, the oxidative reaction could more efficiently be coupled with murzyme activities, which employ diffusible reactive (oxygen) species (DRS/DROS/ROS). Such a murburn strategy would enable the system to tide over the highly unfavorable energy barriers of the sequential dehydrogenase reaction (~450 kJ/mol, or more!), to give kinetically viable bimolecular reactions catering to cellular needs. Further, such a scheme does not necessitate any ‘intelligent governance’ or ‘smart decision-making’ of/by the pertinent redox enzymes
Diffusible reactive (oxygen) species CANNOT be disconnected from cellular functioning or bioenergetics
No full textThe article- “Systems-level analyses dissociate genetic regulators of reactive oxygen species (ROS) and energy production” by Bennett et al. in PNAS (Jan 11, 2024; https://doi.org/10.1073/pnas.230790412) discusses the context for disconnecting the production of diffusible reactive (oxygen) species or DR(O)S/ROS during mitochondrial ATP-synthesis. Their outlook/pursuit based in ‘Chemiosmotic Rotary ATP Synthesis’ (CRAS) is in dissonance with our group’s published iconoclastic thesis of murburn concept, which proposes DRS as the elixir of life, obligatory in acute cellular PCHEMS, i.e. Powering, Coherence, Homeostasis, Electro-Mechanics, and Sensing/response (i.e. physico-chemical stature). ‘Murburn’ is abstracted from ‘mured burning’, connoting a mild unrestricted redox catalytic scheme (a stochastic electron/moiety-transfer paradigm OR a chaotic interactive equilibrium of molecules, unbound ions and radicals). Primarily, this results from effective charge separation (ECS) at some protein redox centers, concomitantly leading to DRS production. Based on the murburn postulation, >50 articles detailed novel chemico-physical explanations for the catalytic activity of heme-peroxidases/P450s, along with comprehensive models for diverse metabolic/physiological contexts, and these were recently summated in a two-part review (contrasting with the acclaimed/classical models) at an American Institute of Physics portal (1). Pre-empting the ‘problem’ addressed in the above PNAS-article, my group’s publication- “Why do cells need oxygen? Insights from mitochondrial composition and function” in Cell Biology International (2) attests that DRS directly mediates the oxidative phosphorylation “powering reaction”. Via our publications in Journal of Biomolecular Structure and Dynamics (3), we demonstrated that Complex V cannot be a physiological rotary ATP-synthase, but serves a chemostatic function. Our article presenting the thermodynamic/kinetic aspects for murburn model of cellular respiration was given cover-page credits in Progress in Biophysics and Molecular Biology (4). Our papers published in Biochemical and Biophysical Research Communications / Biochimie (5) and Toxicology / Biomolecular Concepts (6) explained the acutely debilitating effects of low doses of cyanide owing to an alteration of DRS-dynamics. Invited reviews on the predictive abilities of murburn model of cellular respiration was published in Archives of Biochemistry & Biophysics (7) and structure-function correlations of membrane-embedded murburn systems was covered in Biochimica et Biophysica Acta-Biomembranes (8). A summative overview of murburn concept’s centrality in electrophysiology, roles in the origin-evolution-sustenance of life and its fundamental stature along with central dogma in cellular function was published in Journal of Cellular Physiology (9). Given that: (i) several reputed journals’ reviewers/editors have deemed murburn model to be a tangible/tenable theory for diverse routine cellular physiology (1-9), and (ii) post the publication of my exhaustive critique of CRAS model in Biochemistry Insights (10), the usage of classical “proton motive force/chemiosmosis” terminology in bioenergetics parlances is evidently declining since 2018 (Figures 6-7; https://journals.mu-varna.bg/index.php/bmr/article/view/9115/8001), a display item is presented herewith to highlight the perception-change regarding mitochondrial bioenergetics. These developments necessitate revisiting Bennett et al.’s interpretation of results and reorientation of research community’s perspectives. We first need to appreciate the Dr. Jekyll face of DRS and thereafter address the contexts of its Mr. Hyde persona. Therefore, it is mandated to probe/understand spatio-temporal DRS-dynamics as a fundamental rationale for both routine physiology and pathological outcomes
Murburn concept: A tangible bioenergetic rationale for the origin, sustenance, termination, and evolution of life
No full textThe deterministic affinity-based sequential electron transport chain (ETC) of donors/acceptors and trans-membrane potential (TMP)-based chemiosmotic rotary ATP synthesis (CRAS) are the acclaimed components/principles of cellular bioenergetics. The recently floated alternative of ‘murburn concept’ advocates that diffusible reactive (oxygen) species (DRS/ROS) catalyze key physiological electron/moiety transfers. Herein, examples of organisms that disclaim the ETC-CRAS mechanism are highlighted, such as: (i) The cellular milieu of Cyanobacteria (Prochlorococcus) with volume of <0.1 femtoliter cannot afford free protons to pump and build TMP thereafter, precluding the functioning of chemiosmosis within this organism. Further, the anti-parallel ETCs of NADH→H2O in respiration and H2O→NADH in photosynthesis cannot be functional simultaneously, owing to the commonality of cytochromes b6f and c6. (ii) Multi-cellular cnidarian Henneguya salminicola lacks respiratory Complexes I, III & IV and the unicellular protist Plasmodium berghii does not possess Complex V when living within blood. Since these proteins (‘proton-pumps’ and ‘rotary ATP synthase’, respectively) are obligatorily required to synthesize ATP in the classical model, the ETC-CRAS mechanism is untenable. Based on several such exceptional examples, a strong case is built against the ‘irreducibly complex’ classical explanation. Further, the agendas that validate the facile, bimolecular DRS/oxygen-based rationale of murburn concept are also presented
Explaining the physiological cationic distribution in erythrocytes: The murburn perspective
No full textLiving cells are characterized by the interesting disparity in the distribution of monovalent and divalent cations, as per the order: K+ > Na+ > Mg2+ >> Ca2+. Classical biologists attribute this to energy-expended and affinity-driven processes mediated by membrane-embedded proteins. Independent physicists had proposed ionic adsorption at various interfaces and/or differences in hydration shell characteristics of the ions as the reasons for the same Herein, human erythrocytes are considered as a simple ‘living cell’ model. Energy metabolism-based outcomes (murburn equilibriums) and the dissolved-phase proteins’ innate ability to bind/adsorb ions selectively are suggested as the integral rationale for the observed phenomenon
The murzyme role of respiratory Complex I and understanding its modulation
No full texteLetter (21st July 2023) to Science (AAAS) in response to: Bridges et al. (Hirst group), Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides. https://www.science.org/doi/10.1126/science.ade3332
Abstract: Bridges et al. try to explain that the anti-diabetic drug of metformin binds to CoQ binding site of Complex I and thus interferes with respiratory electron transport chain (ETC). We have conclusively debunked the ETC concept and advocated the murburn model for mitochondrial oxidative metabolism and herein, we critique the author’s interpretations and advance our model
The murburn explanation for redox-phosphorylative coupling by Complex I
No full texteLetter (July, 2023) on Kampjut & Sazanov’s (2020) Science (AAAS) paper: The coupling mechanism of mammalian respiratory complex I. https://www.science.org/doi/10.1126/science.abc4209
Abstract: Here, the authors argue for a proton-translocating pathway in Complex I (using cryo-electron microscopy using a structure resolved at ~2.4 Angstroms, when protons are ~0.00002 Angstroms in dimension!). We point out the inapplicability of the chemiosmosis and ETC view of classical approach for understanding Complex I function, which makes the arguments between Sazanov and Hirst irrelevant! Further, we also provide a murburn model for understanding Complex I’s respiratory role
Complex V is an ATPase-based proton-chemostat, not a rotary ATP-synthase
No full texteLetter submitted (25/07/2023) to Science (AAAS) regarding: Murphy et al. Kuhlbrandt group, Rotary substates of mitochondrial ATP synthase reveal the basis of flexible F1-Fo coupling.
https://www.science.org/doi/10.1126/science.aaw9128
Abstract: Kuhlbrandt group continues to advocate the chemiosmotic rotary ATP synthesis mechanism for Complex V, which is demonstrably improbable/untenable. The murburn model provides a more thermodynamically/structurally viable explanation for Complex V function
Murburn electron-transfers versus the concept of ‘electron transport chain’: Probability versus determinism
No full texteLetter (submitted on 22nd July, 2023) to Science (AAAS) in response to: Spinelli et al., 2021.
https://www.science.org/doi/10.1126/science.abi7495
Abstract: Authors interpret their data on mitochondrial metabolism using the concept of deterministic electron transport chains (ETC), which we had conclusively demonstrated to be an untenable idea and explained standing observations with the new proposal of murburn concept
Oxygenic photosynthesis: Critiquing the standing explanations and proposing explorative solutions based in murburn concept
No full textThe available explanations for oxygenic photosynthesis for the light reaction of photolysis and photophosphorylation (Pl-Pp) are critically analyzed. Based on the structure cum distribution of protagonist molecules and the new mechanistic explanations in redox biochemistry, the interactive dynamics of key reactants are re-assessed for viability. The Z-scheme for electron transfer and Kok-Joliot cycle for water-lysis are found to be physiologically non-viable. Further, mechanistic explorations based on murburn concept are advocated for Pl-Pp
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