On the physiological significance of positive and negative co-operativity.

Abstract

Negative co-operativity of binding was first predicted from the allosteric model of Koshland, Nemethy & Filmer (1966) and established experimentally for the glyceraldehyde-3-phosphate dehydrogenase present in rabbit muscle (Conway & Koshland, 1968; Meunier & Dalziel, 1978). Catalytic negative co-operativity (which may not reflect binding co-operativity) has also been well established for a number of systems: purine nucleoside phosphorylase (Savage & Spencer, 1979), alkaline phosphatase (Waight, Lett & Bardsley, 1977), AMP deaminase (Raggi & RannieriRaggi, 1979), glycogen synthase (Stilling, 1979), methanol oxidase (Van Dijken, 1975), methanol dehydrogenase (Ghosh, 1980a,b), pyruvate kinase (Gregory, 1980), hexokinase (Meunier et al., 1974). Negative co-operativity of binding has also been proposed for many hormone receptors (Levitski, 1974), though this has recently been disputed (Pollet, Standert & Haase, 1980). Kinetic rather than binding negative co-operativity does not affect the conclusions to be presented below. Indeed, it could be argued that selective pressure will not distinguish between these two possibilities. Despite the evidence that kinetic and binding negative co-operativity c,an .be observed for many enzymes, a physiological rationale for this phenomenon has been difficult to find. However, several workers have attempted an explanation of the phenomena (Levitski & Koshland, 1969; L.evitski, 1974; Cornish-Bowden, 1975; Friedrich, 1979) with varying degrees of success. The present study attempts to show a fresh light on this subject by adopting the general approach given by Cornish-Bowden (‘1975), but also by using a recently introduced phenomenological analysis of co-operative systems (Ainsworth, 1977). Recently Cornish-Bowden (1975) has shown that the sensitivity of a reaction characterized by the Hill equation to changes in the concentration of a ligand A is given by: dF ----= nP(lT) d In [A] (1)