The soul of enzymes : the mystery of biocatalysis

Proteins are molecular objects endowed with exceptional properties. Their structural organization and amino acid content, which modulate their stereoelectronic properties and dynamics, enable them to control the entry and exit of small molecules and the complementarity between reactive sites and substrates. Enzymes are in fact capable of fantastically accelerating the chemical reactions they catalyze, and measurement of the acceleration factor is often very difficult to obtain. To illustrate the methodologies involved, the case of uroporphyrinogen decarboxylase, an enzyme involved in the biosynthesis of heme, chlorophyll and cytochromes, was discussed (R. Wolfenden, PNAS 2008, 105, 17328). The acceleration factor is of the order of 1017. Various theories to explain these accelerations were presented, in particular the famous theory of transition-state stabilization proposed by L. Pauling in 1948. Even today, the catalytic power of enzymes remains a mystery and a subject of deep controversy, as regards the relative weight of entropic and enthalpic effects, and the reality of a defined transition state, to which classical thermodynamics can be applied. With a presentation of lysozyme, triose phosphate isomerase and cytidine deaminase to illustrate the various hypotheses, it emerges that the relative positions of the amino acids of the active sites and substrates, and the electrostatic interactions that result, play a major role in catalysis. This means, as A. Warshel suggests, that the origin of catalysis lies in the structure of the protein and that its catalytic power, the catalytic energy, is somehow implemented at the time of synthesis and not at the time of reaction.