Three human diseases of sialic acid metabolism (sialidosis, Salla disease and infantile sialic acid storage disease) result from defects in catabolism of sialic acid and lead to lysosomal storage. A fourth disorder of sialic acid metabolism, sialuria, has been postulated to result from defective regulation of sialic acid synthesis, in which the enzyme UDP-N-acetylglucosamine 2epimerase (UDP-GlcNAc epimerase) fails to be feedback inhibited by CMP-sialic acid, the final end-product of sialic acid synthesis, leading to excess synthesis of free sialic acid. This unique inborn error, described thus far in only three patients, is characterized by variable degrees of developmental delay, coarse facial features and massive urinary excretion of unconjugated sialic acid. Cultured skin fibroblasts from patients with this disease contain greatly increased quantities of free sialic acid localized within the cytosolic compartment (50-100 nmoles/mg cell protein) in comparison with the amount found in normal fibroblasts (ca. I nmole/mg protein). We have explored the postulated role of defective feedback inhibition of UDP-GlcNAc epimerase activity in the pathogenesis of human sialuria by direct measurement of enzyme activity in cultured fibroblasts from all three known patients with sialuria and in normal subjects. our studies have shown that 50 microM CMP-sialic acid inhibited the UDP-GlcNAc epimerase of normal cells by 84-100% but inhibited the epimerase from sialuria cells by only 19-31%. We conclude that the basic biochemical defect in all known cases of sialuria is a failure of CMP-sialic acid to feedback inhibit UDP-GlcNAc epimerase. Sialuria may represent a rare, and possibly unique, example of a human mutation affecting an enzyme allosteric center.
