Next Article in Journal
HbAdrian (α1:c.251del, p.Leu84Argfs*19)—A Novel Pathogenic Variant in the α1-Globin Gene Associated with Microcytosis from the North of Iran
Next Article in Special Issue
Understanding the Intricacies of Iron Overload Associated with β-Thalassemia: A Comprehensive Review
Previous Article in Journal / Special Issue
Spectrum of Thalassemia and Hemoglobinopathy Using Capillary Zone Electrophoresis: A Facility-Based Single Centred Study at icddr,b in Bangladesh
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Perspective

What Is the Relevance of Murburn Concept in Thalassemia and Respiratory Diseases?

Satyamjayatu, The Science & Ethics Foundation, Snehatheeram, Shoranur-2 (PO), Kulappully 679122, India
Thalass. Rep. 2023, 13(2), 144-151; https://doi.org/10.3390/thalassrep13020013
Submission received: 28 February 2023 / Revised: 3 May 2023 / Accepted: 10 May 2023 / Published: 12 May 2023
(This article belongs to the Special Issue Thalassemia Syndromes in Developing Countries: Has Anything Changed?)

Abstract

:
Murburn concept is a novel perspective for understanding cellular function, deeming cells as simple chemical engines (SCE) that are powered by redox reactions initiated by effective charge separation (ECS). The 1-electron active diffusible reactive (oxygen) species, or DR(O)S, equilibriums involved in these processes are also crucial for homeostasis, coherently networking cells, and rendering electromechanical functions of sensing and responding to stimuli. This perspective presents the true physiological function of oxygen, which is to enable ECS and the generation of DR(O)S. Therefore, DR(O)S must now to be seen as the quintessential elixir of life, although they might have undesired effects (i.e., the traditionally perceived oxidative stress) when present in the wrong amounts, places and times. We also elaborated that tetrameric hemoglobin (Hb) is actually an ATP-synthesizing murzyme (an enzyme working via murburn concept) and postulated that several post-translational modifications (such as glycation) on Hb could result from murburn activity. Murburn perspective has also enabled the establishment of a facile rationale explaining the sustenance of erythrocytes for 3–4 months, despite their lacking nucleus or mitochondria (to coordinate their various functions and mass-produce ATP, respectively). Although thalassemia has its roots in genetic causation, the new awareness of the mechanistic roles of oxygen-hemoglobin-erythrocyte trio significantly impacts our approaches to interpreting research data and devising therapies for this malady. These insights are also relevant in other clinical manifestations that involve respiratory distress (such as asthma, lung cancer, COVID-19 and pneumonia) and mitochondrial diseases. Herein, these contexts and developments are briefly discussed.

1. Introduction

Erythrocyte defects/disorders of genetic origin such as thalassemia lead to anemia, respiratory and several other diseases, which pose a significant burden in human society [1]. Murburn concept is a term I originally introduced into the scientific jargon in 2015, while presenting the interpretation of experimental works on heme-enzymes cytochrome P450 (CYP) at the 35th Midwest Enzyme Chemistry Conference (Chicago) and 20th North American ISSX Meeting (Orlando) [2]. In toto, about four dozen articles in mainstream research journals, books and popular web (Internet) portals [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49] have featured murburn concept. They also include invited reviews [10,14,16,39,45] and cover-page credited pieces or special editorial mentions [7,11,12,17,19,27,45]. The first workshop on murburn concept was conducted in March 2023 at IIT Bombay [50].

2. What Is Murburn Concept?

The coining of the term murburn stems from the fusion of “mured” (closed) and “burning” (a rather chaotic redox process that usually involves oxygen) [10]. This terminology is an effort to capture the essentially stochastic scheme of reactions/processes that could involve a DRS such as superoxide (an oxygen-centered ionic radical) or singlet oxygen and derivatives thereof (such as hydrogen peroxide, hydroxyl radical, hydroxide ion, etc.). Murburn concept is as an evidence-based rationale that vouches for the intermediacy of diffusible reactive species (DRS) in routine cellular metabolism and physiology (Figure 1).
This new perspective explains the anomalous kinetics (generic activations, inhibitions, multi-phasic substrate dependence, etc.) and unusual mechanistic signatures (diversity of substrates, kinetic isotope effects, conversion of active-site excluded molecules, etc.) seen in diverse forms of hemo/flavo-protein-mediated catalysis leading to oxygen insertions, bond breakages, and other inter- and intra-molecular electron or moiety/group transfer reactions [51,52,53,54,55,56,57,58,59,60,61]. Questioning the acclaimed and long-standing explanations, this new insight was applied to elaborate upon a bevy of fundamental metabolic and physiological contexts. DRS-mediated oxygen–water-equilibrium-centric murburn models were provided for the roles of biomolecules and processes involved in: powering (respiration, photosynthesis, thermogenesis), homeostasis (xenobiotic clearance, ion differentials, volume constancy, etc.), electro-mechanical activities (water mobilization), sensing and response to stimuli (vision), metabolo-proteomics, physiological dose responses, trans-membrane potential fluctuations, inflammatory immune responses, etc. [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]. In murburn perspective, cells are seen as simple chemical engines (SCE) that are initiated by effective charge separation (ECS) [40]. That is, proteins with cofactors that contain a d-electron or extensively conjugated π-electron system (e.g., heme and flavo proteins, respectively) may enable oxygen activation, particularly in the presence of reduced nicotinamides (which contain two electrons but only one hydrogen atom equivalent). This simple system enables flavin- and oxygen-based ECS and heme-based spin conversions and high potential radical generation. Several redox proteins can stabilize the DRS [23,26] and even proteins that lack redox active centers can utilize DRS [37,40], thereby qualifying upon several poorly understood aspects of bioenergetics and electrophysiology. As a consequence, the stochastic principle of murburn concept serves as a supplementary/complementary principle to the deterministic central dogma for affording a satisfactory explanatory paradigm for the origin, sustenance and termination of cellular activities [44]. Under the new perspective, murzymes are seen as those proteins that work via murburn concept, generating, modulating, stabilizing or utilizing DRS.

3. How Is Murburn Concept Relevant in Thalassemia and Respiratory/Mitochondrial Diseases?

The pathophysiology of thalassemia stems from mutation(s) in hemoglobin (alpha-beta gene(s), leading to poor assembly/function of functional hemoglobin (Hb) and underproduction or poor maturation of erythrocytes [62,63]. The currently adopted clinical approach centers around basic strategies involving: (a) the administration of small/large molecules such as hydroxyurea to enhance Hb production and erythrocyte osmolarity/turgor [64], folate to aid erythropoiesis [65], chelation agents to counter Fe-overload [66], growth hormones to alleviate the limited development of body [67], and recombinant proteins (e.g., luspatercept or Reblozyl) aiding better erythrocyte population [68]; (b) blood transfusion [69]; (c) bone marrow/stem cell transplantation [70,71]; (d) gene therapy (e.g., CRISPR-methodology and Zynteglo) [72,73], etc. Murburn concept is relevant in all of these contexts and also in a bevy of other redox/respiratory and mitochondrial diseases (which are also gene-based ailments) that are supposed to involve “oxidative stress”. Elucidation of the routes and details of the physiological function of DR(O)S shall provide a strong etiology to differentiate the pathological symptoms and enable us to fine-tune the care measures provided in clinical settings. This is because all cellular activities depend also on murzyme/murburn-based activities, and an understanding of pivotal aspects such as redox homeostasis, oxygen utilization by cells/mitochondria, ATP-synthesis and energy metabolism, the functioning of heme proteins such as hemoglobin, etc., is absolutely essential for understanding, detecting and treating such diseases.

3.1. The Modality of Oxygen Utilization by Proteins/Cells

In the classical purview of respiratory physiology, molecular oxygen is primarily needed to serve as the terminal electron acceptor, staying wedded to Complex IV (also called cytochrome oxidase complex, found in the inner membrane of mitochondria), ultimately making two molecules of water. In other metabolic schemes (such as that of CYPs in endoplasmic reticulum mediated xenobiotic clearance), once again, oxygen was supposed to stay bound at the heme center of proteins, hydroxylating or oxidizing molecules tightly bound to the heme protein. In such classical schemes, DRS such as superoxide and hydroxyl radicals (or even molecules such as hydrogen peroxide and singlet oxygen) (Figure 2) were deemed as unavoidable toxic waste products. Although the binding of oxygen at heme centers and O-atom insertion thereafter cannot be denied or refuted, my group’s pursuits have conclusively demonstrated [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61] that without the ECS and form of catalysis afforded by DRS, several of the routine metabolic/physiological functions would not transpire. This is a profound paradigm-shifting perception in biological science, which explains why we need oxygen so critically and how/why aerobic life forms thrive on Planet Earth now [44]. So, when DRS are experimentally observed in erythrocytes or other cells, it should no longer be deemed as purely a manifestation of pathophysiology! The contextual (spatial, temporal and quantitative) aspects are more important, and the purely aesthetic disposition of deeming DRS as unwanted is unwarranted.

3.2. The Novel Function of Hemoglobin as a Murzyme ATP-Synthase

Tetrameric hemoglobin is perhaps one of the most studied proteins and has been recognized to have multiple functions in addition to transporting oxygen [74]. However, it is unclear why the main oxygen binding protein is hetero-tetrameric in blood, whereas in muscle tissues, the oxygen binding protein of myoglobin is monomeric. We found that the highly packed hetero-tetrameric Hb serves as an ATP-synthase in erythrocytes, by virtue of Fe(II)-O2 and Fe(III)-O2*− binding and dissociation equilibriums, and their stochastic nature and statistical outcomes. This role of Hb makes up for the inadequate output of glycolytic ATP-synthesis in RBC and explains the hetero-tetrameric structure of Hb, with the pore on the beta globin monomer [25]. In this connection, it must also be noted that the DR(O)S production ability of Hb enables it to catalyze several auto- and hetero- post translational modifications such as glycations, phosphorylations, etc., which are also important markers in clinical research [42].

3.3. Erythrocyte Sustenance without Mitochondria and Nucleus

The classical perspectives require the nucleus to maintain protein levels and these proteins regulate cellular concentrations of metabolites and ions via purely affinity-driven measures. Furthermore, given the high amounts of energy expense for the ion-pumping perception to maintain Na-K differentials, mitochondria are also expected for energy supplementation in RBCs. Murburn concept obviates these predicaments to explain coherent and homeostatic functions [24,27,30,32,44], and this aspect is also relevant (and explored further) for cellular morpho-mechanics.

4. Future Research Agenda and Therapeutic Regimen

Thalassemia and mitochondrial diseases owe their etiology to genetic causations. Yet, in light of the impacting realities (Section 3.1, Section 3.2 and Section 3.3) unveiled recently, the future research agenda and clinical care in respiratory diseases area should be reoriented to enhance the efficacy of oxygen-aided functionalism, as it is evident that murburn perspective governs the physiological interaction scheme of redox proteins, biomolecules and oxygen. The long-standing aesthetic stigma suggesting that DR(O)S are merely disruptive and unavoidable agents should give way to a more realistic outlook on the viability and obligatory requirement for their necessary roles in the sustenance of life.
To reiterate: given the fact that: (a) NO (nitric oxide, a DROS!) is already recognized as a molecular messenger; (b) the classical bioenergetics paradigm of electron transport chains, proton-pumps and rotary ATP synthesis, etc., are untenable [9]; (c) the DROS-based murburn concept provides a thermodynamically/kinetically and evolutionarily viable explanation for cellular powering [27,44]; and (d) the global and acute toxicity of small doses of cyanide cannot be explained without invoking murburn concept [14], it is highly opportune to reorient redox biomedical research and clinical therapy efforts for respiratory diseases. It is now imperative to understand the contexts of DR(O)S playing Dr. Jekyll and Mr. Hyde, and to accommodate the murburn perspective.

Funding

This research received no external funding.

Data Availability Statement

All data required to peruse this manuscript are provided herein.

Acknowledgments

The pursuit was powered by Satyamjayatu: The Science & Ethics Foundation.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015, 386, 743–800. [Google Scholar] [CrossRef]
  2. Manoj, K.M.; Venkatachalam, A.; Parashar, P. Metabolism of xenobiotics by cytochrome P450: Novel insights into the thermodynamics, kinetics and roles of redox proteins and diffusible reactive species. Drug Metabol. Rev. 2016, 48, 41–42. [Google Scholar] [CrossRef]
  3. Manoj, K.M.; Gade, S.K.; Venkatachalam, A.; Gideon, D.A. Electron transfer amongst flavo- and hemo-proteins: Diffusible species effect the relay processes, not protein–protein binding. RSC Adv. 2016, 6, 24121–24129. [Google Scholar] [CrossRef]
  4. Venkatachalam, A.; Parashar, A.; Manoj, K.M. Functioning of drug-metabolizing microsomal cytochrome P450s: In silico probing of proteins suggests that the distal heme ‘active site’ pocket plays a relatively ‘passive role’ in some enzyme-substrate interactions. Silico Pharmacol. 2016, 4, 2. [Google Scholar] [CrossRef] [PubMed]
  5. Manoj, K.M.; Parashar, A.; Venkatachalam, A.; Goyal, S.; Satyalipsu; Singh, P.G.; Gade, S.K.; Periyasami, K.; Jacob, R.S.; Sardar, D.; et al. Atypical profiles and modulations of heme-enzymes catalyzed outcomes by low amounts of diverse additives suggest diffusible radicals’ obligatory involvement in such redox reactions. Biochimie 2016, 125, 91–111. [Google Scholar] [CrossRef] [PubMed]
  6. Manoj, K.M.; Parashar, A.; Gade, S.K.; Venkatachalam, A. Functioning of Microsomal Cytochrome P450s: Murburn Concept Explains the Metabolism of Xenobiotics in Hepatocytes. Front. Pharmacol. 2016, 7, 161. [Google Scholar] [CrossRef]
  7. Manoj, K.M. Debunking chemiosmosis and proposing murburn concept as the operative principle for cellular respiration. Biomed. Rev. 2017, 28, 31–48. [Google Scholar] [CrossRef]
  8. Parashar, A.; Gideon, D.A.; Manoj, K.M. Murburn Concept: A Molecular Explanation for Hormetic and Idiosyncratic Dose Responses. Dose Response 2018, 16. [Google Scholar] [CrossRef] [PubMed]
  9. Manoj, K.M. Aerobic Respiration: Criticism of the Proton-centric Explanation Involving Rotary Adenosine Triphosphate Synthesis, Chemiosmosis Principle, Proton Pumps and Electron Transport Chain. Biochem. Insights. 2018, 11. [Google Scholar] [CrossRef] [PubMed]
  10. Manoj, K.M. The ubiquitous biochemical logic of murburn concept. Biomed. Rev. 2018, 29, 89–97. [Google Scholar] [CrossRef]
  11. Manoj, K.M.; Gideon, D.A.; Jacob, V.D. Murburn scheme for mitochondrial thermogenesis. Biomed. Rev. 2018, 29, 73–82. [Google Scholar] [CrossRef]
  12. Jacob, V.D.; Manoj, K.M. Are adipocytes and ROS villains, or are they protagonists in the drama of life? The murburn perspective. Adipobiology 2019, 10, 7–16. [Google Scholar] [CrossRef]
  13. Manoj, K.M.; Parashar, A.; David Jacob, V.; Ramasamy, S. Aerobic respiration: Proof of concept for the oxygen-centric murburn perspective. J. Biomol. Struct. Dyn. 2019, 37, 4542–4556. [Google Scholar] [CrossRef] [PubMed]
  14. Manoj, K.M.; Soman, V.; David Jacob, V.; Parashar, A.; Gideon, D.A.; Kumar, M.; Manekkathodi, A.; Ramasamy, S.; Pakshirajan, K.; Bazhin, N.M. Chemiosmotic and murburn explanations for aerobic respiration: Predictive capabilities, structure-function correlations and chemico-physical logic. Arch. Biochem. Biophys. 2019, 676, 108128. [Google Scholar] [CrossRef]
  15. Manoj, K.M. Refutation of the cation-centric torsional ATP synthesis model and advocating murburn scheme for mitochondrial oxidative phosphorylation. Biophys Chem. 2020, 257, 106278. [Google Scholar] [CrossRef] [PubMed]
  16. Manoj, K.M. Murburn concept: A paradigm shift in cellular metabolism and physiology. Biomol. Concepts. 2020, 11, 7–22. [Google Scholar] [CrossRef]
  17. Manoj, K.M.; Soman, V. Classical and murburn explanations for acute toxicity of cyanide in aerobic respiration: A personal perspective. Toxicology 2020, 432, 152369. [Google Scholar] [CrossRef] [PubMed]
  18. Manoj, K.M.; Ramasamy, S.; Parashar, A.; Gideon, D.A.; Soman, V.; Jacob, V.D.; Pakshirajan, K. Acute toxicity of cyanide in aerobic respiration: Theoretical and experimental support for murburn explanation. Biomol Concepts. 2020, 11, 32–56. [Google Scholar] [CrossRef]
  19. Manoj, K.M.; Jacob, V.D. Murburn precepts for photoreception. Biomed. Rev. 2020, 31, 67–74. [Google Scholar] [CrossRef]
  20. Manoj, K.M. In defense of the murburn explanation for aerobic respiration. Biomed. Rev. 2020, 31, 135–160. [Google Scholar] [CrossRef]
  21. Manoj, K.M.; Manekkathodi, A. Light’s interaction with pigments in chloroplasts: The murburn perspective. J. Photochem. Photobiol. 2021, 5, 100015. [Google Scholar] [CrossRef]
  22. Manoj, K.M.; Gideon, D.A.; Parashar, A. What is the Role of Lipid Membrane-embedded Quinones in Mitochondria and Chloroplasts? Chemiosmotic Q-cycle versus Murburn Reaction Perspective. Cell Biochem. Biophys. 2021, 79, 3–10. [Google Scholar] [CrossRef] [PubMed]
  23. Gideon, D.A.; Nirusimhan, V.; Manoj, K.M. Are plastocyanin and ferredoxin specific electron carriers or generic redox capacitors? Classical and murburn perspectives on two photosynthetic proteins. J. Biomol. Struct. Dyn. 2022, 40, 1995–2009. [Google Scholar] [CrossRef]
  24. Parashar, A.; Manoj, K.M. Murburn Precepts for Cytochrome P450 Mediated Drug/Xenobiotic Metabolism and Homeostasis. Curr. Drug Metab. 2021, 22, 315–326. [Google Scholar] [CrossRef]
  25. Parashar, A.; Jacob, V.D.; Gideon, D.A.; Manoj, K.M. Hemoglobin catalyzes ATP-synthesis in human erythrocytes: A murburn model. J. Biomol. Struct. Dyn. 2022, 40, 8783–8795. [Google Scholar] [CrossRef] [PubMed]
  26. Gideon, D.A.; Nirusimhan, V.; Edward, J.C.; Sudarsha, K.; Manoj, K.M. Mechanism of electron transfers mediated by cytochromes c and b5 in mitochondria and endoplasmic reticulum: Classical and murburn perspectives. J. Biomol. Struct. Dyn. 2022, 40, 9235–9252. [Google Scholar] [CrossRef]
  27. Manoj, K.M.; Bazhin, N.M. The murburn precepts for aerobic respiration and redox homeostasis. Prog. Biophys. Mol. Biol. 2021, 167, 104–120. [Google Scholar] [CrossRef]
  28. Manoj, K.M.; Bazhin, N.M.; Jacob, V.D.; Parashar, A.; Gideon, D.A.; Manekkathodi, A. Structure-function correlations and system dynamics in oxygenic photosynthesis: Classical perspectives and murburn precepts. J. Biomol. Struct. Dyn. 2021, 40, 10997–11023. [Google Scholar] [CrossRef]
  29. Manoj, K.M.; Gideon, D.A.; Parashar, A.; Nirusimhan, V.; Annadurai, P.; Jacob, V.D.; Manekkathodi, A. Validating the predictions of murburn model for oxygenic photosynthesis: Analyses of ligand-binding to protein complexes and cross-system comparisons. J. Biomol. Struct. Dyn. 2022, 40, 11024–11056. [Google Scholar] [CrossRef]
  30. Manoj, K.M.; Bazhin, N.; Tamagawa, H. The murburn precepts for cellular ionic homeostasis and electrophysiology. J. Cell. Physiol. 2022, 237, 804–814. [Google Scholar] [CrossRef]
  31. Manoj, K.M.; Bazhin, N.; Wu, Y.; Manekkathodi, A. Murburn model of photosynthesis: Effect of additives like chloride and bicarbonate. In Chlorophylls; Ameen, S., Akhtar, M.S., Shin, H.-S., Eds.; Intech Open: London, UK, 2022. [Google Scholar] [CrossRef]
  32. Manoj, K.M.; Tamagawa, H. Critical analysis of explanations for cellular homeostasis and electrophysiology from murburn perspective. J. Cell. Physiol. 2022, 237, 421–435. [Google Scholar] [CrossRef]
  33. Manoj, K.M.; Gideon, D.A.; Jaeken, L. Why do cells need oxygen? Insights from mitochondrial composition and function. Cell Biol. Int. 2022, 46, 344–358. [Google Scholar] [CrossRef] [PubMed]
  34. Gideon, D.A.; Parashar, A.; Robin, J.; Annadurai, P.; Nirusimhan, V.; Manoj, K.M. Do cyclooxygenases possess a murzyme activity? Biomed. Rev. 2021, 32, 47–59. [Google Scholar]
  35. Manoj, K.M.; Nirusimhan, V.; Parashar, A.; Edward, J.; Gideon, D.A. Murburn precepts for lactic-acidosis, Cori cycle, and Warburg effect: Interactive dynamics of dehydrogenases, protons, and oxygen. J. Cell. Physiol. 2022, 237, 1902–1922. [Google Scholar] [CrossRef] [PubMed]
  36. Manoj, K.M.; Gideon, D.A.; Jaeken, L. Interaction of membrane-embedded cytochrome b-complexes with quinols: Classical Q-cycle and murburn model. Cell Biochem. Funct. 2022, 40, 118–126. [Google Scholar] [CrossRef]
  37. Manoj, K.M.; Bazhin, N.M.; Tamagawa, H.; Jaeken, L.; Parashar, A. The physiological role of complex V in ATP synthesis: Murzyme functioning is viable whereas rotary conformation change model is untenable. J. Biomol. Struct. Dyn. 2023, 41, 3993–4012. [Google Scholar] [CrossRef] [PubMed]
  38. Manoj, K.M.; Tamagawa, H.; Bazhin, N.; Jaeken, L.; Nirusimhan, V.; Faraci, F.; Gideon, D.A. Murburn model of vision: Precepts and proof of concept. J. Cell. Physiol. 2022, 237, 3338–3355. [Google Scholar] [CrossRef]
  39. Manoj, K.M.; Gideon, D.A. Structural foundations for explaining the physiological roles of murzymes embedded in diverse phospholipid membranes. Biochim. Biophys. Acta Biomembr. 2022, 1864, 183981. [Google Scholar] [CrossRef]
  40. Manoj, K.M.; Gideon, D.A.; Bazhin, N.M.; Tamagawa, H.; Nirusimhan, V.; Kavdia, M.; Jaeken, L. Na, K-ATPase: A murzyme facilitating thermodynamic equilibriums at the membrane-interface. J. Cell. Physiol. 2023, 238, 109–136. [Google Scholar] [CrossRef]
  41. Manoj, K.M.; Manekkathodi, A.; Bazhin, N.; Parashar, A.; Wu, Y. Comprehensive Analyses of Enhancement of Oxygenesis in Photosynthesis by Bicarbonate and Effects of Diverse Additives: Classical Explanation versus Murburn Model. In Plant Physiology; Tsung-Chen, J., Ed.; Intech Open: London, UK, 2023. [Google Scholar] [CrossRef]
  42. Manoj, K.M. Murburn posttranslational modifications of proteins: Cellular redox processes and murzyme-mediated metabolo-proteomics. J. Cell. Physiol. 2023. [Google Scholar] [CrossRef]
  43. Manoj, K.M.; Jacob, V.D.; Kavdia, M.; Tamagawa, H.; Jaeken, L.; Soman, V. Questioning physiological rotary functionality in the bacterial flagellar system and proposing a murburn model for motility. J. Biomol. Struct. Dyn. 2023. [Google Scholar] [CrossRef] [PubMed]
  44. Manoj, K.M.; Jaeken, L. Synthesis of Theories on Cellular Powering, Coherence, Homeostasis and Electro-mechanics: Murburn Concept & Evolutionary Perspectives. J. Cell. Physiol. 2023. [Google Scholar] [CrossRef]
  45. Manoj, K.M. Murburn concept and murzymes in 2023: Celebrating 25th year of pursuit. Biomed. Rev. 2022, in press. [Google Scholar]
  46. Chaldakov, G.N. Principles of Cell Biology (Eureka for Thought—5); BioMedES Ltd.: London, UK, 2022. [Google Scholar]
  47. Jaeken, L. The Coacervate-Coherence Nature of Life: Fundamentals of Cell Physiology (Chapter 6); BioMedES Ltd.: London, UK, 2021. [Google Scholar]
  48. Manoj, K.M. Murburn concept explains why oxygen is acutely needed to sustain life. Atlas Sci. 2023. Available online: https://atlasofscience.org/murburn-concept-explains-why-oxygen-is-acutely-needed-to-sustain-life/ (accessed on 3 March 2023).
  49. Wikipedia. Murburn Concept. 2019. Available online: https://en.wikipedia.org/wiki/Murburn_concept (accessed on 3 March 2023).
  50. Sethi, A.; Bhartiya, S.; Venkatesh, K.V. First Workshop on Murburn Concept. March 15 & 16, 2023, at IIT Bombay. Available online: https://www.youtube.com/@satyamjayatu5613/videos (accessed on 3 March 2023).
  51. Manoj, K.M.; Hager, L.P. Utilization of peroxide and its relevance in oxygen insertion reactions catalyzed by chloroperoxidase. Biochim. Biophys. Acta 2001, 1547, 408–417. [Google Scholar] [CrossRef]
  52. Manoj, K.M. Chlorinations catalyzed by chloroperoxidase occur via diffusible intermediate (s) and the reaction components play multiple roles in the overall process. Biochim. Biophys. Acta (BBA) Proteins Proteom. 2006, 1764, 1325–1339. [Google Scholar] [CrossRef] [PubMed]
  53. Manoj, K.M.; Hager, L.P. Chloroperoxidase, a janus enzyme. Biochemistry 2008, 47, 2997–3003. [Google Scholar] [CrossRef] [PubMed]
  54. Manoj, K.M.; Baburaj, A.; Ephraim, B.; Pappachan, F.; Maviliparambathu, P.P.; Vijayan, U.K.; Narayanan, S.V.; Periasamy, K.; George, E.A.; Mathew, L.T. Explaining the atypical reaction profiles of heme enzymes with a novel mechanistic hypothesis and kinetic treatment. PLoS ONE 2010, 5, e10601. [Google Scholar] [CrossRef] [PubMed]
  55. Manoj, K.M.; Gade, S.K.; Mathew, L. Cytochrome P450 reductase: A harbinger of diffusible reduced oxygen species. PLoS ONE 2010, 5, e13272. [Google Scholar] [CrossRef]
  56. Andrew, D.; Hager, L.; Manoj, K.M. The intriguing enhancement of chloroperoxidase mediated one-electron oxidations by azide, a known active-site ligand. Biochem. Biophys. Res. Commun. 2011, 415, 646–649. [Google Scholar] [CrossRef]
  57. Parashar, A.; Manoj, K.M. Traces of certain drug molecules can enhance heme-enzyme catalytic outcomes. Biochem. Biophys. Res. Commun. 2012, 417, 1041–1045. [Google Scholar] [CrossRef] [PubMed]
  58. Gideon, D.A.; Kumari, R.; Lynn, A.M.; Manoj, K.M. What is the Functional Role of N-terminal Transmembrane Helices in the Metabolism Mediated by Liver Microsomal Cytochrome P450 and its Reductase? Cell. Biochem. Biophys. 2012, 63, 35–45. [Google Scholar] [CrossRef]
  59. Gade, S.K.; Bhattacharya, S.; Manoj, K.M. Redox active molecules cytochrome c and vitamin C enhance heme-enzyme peroxidations by serving as non-specific agents for redox relay. Biochem. Biophys. Res. Commun. 2012, 419, 211–214. [Google Scholar] [CrossRef]
  60. Parashar, A.; Gade, S.K.; Potnuru, M.; Madhavan, N.; Manoj, K.M. The curious case of benzbromarone: Insight into super-inhibition of cytochrome P450. PLoS ONE 2014, 9, e89967. [Google Scholar] [CrossRef]
  61. Parashar, A.; Venkatachalam, A.; Gideon, D.A.; Manoj, K.M. Cyanide does more to inhibit heme enzymes, than merely serving as an active-site ligand. Biochem. Biophys. Res. Commun. 2014, 455, 190–193. [Google Scholar] [CrossRef] [PubMed]
  62. Angastiniotis, M.; Lobitz, S. Thalassemias: An Overview. Int. J. Neonatal Screen. 2019, 5, 16. [Google Scholar] [CrossRef]
  63. Sanchez-Villalobos, M.; Blanquer, M.; Moraleda, J.M.; Salido, E.J.; Perez-Oliva, A.B. New Insights Into Pathophysiology of β-Thalassemia. Front. Med. 2022, 9, 880752. [Google Scholar] [CrossRef]
  64. Keikhaei, B.; Yousefi, H.; Bahadoram, M. Clinical and Haematological Effects of Hydroxyurea in β-Thalassemia Intermedia Patients. J. Clin. Diagn. Res. 2015, 9, OM01. [Google Scholar] [CrossRef] [PubMed]
  65. Tabei, S.M.; Mazloom, M.; Shahriari, M.; Zareifar, S.; Azimi, A.; Hadaegh, A.; Karimi, M. Determining and surveying the role of carnitine and folic acid to decrease fatigue in β-thalassemia minor subjects. Pediatr. Hematol. Oncol. 2013, 30, 742–747. [Google Scholar] [CrossRef]
  66. Reddy, P.S.; Locke, M.; Badawy, S.M. A systematic review of adherence to iron chelation therapy among children and adolescents with thalassemia. Ann. Med. 2022, 54, 326–342. [Google Scholar] [CrossRef] [PubMed]
  67. Ngim, C.F.; Lai, N.M.; Hong, J.Y.; Tan, S.L.; Ramadas, A.; Muthukumarasamy, P.; Thong, M.K. Growth hormone therapy for people with thalassaemia. Cochrane Database Syst. Rev. 2017, 9, CD012284. [Google Scholar] [CrossRef] [PubMed]
  68. Dighriri, I.M.; Alrabghi, K.K.; Sulaiman, D.M.; Alruwaili, A.M.; Alanazi, N.S.; Al-Sadiq, A.A.; Hadadi, A.M.; Sahli, B.Y.; Qasem, B.A.; Alotaibi, M.T.; et al. Efficacy and Safety of Luspatercept in the Treatment of β-Thalassemia: A Systematic Review. Cureus. 2022, 14, e31570. [Google Scholar] [CrossRef] [PubMed]
  69. Shah, F.T.; Sayani, F.; Trompeter, S.; Drasar, E.; Piga, A. Challenges of blood transfusions in β-thalassemia. Blood Rev. 2019, 37, 100588. [Google Scholar] [CrossRef]
  70. Gaziev, J.; Sodani, P.; Polchi, P.; Andreani, M.; Lucarelli, G. Bone marrow transplantation in adults with thalassemia: Treatment and long-term follow-up. Ann. N. Y. Acad. Sci. 2005, 1054, 196–205. [Google Scholar] [CrossRef]
  71. Lucarelli, G.; Isgrò, A.; Sodani, P.; Gaziev, J. Hematopoietic stem cell transplantation in thalassemia and sickle cell anemia. Cold Spring Harb. Perspect. Med. 2012, 2, a011825. [Google Scholar] [CrossRef]
  72. Khiabani, A.; Kohansal, M.H.; Keshavarzi, A.; Shahraki, H.; Kooshesh, M.; Karimzade, M.; Gholizadeh Navashenaq, J. CRISPR/Cas9, a promising approach for the treatment of β-thalassemia: A systematic review. Mol. Genet. Genomics. 2023, 298, 1–11. [Google Scholar] [CrossRef]
  73. Asghar, A.A.; Khabir, Y.; Hashmi, M.R. Zynteglo: Betibeglogene autotemcel—An innovative therapy for β-thalassemia patients. Ann. Med. Surg. 2022, 82, 104624. [Google Scholar] [CrossRef] [PubMed]
  74. Giardina, B.; Messana, I.; Scatena, R.; Castagnola, M. The multiple functions of hemoglobin. Crit. Rev. Biochem. Mol. Biol. 1995, 30, 165–196. [Google Scholar] [CrossRef]
Figure 1. The essential principles of murburn concept are depicted graphically. Topological complementation of the enzyme–substrate as a lock–key or induced fit complex is not necessary in murburn catalytic (top panel) or e-transfer (mid-panel) schemes between the donor and acceptor, as it involves the intermediacy of enzyme-produced or enzyme-stabilized DR(O)S. The DR(O)S generated in milieu can also move moieties onto proteins/biomolecules, thereby enlarging the metabolo-proteomic landscape of the cell (bottom panel).
Figure 1. The essential principles of murburn concept are depicted graphically. Topological complementation of the enzyme–substrate as a lock–key or induced fit complex is not necessary in murburn catalytic (top panel) or e-transfer (mid-panel) schemes between the donor and acceptor, as it involves the intermediacy of enzyme-produced or enzyme-stabilized DR(O)S. The DR(O)S generated in milieu can also move moieties onto proteins/biomolecules, thereby enlarging the metabolo-proteomic landscape of the cell (bottom panel).
Thalassrep 13 00013 g001
Figure 2. Murburn concept postulates that DRS produced in oxygen–water equilibriums are not to be seen purely as “oxidative stress” agents (dangerous and toxic waste products), but they serve as obligatorily required intermediates essential for cellular powering, coherence, homeostasis, electro-mechanics, etc.
Figure 2. Murburn concept postulates that DRS produced in oxygen–water equilibriums are not to be seen purely as “oxidative stress” agents (dangerous and toxic waste products), but they serve as obligatorily required intermediates essential for cellular powering, coherence, homeostasis, electro-mechanics, etc.
Thalassrep 13 00013 g002
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Manoj, K.M. What Is the Relevance of Murburn Concept in Thalassemia and Respiratory Diseases? Thalass. Rep. 2023, 13, 144-151. https://doi.org/10.3390/thalassrep13020013

AMA Style

Manoj KM. What Is the Relevance of Murburn Concept in Thalassemia and Respiratory Diseases? Thalassemia Reports. 2023; 13(2):144-151. https://doi.org/10.3390/thalassrep13020013

Chicago/Turabian Style

Manoj, Kelath Murali. 2023. "What Is the Relevance of Murburn Concept in Thalassemia and Respiratory Diseases?" Thalassemia Reports 13, no. 2: 144-151. https://doi.org/10.3390/thalassrep13020013

Article Metrics

Back to TopTop