Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.2.2.7 (heparinase)
 1,270 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Lactoferrin and aminopeptidase M-modified lactoferrin (APM-lactoferrin; which lacks its 14 N-terminal amino acids) inhibit the liver uptake of lipoprotein remnant. In the present study, the role of proteoglycans in the initial interaction of beta-migrating very-low-density lipoprotein (beta-VLDL), native and APM-lactoferrin with isolated rat parenchymal liver cells was investigated. Treatment of the cells with chondroitinase lowered the Kd of lactoferrin binding (from 10 to 2.4 microM), and the number of sites/cell (from 20 x 10(6) to 7 x 10(6)), while heparinase treatment did not affect the binding. The binding characteristics of APM-lactoferrin and beta-VLDL were not altered by treatment of the cells with chondroitinase or heparinase. It is concluded that proteoglycans are not involved in the initial binding of APM-lactoferrin and beta-VLDL to parenchymal cells, while chondroitin sulphate proteoglycans are mainly responsible for the massive, low-affinity binding of native lactoferrin..2. The binding of lactoferrin, APM-lactoferrin and beta-VLDL to parenchymal liver cells was not influenced by the glutathione S-transferase-receptor-associated protein (GST-RAP) (97.2% +/- 4.0%, 95.5 +/- 3.7% and 98.5% of the control binding), while the binding of alpha 2-macroglobulin was fully blocked at 10 micrograms/ml GST-RAP (1.8 +/- 0.5% of the control binding). Since GST-RAP blocks the binding of all the known ligands to the low-density lipoprotein (LDL)-receptor-related protein (LRP), it is concluded that LRP is not the initial primary recognition site for lactoferrin, APM-lactoferrin and beta-VLDL on parenchymal liver cells. 3. We showed earlier that.APM-lactoferrin, as compared with lactoferrin, is a more effective inhibitor of the liver uptake of lipoprotein remnants (49.4 +/- 4.0% versus 80.8 +/- 4.8% of the control at 500 micrograms/ml respectively). We found in the present study that beta-VLDL is able to inhibit the binding of APM-lactoferrin to parenchymal liver cells significantly (74.9 +/- 3.3% of the control; P < 0.002), while the lactoferrin binding was unaffected. It is concluded that a still unidentified specific recognition site (the putative remnant receptor) is responsible for the initial binding of remnants to parenchymal cells and it is suggested that the partial cross-competition between APM-lactoferrin and beta-VLDL may be of further help in the elucidation of the molecular nature of this recognition site.
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PMID:Recognition of lactoferrin and aminopeptidase M-modified lactoferrin by the liver: involvement of proteoglycans and the remnant receptor. 854 97

The extracellular sulfatases Sulf1 and Sulf2 remodel the 6O-sulfation state of heparan sulfate proteoglycans on the cell surface, thereby modulating growth factor signaling. Different from all other sulfatases, the Sulfs contain a unique, positively charged hydrophilic domain (HD) of about 320 amino acid residues. Using various HD deletion mutants and glutathione S-transferase (GST)-HD fusion proteins, this study demonstrates that the HD is required for enzymatic activity and acts as a high affinity heparin/heparan sulfate interaction domain. Association of the HD with the cell surface is sensitive to heparinase treatment, underlining specificity toward heparan sulfate chains. Correspondingly, isolated GST-HD binds strongly to both heparin and heparan sulfate in vitro and also to living cells. Surface plasmon resonance studies indicate nanomolar affinity of GST-HD toward immobilized heparin. The comparison of different mutants reveals that especially the outer regions of the HD mediate heparan sulfate binding, probably involving "tandem" interactions. Interestingly, binding to heparan sulfate depends on the presence of 6O-sulfate substrate groups, suggesting that substrate turnover facilitates release of the enzyme from its substrate. Deletion of the inner, less conserved region of the HD drastically increases Sulf1 secretion without affecting enzymatic activity or substrate specificity, thus providing a tool for the in vitro modulation of HS-dependent signaling as demonstrated here for the signal transduction of fibroblast growth factor 2. Taken together, the present study shows that specific regions of the HD influence different aspects of HS binding, cellular localization, and enzyme function.
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PMID:Characterization of the human sulfatase Sulf1 and its high affinity heparin/heparan sulfate interaction domain. 1966 66