The far reaches of enzymology.

essential prerequisite for understanding the underlying chemical processes in biological systems, well before the advent of modern methods for overexpression and affinity tagging 2. In addition to the most basic task of identifying distinct enzymes that catalyze distinct reactions (an endeavor that continues in the genomic era), enzymes were shown to exhibit high specificity, enforce stereochem-istry, react via covalent catalysis, utilize general acid/base catalysis in proton transfer steps and manipulate the pK a (protonation state) of active site residues 3–8. What may be unimaginable to the contemporary scientist is that these physical models for the action of enzymes were developed in the absence of direct structural models. How would modern-day protein sciences proceed if we were suddenly blinded to the general and specific properties and features of proteins and their active sites? Today, as the frontiers of biochemistry encompass complex and dynamic macromolecular assemblies that carry out complex biological functions but are difficult to visualize structurally, the field is in need of modern-day enzymologists and biologists to make analogous conceptual advances into the workings of complex systems. A key insight in the transformation of enzy-mology into a rigorous science was the realization that basic chemical principles could be applied to enzyme action. As we understand its history, the earliest recognition that binding to a catalyst could lower the energy barrier for a chemical reaction came from Polanyi in 1921 (refs. 9,10). More than 20 years later, Pauling articulated this idea in terms of preferential transition-state recognition to account for enzyme activity: of modern enzymology. The discovery of vitamins and then of metabolic pathways and products in the early twentieth century spurred interest in understanding the underlying chemical transformations that produce these molecules. Around mid-century, this knowledge and the chemical tools and assays available, coupled with the emerging area of protein purification, led to an explosion of information about biological reactions and the enzymes that catalyze them. The stage was set for the emergence of enzymology as a central science of biochemistry. Though chemistry was the foundation for revealing the inner workings of biology at the time, biology spurred new advances in chemistry , with a plethora of new compounds and new reactions to study, efforts to mimic biological processes, and the overarching question of how enzymes could achieve their enormous rate enhancements and exquisite specificities. Many of the 'new' biological reactions, such as those involving phosphate esters and anhydrides, were …