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In the field of enzymology and cellular physiology, murburn is a term coined by Kelath Murali Manoj that explains the catalytic mechanism of certain redox-active proteins, providing an enhanced and more physically comprehensive framework for understanding diverse physiological processes.^[1][2][3] The term describes the spontaneous interactive equilibria among molecules, unbound ions and radicals or radiations, signifying a process of "mild unrestricted redox catalysis". Over the past decade, the concept has evolved from a mechanistic explanation for certain enzymatic reactions into a broader theoretical framework encompassing cellular bioenergetics, homeostasis, electrophysiology, sensory functions, biological coherence and intelligence.

Murburn was originally abstracted from "mured burning" (connoting a "closed burning", an oxidative process), and implies equilibriums involving diffusible reactive (oxygen/nitrogen/halogen) species (DRS/ROS/RNS/RHS). Though akin to the oxygen assisted combustion of fuel, unlike the flames produced in the open burning process, the biological reaction occurs in enclosed premises, is mild and does chemical, mechanical, and electrical work besides generating heat (but no flames). Such a reaction could also incur the chemical work of selective and specific electron or moiety transfers.

Further, though burning is a reaction that usually involves oxygen (aerobic process), "burning flames"^[4] produced by anoxic oxidants are also well-known.^[4] Therefore, the enzymes working via murburn scheme (in aerobic or anaerobic systems) could be called murzymes and the region around the biomolecule where the DRS interacts with the final 'substrate' is called 'murzone'.^[5] Murzymes are now more formally defined as biomolecules or proteins that generate, modulate, sustain, or utilize DRS, with the region of interaction termed the murzone.^[6] As per this perspective, the most fundamental reaction of aerobic life is identified as: O₂ + e^- → O₂^*- ; ΔG = -250 kJ/mol, with the superoxide radical and its downstream products (hydrogen peroxide and hydroxyl radical) characterized as the "elixirs of life", rather than toxic waste (as deemed conventionally).^[7]

A hand-held electronic gadget is driven by the potential difference supplied by its battery and the current it draws, while a plugged-in appliance is driven by the voltage supplied by the outlet and the current it takes in. Murburn is the chemico-physical process that harnesses electromagnetic forces to fundamentally power cells, quite akin to the powering of electronic gadgets and electrical appliances. The wiring is solid and well-defined in the electrical gadgets/appliances, whereas in the soft and fluidic matter of the cells, it is rather undefined.

The basic components and processes

Powering in cells entails the movement of electrons (or ions/moieties), setting forth the electromagnetic force. The cells and their immediate natural environments are composed of molecules, unbound ions, and radicals or radiations. They naturally spontaneously interact with each other, and move electrons. Erstwhile perceptions of useful/powering cellular reactions and biological intelligence entailed 2-electron movements and trans-phase ion-pumping. In the context of murburn, 1-electron movements form the fundamental pivots and such interactions (wherein electrons/ions/moieties are moved) are regulated by several components and factors.

Molecules – Usually any electron-rich or reduced molecule, but particularly with an extended pi-electronic system or metallic centers with d electrons or a combination of both, could serve as a murzyme catalyst. A redox protein/enzyme optimally qualifies for this role because it has one or more cofactors with the required attribute. (e.g. hemeproteins, flavoproteins, Cu/Zn proteins, etc.). Occasionally, some proteins that lack the above cofactors but have high amounts of charged residues and suitably located substrate binding sites could also aid DROS dynamics and catalysis (e.g. lactate dehydrogenase, transducin in outer disks of rod cells in eye, Complex V, basal module of bacterial flagellar assembly, etc.)

Unbound ions – naturally occurring ions of several types, carrying or relaying charges

Radicals – transiently generated reactive species in milieu (particularly, oxygen-centric), also formed from any additive or in situ components

Radiations – transiently impinging or exchanged in the system, of a broad spectral range

Murburn concept postulates that cells are fundamentally powered by electron-displacements (or electron-movements) spontaneously brought out because of the interactions of its component redox-active molecules, unbound ions, and radicals or radiations, setting forth electromagnetic force, thereof. Cells are deemed as reducing environments in which oxygen can spontaneously gain electron (to make DRS like superoxide (via the fundamental equation mentioned in 3rd paragraph). Such inevitable DRS formation is an inherently stochastic process, which involves Effective Charge Separation (ECS), thereby setting up a Chemico-Electromagnetic Matrix (CEM). This ECS-DRS-CEM enables the Powering, Coherence, Homeostasis, Electro-Mechanical and Sensing-response (PCHEMS, the immediate physico-chemical features) activities within a cell and facilitates cellular functioning as Simple Chemical Engine (SCE). This fundamental logic forms the core of biological intelligence also. Thus, the stochastic murburn concept becomes a fundamental operational principle of life, complementing the central dogma (which charts out the deterministic flow of biological information, that is genetic sequences form mRNA which serve as the scaffolds for the formation of proteins, which in turn carry out very deterministic and "manufacturing line" like reactions in cells).

Salient features

While enzyme activities are classically defined by the deterministic interaction of the protein with its substrate at a defined active-site (necessitating a topological recognition of the interactive participants), murburn scheme obligatorily invokes a DRS (or a diffusible radical) for carrying out this agenda.^[8] The conventional enzyme-substrate interaction scheme invokes Fischer's lock and key type affinity or Koshland's induced fit theory. That is a substrate is identified by the enzyme by virtue of a topographical complementation, and thereafter, the enzyme-substrate complex undergoes a "transition-state", leading to products.^[9] Such a system shows certainty/determinism and stoichiometry (like a manufacturing line of any product in an industry), usually abides by the standard Michaelis-Menten scheme of catalysis and the inhibitors may be competitive, non-competitive, uncompetitive, etc. The classical enzymes have a unique substrate or a well-defined set of substrates.

The murburn paradigm does not deny the well-established classical mechanism above. However, it goes beyond the contexts of active-site catalysis. There are also important caveats like an additive may serve as an inhibitor or activator, depending on its own or/and the reaction-components' concentrations.

Murburn schemes (as shown in Figure 1) may invoke an enzyme-substrate complementation, but this aspect is not obligatory. The binding may be of high or low affinity (if any), it may also be delocalized and could be outside the active site. Murzymes may have multiple reaction sites and transition states (TS), as shown in Figure 2, owing to the involvement of DRS. Therefore, the classical enzyme catalysis can be deemed as a subset or special case of the larger schematic set of murburn, wherein the reactive locus is the unique active-site and reaction mechanism follows a unique transition state (TS). The kinetics of the reaction may at times not be traceable with standard models because the DRS is subjected to multiple equilibriums (which are contingent upon diverse reaction components) and the product of interest may be favorably formed in discrete concentrations of the protagonists involved.

Therefore, the outcomes in such murzyme/murburn systems could be subjected to a lot of uncertainty and the overall reaction scheme might exhibit varying and non-integral stoichiometry. The modulators/influencers (activators or inhibitors) may work by mixed modalities, owing to interactions with the protein, substrate, DRS or the reaction intermediates thereof. The murzymes may have a wide variety of substrates, as the reaction scheme is dependent on multiple modalities of interactions and outcomes. These realities of physiological function seek us to overcome the aesthetic perspective that DRS are mere manifestations of pathophysiology.^[11][12]

A relevant comparison in the context is that of the role of knife in the kitchen. The fact that knives (analogous to the reactive DRS) can easily inflict wounds, and the presence of knife-racks, cutting boards and gloves in kitchen (analogous to enzymes like superoxide dismutase and catalase, membrane-embedded proteins with one-electron active redox centers, etc.) does not mean that knife is a dangerous component that is avoided. On the contrary, it is an important tool that is used with adequate care. Quite similarly, the cellular machinery has evolved to harness the reaction potential and utility of DRS. The stigmatic perspective/concern that DRS would wreak havoc in routine physiology is no more relevant because several decades of research has now clearly established that DRS are routinely observed and unavoidable in physiology, and they cannot be just wished away.^[13] It has also been demonstrated that Sustained Release Dynamics (SRD) of DRS could afford selectivity (choice of a particular reactant from a variety, say B from A, B, C and D) and specificity (attack at a specific locus, like alpha- or para- positions of a reactant).^[8] Therefore, such a selectivity can be compared to how setting fire to a damp cloth dipped in oil burns the oil first and minimally chars the cloth's fabric. Analogously, murburn activity entails cumulative collateral damage as an inevitable consequence, which leads to aging, and ultimately, death. This also explains why animals and plant components with high redox metabolism perish sooner.

Murburn concept stresses on the already well-established fundamental awareness that all molecules and processes in life have spatial, temporal, quantitative and contextual relevance. A comparison of the classical perspectives and murburn concept is given in the figure and the perceptional changes ushered in by murburn concept can be captured in the Table 1.^[14]

The new mechanism has been proposed as a fundamental (supplementary or complementary or abrogative) explanation for phenomena involving catalytic electron or moiety transfers, chemico-physical changes and unusual observations in various experimental, ecological, metabolic and physiological scenarios. Fundamentally, in its essence, murburn concept advocates the thesis that DRS are vital requirements for routine metabolic and physiological functions. Biological theories are ratified by their ability to explain the effects of toxic principles. The murburn theory is validated by its ability to explain the bioenergetic toxicity of low doses of cyanide and many other small ions to a variety of important life processes (like respiration and photosynthesis).^[7][15][16] In its expanded form, the framework now encompasses the ECS-DRS-CEM-PCHEMS-SCE postulates, which collectively present murburn as a systems-level seamlessly integrating principle for understanding life's operations.^[17]

Application

Relation to classical theories and criticism

Murburn concept has been used to criticize classical perceptions like Peter Mitchell's and Paul Boyer's chemiosmotic rotary ATP synthesis mechanism.^[68][69][70] These criticisms have been called into question.^[71][72] These criticisms have in turn been responded to.^[73][74] A 2025 article in *Biomedical Reviews* presents a detailed analysis of how acute toxicity of cyanide and several ions conclusively negate electron transport chains and proton pumps, arguing that the classical membrane-pump theory and ETC-CRAS (electron transport chain - chemiosmotic rotary ATP synthesis) model are unequivocally falsified and must be replaced by the murburn paradigm.^[7] The work lists several blatant anti-realistic issues with the classical model, including evolutionary probability concerns, the thermodynamic and kinetic realities of oxygen reactivity in a reducing environment, the physical impossibility of proton pumping given the aprotic nature of mitochondrial matrices, and the untenability of rotary reversible function in complex macromolecular assemblies.^[7][7] In spite of scathing criticisms of established models, the mainstream researchers do not engage murburn and this was called out by the proponent of murburn concept.^[75][75+]

Reception, outreach and independent assessments

The late Lowell Hager (Member, NAS-USA and Professor of Biochemistry at UIUC) recognized the DRS-mediated murburn selectivity/specificity mechanism in chloroperoxidase.^[76] Two books authored by respected European researchers were published in the UK that favorably discussed murburn concept.^[77][78][79] Articles based in murburn concept were given cover-page credits in four annual volumes (2017, 2018, 2019 and 2020) of Biomedical Reviews (the official journal of Bulgarian Society for Cell Biology) and the 167th (December 2021) volume of Progress in Biophysics and Molecular Biology (Elsevier). The American Institute of Physics portal published a two-part review of murburn concept explaining multiple metabolic and physiological routines.^[40][41]

Independent citations and growing recognition

Recent literature demonstrates growing recognition of the murburn concept beyond the originating group. A landmark 2025 review by Zhang et al. in *Cell Stress* positions murburn as a pivotal founding principle of life, integrating it as a foundational element for explaining cellular function. The authors portray murburn as a "novel paradigm shift in redox-integrated bio-physico-chemical sciences," integrating stochastic processes via DRS, murzymes and murzone networks, with DRS reframed as "versatile elixirs" essential for respiration, immunity, and metabolic flexibility.^[80]

Yuan et al. (2025) in *Cell & Molecular Biology Letters* discuss murburn's role in ROS heterogeneity and carcinogenesis, noting that "According to this model, DROS such as superoxide anion and peroxide are not merely metabolic waste; they actively mediate reactions through free radical mechanisms," while tempering enthusiasm by stating, "Despite its explanatory potential, the murburn model remains a subject of vigorous debate, necessitating rigorous experimental validation."^[81]

Francati et al. (2023) in *Biomedical Reviews* examine the Janus face of oxidative stress and portray murburn as an alternative enzyme mechanism involving "closed burning" with DRS, noting that "Enzymes carrying out the Murburn system are defined as 'Murzymes,' and the region where DRS interact is termed 'Murzone'."^[82] Chaldakov et al. (2024) in *Pharmaceuticals* invoke murburn to explain ROS/RNS interference in NGF-TrkA-microtubule-lipid raft signaling in Alzheimer's disease.^[83]

Abadie (2024) in *Frontiers in Bioscience* highlights murburn as a "thermodynamically and kinetically valid model" superseding proton-centric ETC views, stating: "However, a more recent model based on the Murburn concept was explained by Manoj."^[84] These favorable citations across diverse disciplines signal murburn's growing global traction, elevating it from a challenger hypothesis to a framework increasingly acknowledged in mainstream literature.^[30]

Algorithmic identification and formal modeling

Recent developments have seen the application of algorithmic and AI/ML-based approaches to analyze the murburn framework. A 2026 publication in *Biomed Research International* presents algorithmic identification of murzymes and murburn mechanisms based on structural, theoretical, experimental and generic features.^[85] The work demonstrates that enzymes and reaction systems can now be parsed into murburn/murzyme systems using algorithic nd AI-ML logic, breaking the monotonous dominance of enforced consensus.^[85] A 2025 publication on quantitative treatments for murburn kinetics in *Biomed Research International* provides the mathematical formalism for murburn electron-transfer and catalysis rates.^[23] website is also provided to parse proteins into classical or murburn type.^[85]

Future Prospects

The murburn concept continues to evolve, with recent publications extending its applications to post-translational modifications, bacterial motility, inflammation, disease pathophysiology, bionics-cyborg systems, ecology-biodiversity-evolution, and the wet-and-murburn-membrane-model.^{[6][30][42][58][60][63][66][67]} The concept's proponents argue for its incorporation in teaching and research as the next step in the sequence of scientific progression. A 2025 article in *Biomedical Reviews* outlines strategies ahead for enhancing murburn's outreach and acceptance, emphasizing that paradigm-challenging concepts advance by solving problems orthodoxy cannot solve, quietly, repeatedly, and reproducibly.^[30] The focus is shifting to building a "murburn research ecosystem" and decentralizing validation from self-appointed authorities, with students now able to engage in real-time debate with AI portals to see that reasoning can critically acclaim the murburn concept, slowly breaking the authority-enforced consensus.^[30]

References