Allosteric cofactor-mediated enzyme cooperativity: a theoretical treatment.

Abstract

The situation under which substrate cooperativity is apparent only in the presence of an inhibitor was investigated. When a substrate and an inhibitor bind independently to a cooperative enzyme that conforms to the concerted Monod-Wyman-Changeux model, each of the 2 ligands must induce intersubunit transitions in the protein molecule in order to have their allosteric effects coupled to one another. The inhibitor exerts a heterotropic influence on the saturation function of the substrate and enhances the otherwise recondite homotropic effect of the latter. If the ligands bind competitively to the enzyme, however, intersubunit transitions in the enzyme need be induced only by the inhibitor. A sigmoidal substrate saturation curve is then obtained as a result of displacement of the inhibitor from the enzyme by the substrate. In this mechanism, the competitive inhibitor participates as a cofactor required for the expression of substrate cooperativity and the familiar ability of regulatory enzymes to mediate homotropic interactions directly between substrate molecules is absent. Experimental tests are proposed to elucidate the nature of cooperative interactions for enzymes [Escherichia coli ornithine transcarbamoylase] that appear to retain heterotropic but not homotropic effects in substrate binding.