Linked Life Data

16096271

Source:http://linkedlifedata.com/resource/pubmed/id/16096271

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
41
pubmed:dateCreated
2005-10-10
pubmed:abstractText
Homocystinuria, a disorder originating in defects in the methionine metabolism, is characterized by an elevated plasma concentration of homocysteine. Most patients have a defect in the cystathionine-beta-synthase, the key enzyme in the conversion of homocysteine to cysteine. Many abnormalities in the connective tissue of patients with homocystinuria resemble those seen in Marfan syndrome, caused by mutations in fibrillin-1. These observations led to the hypothesis that the structure and function of fibrillin-1 is compromised in patients with homocystinuria. To test this hypothesis we produced recombinant human fibrillin-1 fragments spanning the central portion of the molecule (8-Cys/transforming growth factor-beta binding domain 3 to calcium binding EGF domain 22) and extensively analyzed the potential of homocysteine to modify structural and functional properties of these proteins. Circular dichroism spectroscopy revealed moderate changes of their secondary structures after incubation with homocysteine. Equilibrium dialysis demonstrated a number of high affinity calcium binding sites in the tandemly repeated calcium binding epidermal growth factor-like domains 11-22. Calcium binding of homocysteine-modified fragments was completely abolished. Incubation of the recombinant proteins with homocysteine rendered the analyzed calcium binding EGF domains as well as the 8-Cys/transforming growth factor-beta binding domain 3 significantly more susceptible to proteolytic degradation. Furthermore, data were obtained demonstrating that homocysteine can covalently modify fibrillin-1 via disulfide bonds. These data strongly suggest that structural and functional modifications as well as degradation processes of fibrillin-1 in the connective tissues of patients with homocystinuria play a major role in the pathogenesis of this disorder.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
14
pubmed:volume
280
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
34946-55
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:16096271-Amino Acid Sequence, pubmed-meshheading:16096271-Calcium, pubmed-meshheading:16096271-Cells, Cultured, pubmed-meshheading:16096271-Chymotrypsin, pubmed-meshheading:16096271-Circular Dichroism, pubmed-meshheading:16096271-Dose-Response Relationship, Drug, pubmed-meshheading:16096271-Epidermal Growth Factor, pubmed-meshheading:16096271-Extracellular Matrix, pubmed-meshheading:16096271-Fibroblasts, pubmed-meshheading:16096271-Glycosylation, pubmed-meshheading:16096271-Homocysteine, pubmed-meshheading:16096271-Homocystinuria, pubmed-meshheading:16096271-Humans, pubmed-meshheading:16096271-Marfan Syndrome, pubmed-meshheading:16096271-Microfilament Proteins, pubmed-meshheading:16096271-Microscopy, Fluorescence, pubmed-meshheading:16096271-Molecular Sequence Data, pubmed-meshheading:16096271-Peptides, pubmed-meshheading:16096271-Protein Binding, pubmed-meshheading:16096271-Protein Conformation, pubmed-meshheading:16096271-Protein Structure, Secondary, pubmed-meshheading:16096271-Protein Structure, Tertiary, pubmed-meshheading:16096271-Recombinant Proteins, pubmed-meshheading:16096271-Sequence Homology, Amino Acid, pubmed-meshheading:16096271-Transfection, pubmed-meshheading:16096271-Trypsin
pubmed:year
2005
pubmed:articleTitle
Modification of the structure and function of fibrillin-1 by homocysteine suggests a potential pathogenetic mechanism in homocystinuria.
pubmed:affiliation
Faculty of Medicine, Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A2B2, Canada.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't