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. 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" produced by anoxic oxidants are also well-known. 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'. 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. 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).
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. 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. 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.
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. 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). 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.
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). 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.