The branch point effect. Ultrasensitivity and subsensitivity to metabolic control

Abstract

The interdependence of the activities of branch point enzymes which compete for a common substrate can yield ultrasensitivity or subsensitivity to control, even if the competing enzymes follow Michaelis-Menten kinetics. The nature of this "branch point effect" for a particular system depends on the kinetic parameters of the competing enzymes, the rate of substrate production leading into the branch point and the type of regulatory mechanism involved. With physiologically reasonable parameter values, the branch point effect can give ultrasensitivity equivalent to an allosteric enzyme with a Hill coefficient of 8 or higher. An experimental example of this ultrasensitivity was provided by the branch point between isocitrate lyase (of the glyoxylate bypass) and isocitrate dehydrogenase in Escherichia coli. The glyoxylate bypass is very active during growth on acetate but its flux decreases by a factor of approximately 150 upon addition of glucose. This inhibition is brought about by two relatively modest events: a 4-fold increase in the maximum velocity of isocitrate dehydrogenase and a factor of 5.5 decrease in the rate of isocitrate production. The mechanism which underlies this sensitivity amplification is discussed.