This page contains the introduction of the following chapter:
A. Cornish-Bowden & M. L. Cárdenas
Glucokinase: a monomeric
cooperative enzyme with positive cooperativity,
in Glucokinase and Glycemic Disease: from Basics to Novel Therapeutics
(ed. F. M. Matschinsky & M. A. Magnuson),
Karger, Basle, pp. 125–134
Long before the relationship of glucokinase with MODY was established, its unusual structural and kinetic properties attracted the attention of several groups, the enzyme from rat liver showing mild positive cooperativity with respect to its substrate glucose, with a Hill coefficient of about 1.5. Other cooperative enzymes were already well known, but most showed stronger cooperativity, with Hill coefficients between 3 and 4; glucokinase also lacked other typical characteristics of regulatory enzymes, such as allosteric inhibition by a downstream metabolite and a number of subunits at least as large as the Hill coefficient. Although the mild cooperativity seen with glucokinase suggested that it might be a dimeric enzyme, there was no direct evidence of this: it appeared to be monomeric in all conditions, including those of the assay in which the cooperativity had been found. Models for cooperativity in monomeric enzyme were known, but these appeared not to be needed to explain the positive cooperativity of any enzyme with its natural substrate, and in practice were thought to be mainly of theoretical interest. The mechanism of the kinetic cooperativity of glucokinase therefore presented a problem to be understood, and forms the main topic of this chapter. Although a few other cases of cooperativity in monomeric enzymes have been reported, glucokinase remains the unique example of an important enzyme of primary metabolism for which the kinetic origin of the cooperativity has been clearly established.