Linked Life Data

12213822

Source:http://linkedlifedata.com/resource/pubmed/id/12213822

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
45
pubmed:dateCreated
2002-11-4
pubmed:abstractText
Human heparanase is an endo-beta-d-glucuronidase that degrades heparan sulfate/heparin and has been implicated in a variety of biological processes, such as inflammation, tumor angiogenesis, and metastasis. Although the cloned enzyme has been demonstrated to have a critical role in tumor metastasis, the substrate specificity has been poorly understood. In the present study, the specificity of the purified recombinant human heparanase was investigated for the first time using a series of structurally defined oligosaccharides isolated from heparin/heparan sulfate. The best substrates were deltaHexUA(+/-2S)-GlcN(NS,6S)-GlcUA-GlcN(NS,6S)-GlcUA-GlcN(NS,6S) and deltaHexUA(2S)-GlcN(NS,6S)-GlcUA-GlcN(NS,6S) (where deltaHexUA, GlcN, GlcUA, NS, 2S, and 6S represent unsaturated hexuronic acid, d-glucosamine, d-glucuronic acid, 2-N-sulfate, 2-O-sulfate, and 6-O-disulfate, respectively). Based on the percentage conversion of the substrates to products under identical assay conditions, several aspects of the recognition structures were revealed. 1) The minimum recognition backbone is the trisaccharide GlcN-GlcUA-GlcN. 2) The target GlcUA residues are in the sulfated region. 3) The -GlcN(6S)-GlcUA-GlcN(NS)- sequence is essential but not sufficient as the cleavage site. 4) The IdoUA(2S) residue, located two saccharides away from the target GlcUA residue, claimed previously to be essential, is not indispensable. 5) The 3-O-sulfate group on the GlcN is dispensable and even has an inhibitory effect when located in a highly sulfated region. 6) Based on these and previous results, HexUA(2S)-GlcN(NS,6S)-IdoUA-GlcNAc(6S)-GlcUA-GlcN(NS,+/-6S)-IdoUA(2S)-GlcN(NS,6S) (where HexUA represents hexuronic acid) has been proposed as a probable physiological target octasaccharide sequence. These findings will aid establishing a quantitative assay method using the above tetrasaccharide and designing heparan sulfate-based specific inhibitors of the heparanase for new therapeutic strategies.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
8
pubmed:volume
277
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
42488-95
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2002
pubmed:articleTitle
Structural recognition by recombinant human heparanase that plays critical roles in tumor metastasis. Hierarchical sulfate groups with different effects and the essential target disulfated trisaccharide sequence.
pubmed:affiliation
Department of Biochemistry, Kobe Pharmaceutical University, Higashinada-ku, Kobe 658-8558, Japan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't