Evolution and biophysics of the uric acid degradation pathway

Uric acid is a product of purine metabolism. Many organisms present a degradation pathway on which uric acid is converted to 5-HIU, then to OHCU and finally to S-allantoin. That is not the case for humans, who accumulate uric acid, sometimes to the point of developing conditions such as gout. This is caused by the loss of the uricase gene among some primates, and then other upstream genes due to the lack of selective pressure for the remaining steps of this pathway. The enzymes in the first two steps of this pathway have been investigated by our group and that of Eric Gaucher by reconstruction of ancestral sequences. Using biophysical and computational characterization of these ancestral sequences, we show how the second enzyme in this pathway catalyzed its reaction during the evolution of chordates and how a gene duplication on that period generated a thyroxine binding protein, transthyretin. Curiously, the pseudogene coding for the HIUase in humans is still expressed, and we discuss its possible roles. The third enzyme in the pathway, OHCU decarboxylase, seems to be still functional, and is currently under investigation by our group.