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词条 Draft:Murburn hypothesis
释义

  1. The basic components of the murburn scheme

  2. Salient features of the murburn concept

  3. Application of the murburn concept

  4. References

{{AFC submission|d|reason|Requires inline citation. Please take time to work on this, The topic appears interesting for the wiki world.|ns=118|reviewer=Mgbo120|reviewts=20190125192436|decliner=Mgbo120|declinets=20190125192744|ts=20190125192436}} Murburn is a term coined in 2016 to conceptualize and explain the catalytic mechanism of certain redox enzymes.[1][2][3] In its essence, the term connotes a ubiquitous interactive equilibrium between molecules, unbound ion and radicals, signifying a process involving "mild unrestricted redox catalysis". In aerobic redox enzymology, murburn stands for "mured burning" (connoting a "closed burning"), and implies a spontaneous reaction/equilibrium involving diffusible reactive oxygen species (DROS). Though quite 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 may generate heat alone (and no flames). Such a reaction could also incur selective and specific electron/moiety transfers. Further, though burning is a reaction that usually involves oxygen (aerobic process), "burning flames"[4][5] produced by anoxic oxidants are also well-known.[4][5][6] Therefore, the enzymes working via murburn scheme (aerobic or anaerobic) could be called murzymes.[7]

The basic components of the murburn scheme

  • 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

Salient features of the murburn concept

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 very 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 stoichiometries. 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.

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.

Application of the murburn concept

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),[10][11][12] 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.[13][14]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.[15][16][17][18][19] Thus, the murburn activities of hemeperoxidases are very important for explaining the carbon/halogen cycles.[20]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.[21][22]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. The murburn scheme presents a new interpretation of the physiology of cellular respiration.[23]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.[24][25]

References

1. ^{{cite journal|last1=Venkatachalam|first1=Avanthika|last2=Parashar|first2=Abhinav|last3=Manoj|first3=Kelath Murali|date=19 February 2016|title=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|url=https://link.springer.com/article/10.1186/s40203-016-0016-7|journal=In Silico Pharmacology|volume=4|issue=1|pages=|doi=10.1186/s40203-016-0016-7|via=}}
2. ^{{cite journal |last1=Manoj |first1=Kelath Murali |last2=Gade |first2=Sudeep K. |last3=Venkatachalam |first3=Avanthika |last4=Gideon |first4=Daniel A. |title=Electron transfer amongst flavo- and hemo-proteins: diffusible species effect the relay processes, not protein–protein binding |journal=RSC Advances |date=2016 |volume=6 |issue=29 |pages=24121–24129 |doi=10.1039/C5RA26122H}}
3. ^{{cite journal |last1=Manoj |first1=Kelath Murali |last2=Parashar |first2=Abhinav |last3=Gade |first3=Sudeep K. |last4=Venkatachalam |first4=Avanthika |title=Functioning of Microsomal Cytochrome P450s: Murburn Concept Explains the Metabolism of Xenobiotics in Hepatocytes |journal=Frontiers in Pharmacology |date=23 June 2016 |volume=7 |doi=10.3389/fphar.2016.00161}}
4. ^1 {{Citation|last=Periodic Videos|title=Fluorine - Periodic Table of Videos|date=2010-07-15|url=https://www.youtube.com/watch?v=vtWp45Eewtw|access-date=2019-03-31}}
5. ^1 {{Citation|title=Chlorine trifluoride|date=2019-01-29|url=https://en.wikipedia.org/w/index.php?title=Chlorine_trifluoride&oldid=880819084|work=Wikipedia|language=en|access-date=2019-03-31}}
6. ^{{Citation|title=Hypergolic propellant|date=2019-01-24|url=https://en.wikipedia.org/w/index.php?title=Hypergolic_propellant&oldid=879963042|work=Wikipedia|language=en|access-date=2019-03-31}}
7. ^{{cite journal |last1=Manoj |first1=Kelath Murali |title=Debunking Chemiosmosis and Proposing Murburn Concept as the Operative Principle for Cellular Respiration |journal=Biomedical Reviews |date=22 March 2018 |volume=28 |issue=0 |pages=31 |doi=10.14748/bmr.v28.4450}}
8. ^{{cite journal |last1=Murali Manoj |first1=Kelath |title=Chlorinations catalyzed by chloroperoxidase occur via diffusible intermediate(s) and the reaction components play multiple roles in the overall process |journal=Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics |date=August 2006 |volume=1764 |issue=8 |pages=1325–1339 |doi=10.1016/j.bbapap.2006.05.012}}
9. ^{{cite book |last1=Fersht |first1=Alan |title=Structure and mechanism in protein science : a guide to enzyme catalysis and protein folding |publisher=W.H. Freeman |isbn=0-7167-3268-8 |pages=Enzyme Structure and Mechanism}}
10. ^{{cite book |title=Cytochrome P450: Structure, Mechanism, and Biochemistry |date=2015 |publisher=Springer International Publishing |isbn=9783319121079 |edition=4 |url=https://www.springer.com/us/book/9783319121079 |language=en}}
11. ^{{cite book |last1=Dunford |first1=BH |title=Heme peroxidases |date=1999 |publisher=John Wiley |isbn=0-471-24244-6}}
12. ^{{cite journal |last1=Dawson |first1=J. |title=Probing structure-function relations in heme-containing oxygenases and peroxidases |journal=Science |date=22 April 1988 |volume=240 |issue=4851 |pages=433–439 |doi=10.1126/science.3358128}}
13. ^{{cite journal |last1=Manoj |first1=Kelath Murali |last2=Gade |first2=Sudeep Kumar |last3=Mathew |first3=Lazar |last4=Uversky |first4=Vladimir N. |title=Cytochrome P450 Reductase: A Harbinger of Diffusible Reduced Oxygen Species |journal=PLoS ONE |date=13 October 2010 |volume=5 |issue=10 |pages=e13272 |doi=10.1371/journal.pone.0013272}}
14. ^{{cite journal |last1=Manoj |first1=Kelath Murali |last2=Parashar |first2=Abhinav |last3=Venkatachalam |first3=Avanthika |last4=Goyal |first4=Sahil |last5=Satyalipsu |last6=Singh |first6=Preeti Gunjan |last7=Gade |first7=Sudeep K. |last8=Periyasami |first8=Kalaiselvi |last9=Jacob |first9=Reeba Susan |last10=Sardar |first10=Debosmita |last11=Singh |first11=Shanikant |last12=Kumar |first12=Rajan |last13=Gideon |first13=Daniel A. |title=Atypical profiles and modulations of heme-enzymes catalyzed outcomes by low amounts of diverse additives suggest diffusible radicals' obligatory involvement in such redox reactions |journal=Biochimie |date=June 2016 |volume=125 |pages=91–111 |doi=10.1016/j.biochi.2016.03.003}}
15. ^{{cite journal |last1=Reina |first1=Rachel G. |last2=Leri |first2=Alessandra C. |last3=Myneni |first3=Satish C. B. |title=Cl K-edge X-ray Spectroscopic Investigation of Enzymatic Formation of Organochlorines in Weathering Plant Material |journal=Environmental Science & Technology |date=February 2004 |volume=38 |issue=3 |pages=783–789 |doi=10.1021/es0347336}}
16. ^{{cite journal |last1=Ortiz-Bermudez |first1=P. |last2=Srebotnik |first2=E. |last3=Hammel |first3=K. E. |title=Chlorination and Cleavage of Lignin Structures by Fungal Chloroperoxidases |journal=Applied and Environmental Microbiology |date=5 August 2003 |volume=69 |issue=8 |pages=5015–5018 |doi=10.1128/AEM.69.8.5015-5018.2003}}
17. ^{{cite journal |last1=Niedan |first1=Volker |last2=Pavasars |first2=Ivars |last3=Öberg |first3=Gunilla |title=Chloroperoxidase-mediated chlorination of aromatic groups in fulvic acid |journal=Chemosphere |date=September 2000 |volume=41 |issue=5 |pages=779–785 |doi=10.1016/S0045-6535(99)00471-3}}
18. ^{{cite journal |last1=Carlsen |first1=Lars |last2=Lassen |first2=Pia |title=Enzymatically mediated formation of chlorinated humic acids |journal=Organic Geochemistry |date=July 1992 |volume=18 |issue=4 |pages=477–480 |doi=10.1016/0146-6380(92)90110-J}}
19. ^{{cite journal |last1=Walter |first1=B. |last2=Ballschmiter |first2=K. |title=Biohalogenation as a source of halogenated anisoles in air |journal=Chemosphere |date=January 1991 |volume=22 |issue=5-6 |pages=557–567 |doi=10.1016/0045-6535(91)90067-N}}
20. ^{{cite journal |last1=Manoj |first1=Kelath Murali |last2=Hager |first2=Lowell P. |title=Chloroperoxidase, a Janus Enzyme |journal=Biochemistry |date=March 2008 |volume=47 |issue=9 |pages=2997–3003 |doi=10.1021/bi7022656}}
21. ^{{cite journal |last1=Guengerich |first1=F. Peter |last2=Yoshimoto |first2=Francis K. |title=Formation and Cleavage of C–C Bonds by Enzymatic Oxidation–Reduction Reactions |journal=Chemical Reviews |date=22 June 2018 |volume=118 |issue=14 |pages=6573–6655 |doi=10.1021/acs.chemrev.8b00031}}
22. ^{{cite journal |last1=Manoj |first1=KM |title=ABSTRACTS FROM THE 20TH NORTH AMERICAN ISSX MEETING |journal=Drug Metabolism Reviews |date=15 July 2016 |volume=48 |issue=sup1 |pages=1–1 |doi=10.1080/03602532.2016.1191848}}
23. ^{{cite journal |last1=Manoj |first1=Kelath Murali |last2=Parashar |first2=Abhinav |last3=David Jacob |first3=Vivian |last4=Ramasamy |first4=Surjith |title=Aerobic respiration: proof of concept for the oxygen-centric murburn perspective |journal=Journal of Biomolecular Structure and Dynamics |date=29 November 2018 |pages=1–15 |doi=10.1080/07391102.2018.1552896}}
24. ^{{cite journal |last1=Chirumbolo |first1=Salvatore |last2=Bjørklund |first2=Geir |title=PERM Hypothesis: The Fundamental Machinery Able to Elucidate the Role of Xenobiotics and Hormesis in Cell Survival and Homeostasis |journal=International Journal of Molecular Sciences |date=15 January 2017 |volume=18 |issue=1 |pages=165 |doi=10.3390/ijms18010165}}
25. ^{{cite journal |last1=Parashar |first1=Abhinav |last2=Gideon |first2=Daniel Andrew |last3=Manoj |first3=Kelath Murali |title=Murburn Concept: A Molecular Explanation for Hormetic and Idiosyncratic Dose Responses |journal=Dose-Response |date=9 May 2018 |volume=16 |issue=2 |pages=155932581877442 |doi=10.1177/1559325818774421}}
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