Allosteric activation of pyruvate decarboxylases. A never-ending story?

The allosteric substrate activation of pyruvate decarboxylases was studied for more than 30 years using varying techniques and ending up in different hypotheses on the molecular mechanism of substrate activation of this enzyme. Now, a number of high-resolution structures of the pyruvate decarboxylase species from Saccharomyces cerevisiae and from Kluyveromyces lactis – both wild type and variants in complex with covalently bound substrate or substrate surrogates – provided for the first time structural insights to decipher the mechanism of allosteric activation by describing the signal transduction pathway from the regulatory to the active site in detail. Here, the mechanistic studies on substrate activation of pyruvate decarboxylases are reviewed from a historical point of view, demonstrating that important parts of the different hypotheses got carried away with our new mechanism drawn from latest results of experiments on activation kinetics, small-angle X-ray solution scattering and X-ray crystal diffraction.