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Glycobiology Advance Access published online on December 23, 2005
Glycobiology, doi:10.1093/glycob/cwj072
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© The Author 2005. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org
Received August 30, 2005
Revised December 7, 2005
Accepted December 19, 2005

Article

A Defect in Exo-Degradative Pathways Provides Insight into Endo-Degradation of Heparan and Dermatan Sulfates

Maria Fuller 1 *, Ally Chau 2, Rachael C. Nowak 2, John J. Hopwood 1, and Peter J. Meikle 1

1 Lysosomal Diseases Research Unit, Department of Genetic Medicine, Children, Youth and Women’s Health Service, 72 King William Road, North Adelaide, South Australia, 5006; Department of Paediatrics, University of Adelaide, South Australia, 5005
2 Lysosomal Diseases Research Unit, Department of Genetic Medicine, Children, Youth and Women’s Health Service, 72 King William Road, North Adelaide, South Australia, 5006

* To whom correspondence should be addressed.
Maria Fuller, E-mail: maria.fuller{at}adelaide.edu.au


  Abstract

Within cells, dermatan sulfate and heparan sulfate are degraded in two steps. The initial endohydrolysis of these polysaccharides is followed by the sequential action of lysosomal exoenzymes to reduce the resulting oligosaccharides to monosaccharides and inorganic sulfate. Mucopolysaccharidosis type II is a lysosomal storage disorder caused by a deficiency of the exoenzyme iduronate-2-sulfatase. Consequently, partially degraded fragments of dermatan sulfate and heparan sulfate, have been shown to accumulate in the lysosomes of affected cells and are excreted in the urine. Di- to hexadecasaccharides, isolated from the urine of a mucopolysaccharidosis type II patient using anion exchange and gel filtration chromatography, were identified using electrospray ionization-tandem mass spectrometry. These oligosaccharides were shown to have non-reducing terminal iduronate 2-sulfate residues by digestion with recombinant iduronate 2-sulfatase. A pattern of growing oligosaccharide chains composed of alternating uronic acid and N-acetylhexosamine residues was identified and suggested to originate from dermatan sulfate. A series of oligosaccharides consisting of hexosamine/N-acetylhexosamine alternating with uronic acid residues were also identified and based on the presence of unacetylated hexosamine, these oligosaccharides are proposed to derive from heparan sulfate. The presence of both odd and even length oligosaccharides suggests both endo-{beta}-glucuronidase and endo-N-acetylhexosaminidase activities toward both glycosaminoglycans. Furthermore, the putative heparan sulfate oligosaccharide structures identified indicate that heparanase activities are directed towards regions of both low and high sulfation, whilst the N-acetylhexosaminidase activity acted only in regions of low sulfation in this polysaccharide.

Keywords: dermatan sulphate/endohydrolase/glycosaminoglycans/heparan sulpate/mucopolysaccharidosis II.
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