Glycosaminoglycan degradation fragments in mucopolysaccharidosis I. Glycobiology

The catabolism of glycosaminoglycans begins with endo-hydrolysis 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 mucopoly-saccharidosis I, caused by a deficiency of the exohydrolase a-L-iduronidase, fragments of two different glycosamino-glycans,dermatansulfateandheparan sulfate,havebeenshown 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 a-L-iduronate residues, susceptible to digestion with a-L-iduronidase. The presence of odd and even oligosacchar-ides suggests both endo-b-glucuronidase and endo-N-acetyl-hexosaminidase 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 a-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 a-L-iduronidase, indicating it is an intermediate product of catabolism. These oligosaccharides were elevated in urine samples from mucopolysaccharidosis I patients, and we sug-gest that these glycosaminoglycan-derived oligosaccharides may be useful biochemical markers for the identification and the clinical management of mucopolysaccharidosis I patients. Key words: dermatan sulfate/endohydrolase/ glycosaminoglycans/heparan sulfate