The Role of Negative Cooperativity and Half-of-the-Sites Reactivity in Enzyme Regulation

This chapter discusses the role of negative cooperativity and half-of-the-sites reactivity in enzyme regulation. Negative cooperativity refers to the phenomenon in multisubunit proteins in which the binding affinities of ligands decrease as a function of ligand saturation. In positive cooperativity, the affinity of the protein toward the ligand increases as a function of ligand saturation, thus leading to sigmoidal saturation curves. The chapter analyzes the phenomenon of negative cooperativity from the theoretical point of view, discusses diagnostic tests for the property, and describes some well studied regulatory enzymes. The analysis of the binding of a single ligand to a multisubunit protein is in itself a fairly complex mathematical problem. The problem becomes Herculean when more than one ligand is involved, and yet that is precisely the case for regulatory proteins that usually have more than one substrate, more than one product, several regulatory molecules, and between two and eight subunits, each of which can combine with any of these molecules.