NONLINEAR ENZYME-KINETICS CAN LEAD TO HIGH METABOLIC FLUX CONTROL COEFFICIENTS - IMPLICATIONS FOR THE EVOLUTION OF DOMINANCE

In a classic study, Kacser & Burns (1981, Genetics 97, 639-666) demons trated that given certain plausible assumptions, the flux in a metabol ic pathway was more or less indifferent to the activity of any of the enzymes in the pathway taken singly. It was inferred from this that th e observed dominance of most wild-type alleles with respect to loss-of -function mutations did not require an adaptive, meaning selectionist, explanation. Cornish-Bowden (1987, J. theor. Biol. 125, 333-338) show ed that the Kacser-Burns inference was not valid when substrate concen trations were large relative to the relevant Michaelis constants. We f ind that in a randomly constructed functional pathway, even when subst rate levels are small, one can expect high values of control coefficie nts for metabolic flux in the presence of significant nonlinearities a s exemplified by enzymes with Hill coefficients ranging from two to si x, or by the existence of oscillatory loops. Under these conditions th e flux can be quite sensitive to changes in enzyme activity as might b e caused by inactivating one of the two alleles in a diploid. Therefor e, the phenomenon of dominance cannot be a trivial ''default'' consequ ence of physiology but must be intimately linked to the manner in whic h metabolic networks have been moulded by natural selection. (C) 1996 Academic Press Limited