A Survey of Oxidative Paracatalytic Reactions Catalyzed by Enzymes that Generate Carbanionic Intermediates: Implications for ROS Production, Cancer Etiology, and Neurodegenerative Diseases

Bunik, Victoria I.; Schloss, John V.; Pinto, John T.; Dudareva, Natalia; Cooper, Arthur J. L.

doi:10.1002/9780470920541.ch7

Cited by 25 publications

(36 citation statements)

References 109 publications

(206 reference statements)

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“…With increasing triethylated SP, both mitochondrial polarization and ROS production decreased monotonously . First, these data provide evidence on the contribution to glutamate neurotoxicity of ROS produced by OGDHC . Second, they indicate that strong inhibition of OGDHC by SP under conditions of glutamate excitotoxicity activates the ROS sources other than the 2‐oxoglutarate‐dependent reaction of OGDHC, which is inhibited by SP, and mitochondrial potential/NADH‐dependent reactions of the respiratory chain, which are inhibited by decreases in ΔΨ/NADH (Fig.…”

Section: Modeling the Impaired Function Of Neuronal And Brain Ogdhc Bmentioning

confidence: 72%

Thiamin diphosphate-dependent enzymes: from enzymology to metabolic regulation, drug design and disease models

Bunik

Tylicki

Lukashev

2013

FEBS J

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102

128

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Bringing a knowledge of enzymology into research in vivo and in situ is of great importance in understanding systems biology and metabolic regulation. The central metabolic significance of thiamin (vitamin B 1 ) and its diphosphorylated derivative (thiamin diphosphate; ThDP), and the fundamental differences in the ThDP-dependent enzymes of metabolic networks in mammals versus plants, fungi and bacteria, or in health versus disease, suggest that these enzymes are promising targets for biotechnological and medical applications. Here, the in vivo action of known regulators of ThDP-dependent enzymes, such as synthetic structural analogs of the enzyme substrates and thiamin, is analyzed in light of the enzymological data accumulated during half a century of research. Mimicking the enzyme-specific catalytic intermediates, the phosphonate analogs of 2-oxo acids selectively inhibit particular ThDP-dependent enzymes. Because of their selectivity, use of these compounds in cellular and animal models of ThDP-dependent enzyme malfunctions improves the validity of the model and its predictive power when compared with the nonselective and enzymatically less characterized oxythiamin and pyrithiamin. In vitro studies of the interaction of thiamin analogs and their biological derivatives with potential in vivo targets are necessary to identify and attenuate the analog selectivity. For both the substrate and thiamin synthetic analogs, in vitro reactivities with potential targets are highly relevant in vivo. However, effective concentrations in vivo are often higher than in vitro studies would suggest. The significance of specific inihibition of the ThDP-dependent enzymes for the development of herbicides, antibiotics, anticancer and neuroprotective strategies is discussed.

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Section: Modeling the Impaired Function Of Neuronal And Brain Ogdhc Bmentioning

confidence: 72%

Thiamin diphosphate-dependent enzymes: from enzymology to metabolic regulation, drug design and disease models

Bunik

Tylicki

Lukashev

2013

FEBS J

Self Cite

102

128

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“…2). Most mechanistic proposals [11‐15] describe a streamlined process in which the quinonoid intermediate donates a single electron to oxygen, forming superoxide and a semiquinone as a caged radical pair. Then, the radical pair can collapse to form a hydroperoxy‐intermediate localized at either the C4′ of PLP (Hydroperoxy I) or the α‐carbon of the substrate (Hydroperoxy II).…”

Section: Understanding Reactivity Of Plp‐dependent Enzymes With O2mentioning

confidence: 99%

“…The term ‘paracatalytic’ describes the use of a nonphysiological oxidizing reagent in an enzymatic reaction [11,16,17], a term that also encompasses oxidative side reactions with O 2 [18]. The first enzyme found to undergo a paracatalytic reaction with O 2 itself was Rubisco, which produces two molecules of 3‐phosphoglycerate from ribulose‐1,5‐bisphosphate, but will also use oxygen paracatalytically to make one molecule of 3‐phosphoglycerate and one molecule of 2‐phosphoglycerate [19,20].…”

Section: Paracatalytic Reactions Of Plp‐dependent Enzymes With O2mentioning

confidence: 99%

Emergence of oxygen‐ and pyridoxal phosphate‐dependent reactions

2020

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Pyridoxal 5′‐phosphate (PLP) is an organic cofactor employed by ~ 4% of enzymes. The structure of the PLP cofactor allows for the stabilization of carbanions through resonance. A small number of PLP‐dependent enzymes employ molecular oxygen as a cosubstrate. Here, we review the biological roles and possible mechanisms of these enzymes, and we observe that these enzymes are found in multiple protein families, suggesting that reaction with oxygen might have emerged de novo in several protein families and thus could be directed to emerge again through laboratory evolution experiments.

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“…Other important mechanisms involve delocalization of the charge through the formation of a Schiff base, generally with an active site lysine (e.g., in Class I aldolases), or through interaction with aromatic cofactors such as pyridoxal 5′‐phosphate (PLP) or thiamine diphosphate. Again, amongst enzymes showing these mechanisms, a side reaction with O 2 may or may not be observed (Bunik, Schloss, Pinto, Dudareva, & Cooper, ). It is worth mentioning here that although significant O 2 ‐consuming activities have been well documented for PLP‐ and thiamine diphosphate‐containing enzymes (e.g., ALS II and 2‐oxoglutarate dehydrogenase), the case of Class I aldolases is less clear (Table ).…”

Section: How Slow Is Rubisco?mentioning

confidence: 99%

“…And in all cases (except for aldolases which can bind a range of C 3 to C 5 aldehydes onto DHAP; Schoevaart, van Rantwijk, & Sheldon, ), CO 2 is either a product or a substrate of the reaction. For example, in the wide family of PLP‐dependent enzymes, O 2 ‐consuming side reactions are restricted to members of the decarboxylases class (Bunik et al, ; Table ). One may thus wonder whether there is a link between (de)carboxylation and enzyme sensitivity to O 2 .…”

Section: How Slow Is Rubisco?mentioning

confidence: 99%

Rubisco is not really so bad

Bathellier

Tcherkez

Lorimer

et al. 2018

Plant Cell & Environment

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Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) is the most widespread carboxylating enzyme in autotrophic organisms. Its kinetic and structural properties have been intensively studied for more than half a century. Yet important aspects of the catalytic mechanism remain poorly understood, especially the oxygenase reaction. Because of its relatively modest turnover rate (a few catalytic events per second) and the competitive inhibition by oxygen, Rubisco is often viewed as an inefficient catalyst for CO fixation. Considerable efforts have been devoted to improving its catalytic efficiency, so far without success. In this review, we re-examine Rubisco's catalytic performance by comparison with other chemically related enzymes. We find that Rubisco is not especially slow. Furthermore, considering both the nature and the complexity of the chemical reaction, its kinetic properties are unremarkable. Although not unique to Rubisco, oxygenation is not systematically observed in enolate and enamine forming enzymes and cannot be considered as an inevitable consequence of the mechanism. It is more likely the result of a compromise between chemical and metabolic imperatives. We argue that a better description of Rubisco mechanism is still required to better understand the link between CO and O reactivity and the rationale of Rubisco diversification and evolution.

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A Survey of Oxidative Paracatalytic Reactions Catalyzed by Enzymes that Generate Carbanionic Intermediates: Implications for ROS Production, Cancer Etiology, and Neurodegenerative Diseases

Cited by 25 publications

References 109 publications

Thiamin diphosphate-dependent enzymes: from enzymology to metabolic regulation, drug design and disease models

Thiamin diphosphate-dependent enzymes: from enzymology to metabolic regulation, drug design and disease models

Emergence of oxygen‐ and pyridoxal phosphate‐dependent reactions

Rubisco is not really so bad

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