Molecular basis of enzyme catalysis and control.

Regulatory processes in living systems can be shown to be caused by ligand induced changes in the shape of a protein. By dividing the protein shape changes into molecular parameters a quantitative analysis of the regulation process can be obtained which is shown to correlate with actual data in living systems. The complexity of the analysis increases as the number of subunits in the enzyme and the number of ligands considered in the regulatory proces increases. However, the principles are seen to be fundamentally similar in all cases. The orientation of reaction orbitals may be a key factor in the catalytic power of enzymes and in its regulatory control features. When enzymes were first identified Berzelius and others recognized them as chemical catalysts. As their properties emerged, however, it was clear they had some special features not typical of other chemical catalysts such as acids and bases. One of these unusual properties was their specificity. The second was their enormous catalytic power. Conceptually these two processes are distinct. Experimentally there are some enzymes with high specificity and low catalytic power and some enzymes with high catalytic power and low specificity. Recent studies to unravel the fundamental nature of these processes have led us to the conclusion that there is an intimate connection between these unusual properties which may help to explain some of the unusual chemical and biological roles of these unique catalysts. To explain the specificity of enzymes Emil Fischer proposed the fitting of a substrate to the surface of a protein in a template or keylock arrangement1. The juxtaposition of a catalytic group with the bond to be formed or broken was essential and the rest of the molecule had to fit into a complementary surface to allow this juxtaposition. A combination of steric and electrostatic repulsions plus attractive forces in the substrate—enzyme contacts not directly involved in the bond breaking would thus explain this specificity of the enzyme. Some years ago it occurred to us that this classical theory was not sufficient to explain all the properties of enzymes and an induced fit theory was postulated2. This theory retained the idea of a fit between substrate and enzyme but added the requirement that the substrate must