Linked Life Data

21483943

Source:http://linkedlifedata.com/resource/pubmed/id/21483943

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2011-5-19
pubmed:abstractText
Cyclodextrin-based host-guest chemistry has been exploited to facilitate co-crystallization of recombinant human acid ?-glucosidase (?-glucocerebrosidase, GlcCerase) with amphiphilic bicyclic nojirimycin analogues of the sp(2)-iminosugar type. Attempts to co-crystallize GlcCerase with 5-N,6-O-[N'-(n-octyl)iminomethylidene]nojirimycin (NOI-NJ) or with 5-N,6-S-[N'-(n-octyl)iminomethylidene]-6-thionojirimycin (6S-NOI-NJ), two potent inhibitors of the enzyme with promising pharmacological chaperone activity for several Gaucher disease-associated mutations, were unsuccessful probably due to the formation of aggregates that increase the heterogeneity of the sample and affect nucleation and growth of crystals. Cyclomaltoheptaose (?-cyclodextrin, ?CD) efficiently captures NOI-NJ and 6S-NOI-NJ in aqueous media to form inclusion complexes in which the lipophilic tail is accommodated in the hydrophobic cavity of the cyclooligosaccharide. The dissociation constant of the complex of the amphiphilic sp(2)-iminosugars with ?CD is two orders of magnitude higher than that of the corresponding complex with GlcCerase, allowing the efficient transfer of the inhibitor from the ?CD cavity to the GlcCerase active site. Enzyme-inhibitor complexes suitable for X-ray analysis were thus grown in the presence of ?CD. In contrast to what was previously observed for the complex of GlcCerase with the more basic derivative, 6-amino-6-deoxy-5-N,6-N-[N'-(n-octyl)iminomethylidene]nojirimycin (6N-NOI-NJ), the ?-anomers of both NOI-NJ and 6S-NOI-NJ were seen in the active site, even though the ?-anomer was exclusively detected both in aqueous solution and in the corresponding ?CD:sp(2)-iminosugar complexes. Our results further suggest that cyclodextrin derivatives might serve as suitable delivery systems of amphiphilic glycosidase inhibitors in a biomedical context.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1477-0539
pubmed:author
pubmed:issnType
Electronic
pubmed:day
7
pubmed:volume
9
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4160-7
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Cyclodextrin-mediated crystallization of acid ?-glucosidase in complex with amphiphilic bicyclic nojirimycin analogues.
pubmed:affiliation
Department of Structural Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't