Vitamin-Dependent Multienzyme Complexes of 2-Oxo Acid Dehydrogenases : Structure, Function, Regulation & Medical Implications

This book summarises current data on the architecture, structure-function relationships, reaction mechanisms and active site coupling in multienzyme complexes of 2-oxo acid dehydrogenases. Special focus concerns the mechanisms of function and regulation of a multienzyme structure, additional to those inherent in its component enzymes. The overall physiological process of 2-oxo acid oxidative decarboxylation and the substrate specificity determinants are considered along with side reactions of regulatory significance, such as non-oxidative reactions, formation of reactive oxygen species (ROS) and complex-bound thiyl radicals. The significance of the chemical interplay between the complex-bound dihydrolipoate intermediate, thioredoxin or thioredoxin-like proteins, and peroxiredoxins for sensing metabolic state and adjusting the catalysis accordingly, is considered. Other mechanisms involved in the short- and long-term regulation of 2-oxo acid dehydrogenase complexes are summarized in view of their relevance to physiological functions. Metabolic regulation by natural effectors of 2-oxo acid dehydrogenase complexes and their synthetic analogues is considered. The medical implications of enzymological knowledge on the complexes are also presented.