Overproduction of N-Acetylneuraminic Acid (Sialic Acid) by Sialuria Fibroblasts

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Abstract
ABSTRAC: Fibroblasts from the original sialuria patientare shown to contain high levels of free sialic acid, i.e., anaverage of 87 versus a normal average of 2 nmol/mg ofprotein. Gas liquid chromatography-mass spectrometryanalysis confirmed that the accumulated material is N-acetylneuraminic acid. Addition of D(+) glucosamine (0-5mM) to the media of these cells increased the intracellularfree sialic acid concentrations from 74 to 137 nmol/mgprotein. In contrast, normal cells treated in an identicalmanner maintained their normal free sialic acid level ofless than 4 nmol/mg protein. Addition of 20 mM N-acetylmannosamine in place of glucosamine resulted in amarked increase in free sialic acid in both the patient andthe control, i.e., increases of 157 (from 95 to 252) and 120(from 3 to 123) nmol/mg protein, respectively. Finally,while normal cells in the presence of glucosamine accu-mulated high levels of uridine diphosphate N-acetylhexo-samine, the patient's cells accumulated much loweramounts of this compound. It is concluded that the elevatedsialic acid level in sialuria is due, at least in part, tooverproduction of free N-acetylneuraminic acid. Indirectevidence is presented that this may result from eitherhyperactivity or increased levels of the enzyme (uridinediphosphate N-acetylglucosamine 2-epimerase) that hasbeen shown in other tissues to convert uridine diphosphateN-acetylglucosamine to N-acetylmannosamine.