Different Extent of Inhibition of Pyruvate Dehydrogenase and 2-Oxoglutarate Dehydrogenase Both Containing Endogenous Thiamine Pyrophosphate, by Some Anticoenzyme Analogues

Strumilo, S.; Czygier, Maria; Markiewicz, Jolanta

doi:10.3109/14756369509021472

Cited by 16 publications

(9 citation statements)

References 14 publications

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“…PDHC is one of the key enzymes of glucose metabolism 26 . The K m value of TPP in relation to PDHC determined in our study was similar to the value of the enzyme from bovine heart 27 but ten times lower than the K m of the enzyme from European bison heart 28 . In the presence of OTPP, the K m value of TPP increased by about 50%.…”

Section: Discussionsupporting

confidence: 75%

Differences in the efficiency of 3-deazathiamine and oxythiamine pyrophosphates as inhibitors of pyruvate dehydrogenase complex and growth of HeLa cells in vitro

Grabowska

Czerniecka

Czyżewska

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Section: Discussionsupporting

confidence: 75%

Differences in the efficiency of 3-deazathiamine and oxythiamine pyrophosphates as inhibitors of pyruvate dehydrogenase complex and growth of HeLa cells in vitro

Grabowska

Czerniecka

Czyżewska

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Our results show that PDH is mainly responsible for this effect because this enzyme exhibits a strong, continuous decrease in its specific activity. Therefore, we suggest that oxythiamine does not affect the PDH activity by phosphorylation but modifies PDH activity as an anticoenzyme molecule that blocks the active sites of TPP-dependent enzymes (Wittorf and Gubler 1971;Strumilo et al 1995). It is known that PDH is regulated by phosphorylation and TPP decreases the specific PDH kinase activity (Walsh et al 1976;Czygier and Strumilo 1995).…”

Section: Discussionmentioning

confidence: 87%

Modification of thiamine pyrophosphate dependent enzyme activity by oxythiamine inSaccharomyces cerevisiaecells

Tylicki¹,

Czerniecki²,

Dobrzyń³

et al. 2005

Can. J. Microbiol.

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Oxythiamine is an antivitamin derivative of thiamine that after phosphorylation to oxythiamine pyro phosphate can bind to the active centres of thiamine-dependent enzymes. In the present study, the effect of oxythiamine on the viability of Saccharomyces cerevisiae and the activity of thiamine pyrophosphate dependent enzymes in yeast cells has been investigated. We observed a decrease in pyruvate decarboxylase specific activity on both a control and an oxythiamine medium after the first 6 h of culture. The cytosolic enzymes transketolase and pyruvate decarboxylase decreased their specific activity in the presence of oxythiamine but only during the beginning of the cultivation. However, after 12 h of cultivation, oxythiamine-treated cells showed higher specific activity of cytosolic enzymes. More over, it was established by SDS-PAGE that the high specific activity of pyruvate decarboxylase was followed by an increase in the amount of the enzyme protein. In contrast, the mitochondrial enzymes, pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes, were inhibited by oxythiamine during the entire experiment. Our results suggest that the observed strong decrease in growth rate and viability of yeast on medium with oxythiamine may be due to stronger inhibition of mitochondrial pyruvate dehydrogenase than of cytosolic enzymes.

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“…Although such analogues should affect all thiamine-dependent enzymes, OGDHC was observed to be the physiologically relevant target both following pyrithiamine treatment [14,[74][75][76] and when a single high dose of oxythiamine was injected [77]. By contrast, when the inhibition by the thiamine antagonists was studied in vitro using isolated thiamine-dependent enzymes of central metabolism, OGDHC was inhibited only by concentrations of the thiamine analogues that were three orders of magnitude higher than those affecting transketolase and pyruvate dehydrogenase [78]. This apparent discrepancy is resolved when taking into account different reactivities to the coenzyme analogues of the free (apo) and ThDP-bound (holo) enzymes.…”

Section: Thiamine Antagonists As In Vivo Inhibitors Of Ogdhcmentioning

confidence: 99%

“…Unlike pyruvate dehydrogenase and transketolase, OGDHC isolated from normal animal tissues is a holoenzyme. That is, isolated animal OGDHC contains tightly bound ThDP and does not require the coenzyme addition to the activity assay medium, whereas pyruvate dehydrogenase and transketolase do [78][79][80]. Hence, in vitro, this tightly bound ThDP at the active site of OGDHC obviously interferes with binding the ThDP analogue, which may, however, easily bind to the apoforms of pyruvate dehydrogenase and transketolase.…”

Section: Thiamine Antagonists As In Vivo Inhibitors Of Ogdhcmentioning

confidence: 99%

Metabolic control exerted by the 2-oxoglutarate dehydrogenase reaction: a cross-kingdom comparison of the crossroad between energy production and nitrogen assimilation

Bunik

Fernie

2009

Biochemical Journal

115

120

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Mechanism-based inhibitors and both forward and reverse genetics have proved to be essential tools in revealing roles for specific enzymatic processes in cellular function. Here, we review experimental studies aimed at assessing the impact of OG (2-oxoglutarate) oxidative decarboxylation on basic cellular activities in a number of biological systems. After summarizing the catalytic and regulatory properties of the OGDHC (OG dehydrogenase complex), we describe the evidence that has been accrued on its cellular role. We demonstrate an essential role of this enzyme in metabolic control in a wide range of organisms. Targeting this enzyme in different cells and tissues, mainly by its specific inhibitors, effects changes in a number of basic functions, such as mitochondrial potential, tissue respiration, ROS (reactive oxygen species) production, nitrogen metabolism, glutamate signalling and survival, supporting the notion that the evolutionary conserved reaction of OG degradation is required for metabolic adaptation. In particular, regulation of OGDHC under stress conditions may be essential to overcome glutamate excitotoxicity in neurons or affect the wound response in plants. Thus, apart from its role in producing energy, the flux through OGDHC significantly affects nitrogen assimilation and amino acid metabolism, whereas the side reactions of OGDHC, such as ROS production and the carboligase reaction, have biological functions in signalling and glyoxylate utilization. Our current view on the role of OGDHC reaction in various processes within complex biological systems allows us a far greater fundamental understanding of metabolic regulation and also opens up new opportunities for us to address both biotechnological and medical challenges.

show abstract

Different Extent of Inhibition of Pyruvate Dehydrogenase and 2-Oxoglutarate Dehydrogenase Both Containing Endogenous Thiamine Pyrophosphate, by Some Anticoenzyme Analogues

Cited by 16 publications

References 14 publications

Differences in the efficiency of 3-deazathiamine and oxythiamine pyrophosphates as inhibitors of pyruvate dehydrogenase complex and growth of HeLa cells in vitro

Differences in the efficiency of 3-deazathiamine and oxythiamine pyrophosphates as inhibitors of pyruvate dehydrogenase complex and growth of HeLa cells in vitro

Modification of thiamine pyrophosphate dependent enzyme activity by oxythiamine inSaccharomyces cerevisiaecells

Metabolic control exerted by the 2-oxoglutarate dehydrogenase reaction: a cross-kingdom comparison of the crossroad between energy production and nitrogen assimilation

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