Murburn concept

• Molecule – any molecule with an extended pi-electronic system or metallic centers with d electrons or a combination of both. Usually, a redox protein/enzyme qualifies for this role because it has one or more cofactors with the required attribute.
• Unbound ion – naturally occurring ions of several types, carrying or relaying charges
• Radical – transiently generated species in milieu, from any additive or in situ components

While enzyme activities are classically defined by the interaction of the protein with its substrate at a defined active site, murburn scheme obligatorily invokes a diffusible species (or a reactive 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 usually abides by the standard models of kinetics (like Michaelis-Menten scheme) and the inhibitors may be of competitive, non-competitive, uncompetitive, etc. The classical enzymes have a unique substrate or a well defined set of substrates.

In contrast, murburn scheme (as shown in figure) might invoke an enzyme-substrate complementation, but this aspect is not obligatory. The kinetics of the reaction may at times not be traceable with standard models because the diffusible reactive species is subjected to multiple equilibriums and the product of interest may be favorably formed only in discrete concentrations of the protagonists.

Therefore, the outcomes in such systems could be subjected to a lot of uncertainty and the overall reaction scheme might exhibit varying and non-integral stoichiometry. The inhibitors may work by mixed modalities, owing to affects on the protein, substrate or the diffusible species. The murzymes have a wide variety of substrates, as the reaction scheme is dependent on multiple modalities of interactions and outcomes. These considerations seeks us to overcome the aesthetic perspective that DROS are mere manifestations of pathophysiology.[10][11]

Comparison between classical enzyme mechanism and murburn catalysis mediated by diffusible species

The new mechanism has been proposed as an explanation for electron/moiety transfers, catalysis and unusual observations in various in vitro and in vivo enzymatic, metabolic and physiological systems. Murburn concept is validated by its ability to explain the toxicity of cyanide to a wide variety of life processes.[12][13]

Heme/flavin enzymology: Enzymes containing heme and flavin groups are ubiquitous in cellular systems. While several reactions they catalyze are mediated at the active site (heme/flavin center),[14][15][16] some reactions are mediated via diffusible species. Explaining the outcomes of the latter types of reactions (with various additives and inhibitors) is the core purview of murburn concept.[17][18]

Ecology: Fungal heme haloperoxidases (like chloroperoxidase) are the ultimate source for the generation of the vast majority of all natural halogenated organics in the environment and hemeperoxidases are also responsible for the breakdown of plant lignocellulosic materials.[19][20][21][22][23] Thus, the murburn activities of hemeperoxidases are very important for explaining the carbon/halogen cycles.[24]

Drug/Xenobiotic metabolism: The man-made drugs and xenobiotics present a molecular topology that the cellular system may not be aware of, and therefore, a definite affinity-based identification of the alien molecule may not be feasible. The murburn scheme affords a tangible modality to account for the way the hepatocytes deal with such challenges and could potentially explain several drug interactions.[25][26][27]

Cellular respiration: In the initial phase of evolution, an affinity-based identification may not have been present. Also, oxygen is a highly mobile molecule that cannot be expected to remain non-reactive in the presence of the multitude of redox centers present in the mitochondrial membrane respiratory complexes. With respect to these considerations, the murburn model presents a new interpretation of the physiology of cellular respiration: including oxidative phosphorylation, thermogenesis and dynamic redox homeostasis.[28][29][30][31][32][33][34]

Unusual physiological dose responses: It has been a long-standing conundrum as to how certain molecules may produce a physiological effect at a low concentration whereas little impact is seen at higher concentrations. Murburn concept affords a molecular explanation for such hormetic and certain types of idiosyncratic (person to person or case dependent “reactions”) dose responses.[35][36]

Oxygenic photosynthesis: The tapping of sunlight’s energy forms the primary means of provision of carbon-centered organic molecules for sustaining life on our planet. The classical explanations of Kok-Joliot cycle, Z-scheme, Q-cycle, etc. were demonstrated to be untenable. A murburn model of sunlight harvesting (involving DROS) was recently proposed as a mechanism for the explanation of Emerson effect and several other observations that were incompatible with the classical purview.[37][38][39][40][41]

Ionic differentials and electrophysiology: Classical membrane theory espouses that ionic differentials in and out of cells arise due to pumping by membrane-embedded proteins like Na-K-ATPase. In this purview, the source of trans-membrane potential (TMP) results only due to a difference of concentration of ions across phases. Murburn model brings in a new perspective of effective charge separation leading to an excess of negative charges transiently resulting inside, due to the ability of oxygen to accept free electron(s).[42][43][44]

In spite of the extensive criticism of classical perceptions by the advocates of murburn concept,[45][46][47] only two articles/individuals have addressed a few of the concerns raised. Since the editorial process of Biophysical Chemistry (the only journal which addressed the issue) did not afford the advocates of murburn concept any opportunity to offer a rebuttal, the responses of murburn advocates were subsequently published in other journals. Comments from Sunil Nath (2020) were addressed in Biomolecular Concepts (2020) and the concerns raised by Pedro Silva (2020) were rebutted in Biomedical Reviews (2020).  The accompanying supplementary material in the latter journal offers visual evidence of the nature of peer criticisms and status of affairs in the pertinent field.