Synthesis of theories on cellular powering, coherence, homeostasis and electro-mechanics: Murburn concept and evolutionary perspectives.

If evolution was/is a fact, a simplified/unifying approach to explain cellular physiology is warranted. Such a perspective should agree with the thermodynamic, kinetic, structural, and operational-probabilistic considerations; without invoking overt intelligence or determinism, and must enable a synthesis from chaos. In this regard, we first list salient theories in cellular physiology for (i) powering (generation of chemical/heat energy), (ii) coherence (interconnectivity and workability as a unit), (iii) homeostasis (metabolizing and expelling of unfamiliar/unwanted materials, maintaining concentration/volume), and (iv) cellular electrical-mechanical activities.

Questioning rotary functionality in the bacterial flagellar system and proposing a murburn model for motility.

Bacterial flagellar system (BFS) was the primary example of a purported 'rotary-motor' functionality in a natural assembly. This mandates the translation of a circular motion of components inside into a linear displacement of the cell body outside, which is supposedly orchestrated with the following features of the BFS: (i) A chemical/electrical differential generates proton motive force (, including a trans-membrane potential, TMP), which is electro-mechanically transduced by inward movement of protons via BFS. (ii) Membrane-bound proteins of BFS serve as stators and the slender filament acts as an external propeller, culminating into a hook-rod that pierces the membrane to connect to a 'broader assembly of deterministically movable rotor'.

Murburn posttranslational modifications of proteins: Cellular redox processes and murzyme-mediated metabolo-proteomics.

Murburn concept constitutes the thesis that diffusible reactive species or DRS are obligatorily involved in routine metabolic and physiological activities. Murzymes are defined as biomolecules/proteins that generate/modulate/sustain/utilize DRS. Murburn posttranslational modifications (PTMs) result because murburn/murzyme functionalism is integral to cellular existence.

Na,K-ATPase: A murzyme facilitating thermodynamic equilibriums at the membrane-interface.

The redox metabolic paradigm of murburn concept advocates that diffusible reactive species (DRS, particularly oxygen-centric radicals) are mainstays of physiology, and not mere pathological manifestations. The murburn purview of cellular function also integrates the essential principles of bioenergetics, thermogenesis, homeostasis, electrophysiology, and coherence. In this context, any enzyme that generates/modulates/utilizes/sustains DRS functionality is called a murzyme.

Structural foundations for explaining the physiological roles of murzymes embedded in diverse phospholipid membranes.

The advent of improved structural biology protocols and bioinformatics methodologies have provided paradigm-shifting insights on metabolic or physiological processes catalyzed by homo-/hetero- proteins (super)complexes embedded in phospholipid membranes of cells/organelles. In this panoramic review, we succinctly elucidate the structural features of select redox proteins from four systems: hepatocyte/adrenal cortex endoplasmic reticulum (microsomes), inner mitochondrial membrane (cristae), thylakoid membrane (grana), and in the flattened disks of rod/cone cells (in retina). Besides catalyzing fast/crucial (photo)chemical reactions, these proteins utilize the redox-active diatomic gaseous molecule of oxygen, the elixir of aerobic life.

Murburn model of vision: Precepts and proof of concept.

The classical paradigm of visual physiology comprises of the following features: (i) rod/cone cells located at the rear end of the retina serve as the primary transducers of incoming photo-information, (ii) cis-trans retinal (C H O) transformations on rhodopsin act as the transduction switch to generate a transmittable signal, (iii) signal amplification occurs via GDP-GTP exchange at transducin, and (iv) the amplified signal is relayed (as an action potential) as a flux-based ripple of Na-K ions along the axons of neurons. Fundamental physical principles, chemical kinetics, and awareness of architecture of eye/retina prompt a questioning of these classical assumptions. In lieu, based on experimental and in silico findings, a simple space-time resolved murburn model for the physiology of phototransduction in the retina is presented wherein molecular oxygen plays key roles.

The physiological role of complex V in ATP synthesis: Murzyme functioning is viable whereas rotary conformation change model is untenable.

Complex V or FF-ATPase is a multimeric protein found in bioenergetic membranes of cells and organelles like mitochondria/chloroplasts. The popular perception on Complex V deems it as a reversible molecular motor, working bi-directionally (breaking or making ATP) via a conformation-change based chemiosmotic rotary ATP synthesis (CRAS) mechanism, driven by proton-gradients or trans-membrane potential (TMP). In continuance of our pursuits against the CRAS model of cellular bioenergetics, herein we demonstrate the validity of the murburn model based in diffusible reactive (oxygen) species (DRS/DROS).

Interaction of membrane-embedded cytochrome b-complexes with quinols: Classical Q-cycle and murburn model.

We recently proposed a diffusible reactive (oxygen) species (DRS/DROS) based function for cytochrome b complexes (CBC) and quinones (Q)/quinols (QH ) in the murburn model of bioenergetics. This proposal is in direct conflict with the classical purview of Q-cycle. Via extensive analyses of the structure-function correlations of membrane-quinones/quinols and proteins, we present qualitative and quantitative arguments to infer that the classical model cannot explain the energetics, kinetics, mechanism and probabilistic considerations.

Murburn precepts for lactic-acidosis, Cori cycle, and Warburg effect: Interactive dynamics of dehydrogenases, protons, and oxygen.

It is unresolved why lactate is transported to the liver for further utilization within the physiological purview of Cori cycle, when muscles have more lactate dehydrogenase (LDH) than liver. We point out that the answer lies in thermodynamics/equilibriums. While the utilization of NADH for the reduction of pyruvate to lactate can be mediated via the classical mechanism, the oxidation of lactate (with/without the uphill reduction of NAD ) necessitates alternative physiological approaches.

Why do cells need oxygen? Insights from mitochondrial composition and function.

Mitochondrial membrane-embedded redox proteins are classically perceived as deterministic "electron transport chain" (ETC) arrays cum proton pumps; and oxygen is seen as an "immobile terminal electron acceptor." This is untenable because: (1) there are little free protons to be pumped out of the matrix; (2) proton pumping would be highly endergonic; (3) ETC-chemiosmosis-rotary ATP synthesis proposal is "irreducibly complex"/"non-evolvable" and does not fit with mitochondrial architecture or structural/distribution data of the concerned proteins/components; (4) a plethora of experimental observations do not conform to the postulates/requisites; for example, there is little evidence for viable proton-pumps/pH-gradient in mitochondria, trans-membrane potential (TMP) is non-fluctuating/non-trappable, oxygen is seen to give copious "diffusible reactive (oxygen) species" (DRS/DROS) in milieu, etc. Quite contrarily, the newly proposed murburn model's tenets agree with known principles of energetics/kinetics, and builds on established structural data and reported observations.

Critical analysis of explanations for cellular homeostasis and electrophysiology from murburn perspective.

Pursuits in modern cellular electrophysiology are fraught with disagreements at a fundamental level. While the membrane theory of homeostasis deems the cell membrane and proteins embedded therein as the chief players, the association-induction (or sorption/bulk-phase) hypothesis considers the aqueous phase of dissolved proteins (cytoplasm/protoplasm) as the key determinant of cellular composition and ionic fluxes. In the first school of thought, trans-membrane potential (TMP) and selective ion pumps/channels are deemed as key operative principles.

The murburn precepts for cellular ionic homeostasis and electrophysiology.

Starting from the basic molecular structure and redox properties of its components, we build a macroscopic cellular electrophysiological model. We first present a murburn purview that could explain ion distribution in bulk-milieu/membrane-interface and support the origin of trans-membrane potential (TMP) in cells. In particular, the discussion focuses on how cells achieve disparity in the distribution of monovalent and divalent cations within (K  > Na  > Mg  > Ca ) and outside (Na  > K  > Ca  > Mg ).

Validating the predictions of murburn model for oxygenic photosynthesis: Analyses of ligand-binding to protein complexes and cross-system comparisons.

In this second half of our treatise on oxygenic photosynthesis, we provide support for the murburn model of the light reaction of photosynthesis and ratify key predictions made in the first part. Molecular docking and visualization of various ligands of quinones/quinols (and their derivatives) with PS II/Cytochrome complexes did not support chartered 2e-transport role of quinols. A broad variety of herbicides did not show any affinity/binding-based rationales for inhibition of photosynthesis.

The murburn precepts for aerobic respiration and redox homeostasis.

Murburn concept is a new perspective to metabolism which posits that certain redox enzymes/proteins mediate catalysis outside their active site, via diffusible reactive oxygen species (DROS, usually deemed as toxic wastes). We have recently questioned the proton-centric chemiosmotic rotary ATP synthesis (CRAS) explanation for mitochondrial oxidative phosphorylation (mOxPhos) and proposed an oxygen-centric murburn model in lieu. Herein, the chemical equations and thermodynamic foundations for this new model of mOxPhos are detailed.

Mechanism of electron transfers mediated by cytochromes and in mitochondria and endoplasmic reticulum: classical and murburn perspectives.

We explore the mechanism of electron transfers mediated by cytochrome , a soluble protein involved in mitochondrial oxidative phosphorylation and cytochrome , a microsomal membrane protein acting as a redox aide in xenobiotic metabolism. We found minimal conservation in the sequence and surface amino acid residues of cytochrome proteins among divergent species. Therefore, we question the evolutionary logic for electron transfer (ET) occurring through affinity binding via recognition of specific surface residues/topography.

Hemoglobin catalyzes ATP-synthesis in human erythrocytes: a murburn model.

Blood hemoglobin (Hb), known to transport oxygen, is the most abundant globular protein in humans. Erythrocytes have ∼10 M concentration of ATP in steady-state and we estimate that this high amounts cannot be formed from 10 - 10 M levels of precursors via substrate-level phosphorylation of glycolysis. To account for this discrepancy, we propose that Hb serves as a 'murzyme' (a redox enzyme working along the principles of murburn concept), catalyzing the synthesis of the major amounts of ATP found in erythrocytes.

Are plastocyanin and ferredoxin specific electron carriers or generic redox capacitors? Classical and murburn perspectives on two photosynthetic proteins.

In the light reaction of oxygenic photosynthesis, plastocyanin (PC) and ferredoxins (Fd) are small/diffusible redox-active proteins playing key roles in electron transfer/transport phenomena. In the Z-scheme mechanistic purview, they are considered as specific affinity binding-based electron-relay agents, linking the functions of Cytochrome (Cyt. ), Photosystem I (PS I) and Fd:NADPH oxidoreductase (FNR).

What is the Role of Lipid Membrane-embedded Quinones in Mitochondria and Chloroplasts? Chemiosmotic Q-cycle versus Murburn Reaction Perspective.

Quinones are found in the lipid membranes of prokaryotes like E. coli and cyanobacteria, and are also abundant in eukaryotic mitochondria and chloroplasts. They are intricately involved in the reaction mechanism of redox phosphorylations.

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

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 LD50 (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).

Murburn concept: a paradigm shift in cellular metabolism and physiology.

Two decades of evidence-based exploratory pursuits in heme-flavin enzymology led to the formulation of a new biological electron/moiety transfer paradigm, called murburn concept. Murburn is a novel literary abstraction from "mured burning" or "mild unrestricted burning". This concept was invoked to explain the longstanding conundrum of maverick physiological dose responses and also applied to remodel the prevailing understanding of drug metabolism and cellular respiration.

Refutation of the cation-centric torsional ATP synthesis model and advocating murburn scheme for mitochondrial oxidative phosphorylation.

The acclaimed explanation for mitochondrial oxidative phosphorylation (mOxPhos) is a proton or cation centric scheme. Such ideas were recently disclaimed and in lieu, an evidence-based oxygen-centric explanation, murburn concept, was proposed. The new understanding vouches for catalytic roles of diffusible reactive oxygen species (DROS).

Chemiosmotic and murburn explanations for aerobic respiration: Predictive capabilities, structure-function correlations and chemico-physical logic.

Since mid-1970s, the proton-centric proposal of 'chemiosmosis' became the acclaimed explanation for aerobic respiration. Recently, significant theoretical and experimental evidence were presented for an oxygen-centric 'murburn' mechanism of mitochondrial ATP-synthesis. Herein, we compare the predictive capabilities of the two models with respect to the available information on mitochondrial reaction chemistry and the membrane proteins' structure-function correlations.

Aerobic Respiration: Criticism of the Proton-centric Explanation Involving Rotary Adenosine Triphosphate Synthesis, Chemiosmosis Principle, Proton Pumps and Electron Transport Chain.

The acclaimed explanation for mitochondrial oxidative phosphorylation (mOxPhos, or cellular respiration) is a deterministic proton-centric scheme involving four components: Rotary adenosine triphosphate (ATP)-synthesis, Chemiosmosis principle, Proton pumps, and Electron transport chain (abbreviated as RCPE hypothesis). Within this write-up, the RCPE scheme is critically analyzed with respect to mitochondrial architecture, proteins' distribution, structure-function correlations and their interactive dynamics, overall reaction chemistry, kinetics, thermodynamics, evolutionary logic, and so on. It is found that the RCPE proposal fails to explain key physiological aspects of mOxPhos in several specific issues and also in holistic perspectives.