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

Bringing a knowledge of enzymology into research invivo and insitu is of great importance in understanding systems biology and metabolic regulation. The central metabolic significance of thiamin (vitaminB(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 invivo 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. Invitro studies of the interaction of thiamin analogs and their biological derivatives with potential invivo targets are necessary to identify and attenuate the analog selectivity. For both the substrate and thiamin synthetic analogs, invitro reactivities with potential targets are highly relevant invivo. However, effective concentrations invivo are often higher than invitro 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.