Kinetic Aspects of Regulation of Metabolic Processes

Hysteretic enzymes are defined as those enzymes which respond slowly (in terms of some kinetic characteristic) to a rapid change in ligand, either substrate or modifier, concentration. Such slow changes, defined in terms of their rate relative to the over-all catalytic reaction, result in a lag in the response of the enzyme to changes in the ligand level. Several mechanisms, including ligand-induced isomerization of the enzyme, displacement of tightly bound ligands by other ligands, or polymerization and depolymerization, are discussed and it can be shown that the description of the time-dependent change in enzyme activity is similar for many different cases. Examination of the literature reveals that a large number of enzymes may fall into the category termed hysteretic, that such enzymes are frequently those which are important in metabolic regulation, that the time of conversion from one kinetic form to another may vary between seconds and minutes, and that there are experimental examples of all the mechanisms which are discussed theoretically. The possible relation between those enzymes which are hysteretic and regulation of complex metabolic processes is discussed in terms of the fact that the slow response of the hysteretic enzyme to changes in ligand level will lead to a time-dependent buffering of some metabolites and that this may be important with respect to pathways which utilize common intermediates or in which there are multiple branch points. It is suggested that the question of hysteresis in enzyme systems as defined here be systematically investigated in regulatory enzymes and that this concept may be of value in discussing the regulation of complex processes in vivo.