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

Bunik, V.; Tylicki, A.; Lukashev, N.

Авторы: Bunik VI, Tylicki A., Lukashev NV
Журнал: FEBS Journal
Год издания: 2013
Издательство: Blackwell Publishing Inc.
Местоположение издательства: United Kingdom
DOI: 10.1111/febs.12512
Аннотация: Bringing a knowledge of enzymology into research in vivo and in situ is of great importance for understanding systems biology and metabolic regulation. The central metabolic significance of thiamin (vitamin B1) and its diphosphorylated derivative (ThDP), along with 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 will be 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 thiamin and substrates, is analyzed in light of the enzymological data accumulated during a half-a-century of research. Mimicking the enzyme-specific catalytic intermediates, the phosphonate analogs of 2-oxo acids selectively inhibit particular ThDP-dependent enzymes. Due to their selectivity, the use of these compounds in cellular and animal models of the ThDP-dependent enzyme malfunctions improves the validity of the model and its predictive power when compared to the non-selective 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, the concentrations to be effective in vivo are often higher than in vitro studies would suggest. The significance of specific inihibition of the ThDP-dependent enzymes for development of herbicides, antibiotics, anticancer and neuroprotective strategies is discussed.
Добавил в систему: Буник-Фаренвальд Виктория-Лариса Ивановна

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