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)

The vascular endothelial growth factor (VEGF) family encompasses four polypeptides that result from alternative splicing of mRNA. We have previously demonstrated differences in the secretion pattern of these polypeptides. Stable cell lines expressing VEGFs were established in human embryonic kidney CEN4 cells. VEGF121, the shortest form, was secreted and freely soluble in tissue culture medium. VEGF189 was secreted, but was almost entirely bound to the cell surface or extracellular matrix. VEGF165 displayed an intermediary behavior. Suramin induced the release of VEGF189, permitting its characterization as a more basic protein with higher affinity for heparin than VEGF165 or VEGF121, but with similar endothelial cell mitogenic activity. Heparin, heparan sulfate, and heparinase all induced the release of VEGF165 and VEGF189, suggesting heparin-containing proteoglycans as candidate VEGF-binding sites. Finally, VEGF165 and VEGF189 were released from their bound states by treatment with plasmin. The released 34-kDa dimeric species are active as endothelial cell mitogens and as vascular permeability agents. We conclude that the bioavailability of VEGF may be regulated at the genetic level by alternative splicing that determines whether VEGF will be soluble or incorporated into a biological reservoir and also through proteolysis following plasminogen activation.
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PMID:Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. 146 14

The CC chemokine macrophage inflammatory protein 1alpha (MIP1alpha) is a key regulator of the proliferation and differentiation of hematopoietic progenitor cells. The activity of MIP1alpha appears to be modulated by its binding to heparan sulfate (HS) proteoglycans, ubiquitous components of the mammalian cell surface and extracellular matrix. In this study we show that HS has highest affinity for the dimeric form of MIP1alpha. The predominantly dimeric BB10010 MIP1alpha interacts with an 8.3-kDa sequence in the HS polysaccharide chain, which it protects from degradation by heparinase enzymes. The major structural motif of this HS fragment appears to consist of 2 sulfate-rich S-domains separated by a short central N-acetylated region. The optimum lengths of these S-domains seem to be 12 to 14 saccharides. We propose that this binding fragment may wrap around the MIP1alpha dimer in a horseshoe shape, facilitating the interaction of the S-domains with the heparin-binding domains on each monomer. Molecular modeling suggests that these S-domains are likely to interact with basic residues Arg 17, Arg 45, and Arg 47 and possibly with Lys 44 on MIP1alpha and that the interconnecting N-acetylated region is of sufficient length to allow the 2 S-domains to bind to these sites on opposite faces of the dimer. Elucidation of the structure of the HS-binding site for MIP1alpha may enable us to devise ways of enhancing its myeloprotective or peripheral blood stem cell mobilization properties, which can be used to improve cancer chemotherapy treatments.
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PMID:Characterization of the binding site on heparan sulfate for macrophage inflammatory protein 1alpha. 1217 68

[reaction: see text] CRM646-A (1) and -B (2), two fungal glucuronides with a dimeric 2,4-dihydroxy-6-alkylbenzoic acid (orcinol p-depside) aglycone showing significant heparinase and telomerase inhibition activities, were synthesized for the first time. The successful approach involved construction of the phenol glucuronidic linkage, via coupling of the orsellinate derivative 27 with glucuronate bromide 7, before assembly of the phenolic ester linkage in the depside aglycone. Attempts via direct glycosylation of the depside aglycone derivatives were not successful.
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PMID:Total synthesis of CRM646-A and -B, two fungal glucuronides with potent heparinase inhibition activities. 1623 22