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
alpha-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 alpha-l-
iduronate residues, susceptible to digestion with
alpha-l-iduronidase. The presence of odd and even
oligosaccharides suggests both endo-
beta-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
alpha-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
alpha-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.