  The universality of many pathways of core metabolism suggests a strong role
for evolutionary selection, but it remains unclear whether existing pathways
have been selected from a large or small set of biochemical possibilities. To
address this question, we construct "in silico" all possible biochemically
feasible alternatives to the trunk pathway of glycolysis and gluconeogenesis,
one of the most highly conserved pathways in metabolism. We show that, even
though a large number of alternative pathways exist, the alternatives carry
lower flux than the real pathway under typical physiological conditions.
Alternative pathways that could potentially carry higher flux often lead to
infeasible intermediate metabolite concentrations. We also find that if
physiological conditions were different, different pathways could outperform
those found in nature. Our results demonstrate how the rules of biochemistry
restrict the alternatives that are open to evolution, and suggest that the
existing trunk pathway of glycolysis and gluconeogenesis represents a maximal
flux solution.
