Thiamin diphosphate-dependent enzymes: fromenzymology to metabolic regulation, drug design anddisease models

摘要

Bringing a knowledge of enzymology into research in vivo and in situ is ofgreat importance in understanding systems biology and metabolic regulation.The central metabolic significance of thiamin (vitamin B1) and its diphosphorylatedderivative (thiamin diphosphate; ThDP), and the fundamentaldifferences in the ThDP-dependent enzymes of metabolic networks in mammalsversus plants, fungi and bacteria, or in health versus disease, suggestthat these enzymes are promising targets for biotechnological and medicalapplications. Here, the in vivo action of known regulators of ThDP-dependentenzymes, such as synthetic structural analogs of the enzyme substratesand thiamin, is analyzed in light of the enzymological data accumulatedduring half a century of research. Mimicking the enzyme-specific catalyticintermediates, the phosphonate analogs of 2-oxo acids selectively inhibitparticular ThDP-dependent enzymes. Because of their selectivity, use ofthese compounds in cellular and animal models of ThDP-dependent enzymemalfunctions improves the validity of the model and its predictive powerwhen compared with the nonselective and enzymatically less characterizedoxythiamin and pyrithiamin. In vitro studies of the interaction of thiaminanalogs and their biological derivatives with potential in vivo targets arenecessary to identify and attenuate the analog selectivity. For both the substrateand thiamin synthetic analogs, in vitro reactivities with potential targetsare highly relevant in vivo. However, effective concentrations in vivo areoften higher than in vitro studies would suggest. The significance of specificinihibition of the ThDP-dependent enzymes for the development of herbicides,antibiotics, anticancer and neuroprotective strategies is discussed.