Glycosaminoglycan degradation fragments in mucopolysaccharidosis I

The catabolism of glycosaminoglycans begins with endohydrolysis of polysaccharides to oligosaccharides followed by the sequential action of an array of exoenzymes to reduce these oligosaccharides to monosaccharides and inorganic sulfate. In a lysosomal storage disorder known as mucopolysaccharidosis I, caused by a deficiency of the exohydrolase α-L-iduronidase, fragments of two different glycosaminoglycans, dermatan sulfate and heparan sulfate, have been shown to accumulate. Oligosaccharides isolated from the urine of a mucopolysaccharidosis I patient using anion exchange and gel filtration chromatography were identified as di-, tri-, tetra-, penta-, and hexasaccharides using electrospray ionization-tandem mass spectrometry and shown to have nonreducing terminal α-L-iduronate residues, susceptible to digestion with α-L-iduronidase. The presence of odd and even oligosaccharides suggests both endo-β-glucuronidase and endo-N-acetylhexosaminidase activities toward both glycosaminoglycans. Cultured skin fibroblasts from mucopolysaccharidosis I patients accumulate the same dermatan sulfate- and heparan sulfate-derived di- and trisaccharides as identified in urine, and supplementation of culture medium with recombinant α-L-iduronidase reduced their level to that of unaffected control fibroblasts. A dermatan-derived tetrasaccharide not elevated in mucopolysaccharidosis I fibroblasts transiently increased in these fibroblasts in the presence of recombinant α-L-iduronidase, indicating it is an intermediate product of catabolism. These oligosaccharides were elevated in urine samples from mucopolysaccharidosis I patients, and we suggest that these glycosaminoglycan-derived oligosaccharides may be useful biochemical markers for the identification and the clinical management of mucopolysaccharidosis I patients.