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

Manoj, Kelath Murali; Bazhin, N. M.; Tamagawa, Hirohisa; Jaeken, Laurent; Parashar, Abhinav

doi:10.1080/07391102.2022.2060307

Cited by 17 publications

(44 citation statements)

References 90 publications

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“…Further, if the model is relevant, NKA structure should show DRS-recruiting facets. Although NKA does not have inbuilt redox factors, it could be a murzyme along the lines already established for the membrane protein of Complex V (Manoj et al, 2022d) and the soluble lactate dehydrogenase (Manoj et al, 2022e). In the rest of this document, we provide evidence to support the postulates above, and advance the murburn proposal of trans-phase iondifferentiation by NKA via a redox-phosphorylatory mechanism.…”

Section: Murburn Model Of Nka-mediated Redox Electrophysiology At The...supporting

confidence: 68%

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Is the beta-subunit of Na,K-ATPase (NKA) a murzyme? Explaining the modulations by lithium ion, trans-dermal peptide, cardiotonic steroids, volatile anesthetics, arginine, dinitrophenol, and diverse antioxidants in NKA-aided neuro-musculo-electrophysiology

Manoj¹,

Nirusimhan²,

Gideon³

2022

Preprint

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The redox metabolic and bioenergetic paradigm of murburn concept advocates that diffusible reactive species (DRS, particularly oxygen-centric 1e-active radicals) are a crucial mainstay 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/utilizes/sustains DRS functionality is called a murzyme. We have demonstrated that several water-soluble (hemoglobin, lactate dehydrogenase, peroxidases, etc.) and membrane-embedded (Complexes I-V in mitochondria, Photosystems I/II in chloroplasts, rhodopsin/transducin in rod cells, etc.) proteins serve as murzymes (Manoj & Gideon, BBA-Biomem., 2022). In the first part of our work on NKA (Na,K-ATPase), we had effectively questioned the classical mechanistic understanding of how this protein supposedly aids cells by stoichiometrically pumping 3 Na+ outward and 2 K+ inward per molecule of ATP, at ~ 102 cycles per second (Manoj et al., OSF Preprints 2022). In the second part, herein, we propose and apply a minimalist murburn model of trans-membrane ion differentiation by NKA to address the physiological inhibitory effects of trans-dermal peptide (thereby, clarifying upon the role of beta-subunit of NKA to recruit DRS), lithium ion, cardiotonic steroids, volatile anesthetics, confirmed interfacial DRS+proton modulators like nitrophenolics and oleate/oleic acid, diverse classes of molecules like the amino acid arginine, oximes, N-/O- heteroatom alkyl substituted molecules, etc. These explanations find a pan-systemic connectivity with the inhibitions/uncouplings of other membrane-proteins in cells. Further, we also moot new avenues to explore NKA structure-function correlations.

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Section: Murburn Model Of Nka-mediated Redox Electrophysiology At The...supporting

confidence: 68%

“…We have explained these aspects in our earlier works with lactate dehydrogenase (Manoj et al, 2022c) and Complex V (Manoj et al, 2022d), both of which were shown to be murzymes.…”

Section: Reports Of Drs-involving and Phase-dependent Physiology Of Nkamentioning

confidence: 89%

Is the beta-subunit of Na,K-ATPase (NKA) a murzyme? Explaining the modulations by lithium ion, trans-dermal peptide, cardiotonic steroids, volatile anesthetics, arginine, dinitrophenol, and diverse antioxidants in NKA-aided neuro-musculo-electrophysiology

Manoj¹,

Nirusimhan²,

Gideon³

2022

Preprint

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“…with respect to the ions, attempts could be made to crystallize E1/E2 forms starting with a mixture of Na + and K + ). The zeal to conform and interpret results along expected lines are very strong in research community and we are quite wary of such misinterpretations, as seen from examples in other research fields of membrane biology: xenobiotics metabolism mediated by cytochrome P450 at endoplasmic reticulum (Parashar & Manoj, 2021) or/and oxidative/photo-phosphorylation occurring at mitochondrial cristae or chloroplast thylakoids (Manoj et al, 2022c). In the drug metabolism field, researchers had overlooked the improbable scope for a large molecule like xenobiotic or small molecule like oxygen binding with high affinity at the enzyme active site.T his was because the popular active-site based conformation change mechanistic model formed the lens through which the results had to be interpreted.…”

Section: B Analysis Of Nka Structure-function-inhibition-evolution Co...mentioning

confidence: 99%

Na,K-ATPase: Structure-distribution-mechanism versus physiological and evolutionary mandates

Manoj¹,

Bazhin²,

Tamagawa³

et al. 2022

Preprint

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New techniques and elucidations in structural biology have enabled greater insights into the functioning of proteins. Since its discovery in 1957 by Jens Skou, the membrane protein of Na,K-ATPase (NKA, also known as sodium-potassium pump) has been a focus of intense study, owing to its centrality in neuro-cardio-musculo electrophysiology. Herein, we first take a brief stock of some historical discordance in the field of electrophysiology and revisit the context of formulation of the classical mechanism of NKA. Via a series of critical queries starting from the geometric/spatio-temporal considerations of diffusion/mass transfer of solutes in cells to an update on structural/distributional features of NKA in diverse cellular systems, and from various mechanistic aspects of ion-transport (thermodynamics, osmoregulation, evolutionary dictates, etc.) to assays/explanations of inhibitory principles like cardiotonic steroids, we highlight some unresolved problems in the field. This essay exhorts the scientific community to venture beyond the deterministic/stoichiometric (3Na:2K ratio) of bidirectional ion-pumping by NKA, for reasoning the theoretical foundations, experimental findings, and outstanding conundrums.

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“…Via these works, Mitchellian pmf was shown to be untenable in mitochondria (Manoj, 2018a). Complex V (also known as F o F 1 ATPase), another example known of a rotary bimolecular system, was elucidated to work via much simpler 'murburn' principles (Manoj et al, 2022b). As a consequence, BFS remains as the sole example of a purported "natural/self-assembled rotary machine that uses pmf".…”

Section: Recent Developments Seek a Revisit Of Bfs Powering And Struc...mentioning

confidence: 99%

“…Although in vitro demonstration of rotability in a highly modified and incomplete version of Complex V was achieved in a single-molecule experiment (Noji et al, 1997), we had disclaimed its significance for supporting the Boyer model of rotary ATP synthesis. In lieu, we had mooted a more probable working mechanism of this erstwhile purported rotary protein (Manoj et al, 2022b), wherein the unfavorable reverse reaction (of ATP synthesis) was proposed along the murburn model of lactate dehydrogenase function in liver (Manoj et al, 2022g). Some of the pertinent details from that case are worth considering here because of the deep-rooted similarities with BFS research.…”

Section: A Structure-function-evolution Correlations and Quantitative...mentioning

confidence: 99%

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

Manoj¹,

Jacob²,

Kavdia³

et al. 2022

Preprint

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Bacterial flagellar system (BFS) was the first perceived example of a ‘natural rotary-motor” functionality, mandating the translation of a circular motion of components inside into a linear displacement of the cell body outside. This outcome is supposedly orchestrated with the following features of the BFS: (i) A chemical/electrical differential generates proton motive force (pmf, including a trans-membrane potential, TMP), which is electro-mechanically transduced by inward movement of protons via BFS. (ii) Membrane-bound roteins 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’. We had disclaimed the purported pmf/TMP-based respiratory/photosynthetic physiology involving Complex V, which was also perceived as a “rotary machine” earlier. We pointed out that the murburn redox logic was operative therein. In the context of BFS, we pursue the following similar perspectives: (i) Low probability for the evolutionary attainment of an ordered/synchronized teaming of about two dozen types of proteins (assembled across five-seven distinct phases) towards the singular agendum of rotary motility. (ii) Vital redox activity (not the gambit of pmf/TMP!) powers the molecular and macroscopic activities of cells, including flagella. (iii) Flagellar movement is noted even in ambiances lacking/countering the directionality mandates sought by pmf/TMP. (iv) Structural features of BFS lack component(s) capable of harnessing/achieving pmf/TMP and functional rotation. Falling short of disproving rotability, a viable murburn model for conversion of molecular/biochemical activity into macroscopic/mechanical outcomes is proposed herein for understanding BFS-assisted motility.

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

Cited by 17 publications

References 90 publications

Is the beta-subunit of Na,K-ATPase (NKA) a murzyme? Explaining the modulations by lithium ion, trans-dermal peptide, cardiotonic steroids, volatile anesthetics, arginine, dinitrophenol, and diverse antioxidants in NKA-aided neuro-musculo-electrophysiology

Is the beta-subunit of Na,K-ATPase (NKA) a murzyme? Explaining the modulations by lithium ion, trans-dermal peptide, cardiotonic steroids, volatile anesthetics, arginine, dinitrophenol, and diverse antioxidants in NKA-aided neuro-musculo-electrophysiology

Na,K-ATPase: Structure-distribution-mechanism versus physiological and evolutionary mandates

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

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