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

Thrombin is inhibited by its cognate plasma inhibitor antithrombin, through the formation of covalent thrombin-antithrombin (TAT) complexes that are found as ternary complexes with vitronectin (VN-TAT). To determine whether the metabolism of VN-TAT ternary complexes is different from that previously reported for binary TAT complexes, plasma clearance studies were done in rabbits using human VN-TAT. 125I-VN-TAT was shown to be cleared rapidly from the circulation (t1/2alpha = 3.8 min) in a biphasic manner mainly by the liver. 125I-TAT had a similar initial clearance (t1/2alpha = 5.3 min) but had a significantly faster beta-phase clearance (t1/2beta = 42.8 min versus 85.4 min for VN-TAT; p = 0.005). Protamine sulfate and heparin abolished the rapid initial alpha-phase of 125I-VN-TAT clearance and reduced its liver-specific association and in vivo degradation. Heparin also reduced the alpha-phase clearance of 125I-TAT and was associated with the appearance of high molecular weight complexes, suggesting enhanced complex formation between VN and TAT. 125I-VN-TAT binding to HepG2 cells was reduced by competition with VN-TAT or heparin but to a much lesser extent in the presence of TAT. The binding of VN-TAT to HepG2 cells was not inhibited by competition with the low density lipoprotein receptor-related protein ligand, methylamine-alpha2-macroglobulin. 125I-VN-TAT binding was also inhibited by treating HepG2 cells with heparinase or by growing the cells in the presence of beta-D-xyloside. Finally, both heparin and chloroquine, but not methylamine-alpha2-macroglobulin, reduced the internalization and degradation of VN-TAT by HepG2 cells. Taken together, these data indicate the importance of VN in TAT metabolism and demonstrate that VN-TAT binds to liver-associated heparan sulfate proteoglycans, which mediate its internalization and subsequent intracellular degradation.
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PMID:In vivo clearance of ternary complexes of vitronectin-thrombin-antithrombin is mediated by hepatic heparan sulfate proteoglycans. 972 80

Heparin is usually obtained from mammalian organs, such as beef lung, beef mucosa, porcine mucosa, and sheep intestinal mucosa. Because of the increased use of heparin in the production of low-molecular-weight heparin (LMWH), there is a growing shortage of the raw material needed to produce LMWHs. A previous report described the structural features of a novel LMWH from the shrimp (Penaeus brasiliensis). In order to compare anticoagulant and antiprotease effects of this heparin, global anticoagulant tests, such as the prothrombin time, activated partial thromboplastin time, thrombin time, and Heptest, were used. Amidolytic anti-Xa and anti-IIa activities were also measured. The relative susceptibility of this heparin to flavobacterial heparinase was also evaluated. The United States Pharmacopeia (USP) potency of shrimp heparin (SH) was found to be 28 U/mg. SH produced a concentration-dependent prolongation of all of the clotting tests and exhibited marked inhibition of FXa and FIIa. Heparinase treatment resulted in a marked decrease of the anticoagulant effects and neutralized the in vitro anti-IIa actions. However, the anti-Xa activities were only partially neutralized. Protamine sulfate was only partially effective in neutralizing the anticoagulant and antithrombin effects of SH. SH also produced marked prolongation of activated clotting time, which was neutralized by heparinase but not by protamine sulfate. These results suggest that SH is a strong anticoagulant with comparable properties to mammalian heparins and can be used in the development of clinically useful antithrombotic-anticoagulant drugs.
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PMID:Anticoagulant and antiprotease effects of a novel heparinlike compound from shrimp (Penaeus brasiliensis) and its neutralization by heparinase I. 1119 Sep 4

The effects of heparinase I and protamine sulfate on the mean arterial pressure and hindlimb perfusion pressure in the male rat were studied. With institutional approval, 21 male Sprague-Dawley rats were anesthetized, and the carotid artery and abdominal aorta were cannulated by cutdown. To isolate the hindlimb, a semi-closed peristaltic perfusion circuit was used. Heparinase I or protamine sulfate was injected into the hindlimb vascular bed, and changes in mean arterial pressure and hindlimb perfusion pressure were recorded. Analysis of variance with a post hoc Scheffe's test was used for statistical analysis, and a P value less than.05 was considered significant. Increasing doses of heparinase I caused a small but significant decrease in mean arterial pressure only at the two highest doses. At all doses, hindlimb perfusion pressure was significantly less than the baseline value and than the value with saline administration at 1 minute. At the clinically applicable doses of heparinase I (0.625 and 1.25 IU/kg), the decrease in hindlimb perfusion pressure was less than 7. At the next two higher doses, the change was less than 15%. The vehicle of heparinase caused a significant decrease in mean arterial pressure (from -15% to -30%) and hindlimb perfusion pressure (from -10% to -20%). Increasing doses of protamine sulfate caused an increase in hindlimb perfusion pressure from baseline, including a 58% change with the 10-mg/kg dose. There was a transient decrease in mean arterial pressure, which peaked 4 to 5 minutes after injection, to a 21% decrease from baseline with the 5- and 10-mg/kg doses. Heparinase I caused vasodilation in the hindlimb and decreased mean arterial pressure only at supraclinical doses. Protamine sulfate caused a significant dose-dependent increase in hindlimb vascular resistance and a transitory decrease in mean arterial pressure.
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PMID:Analysis of the hemodynamic effects of heparinase I and protamine sulfate in the systemic and hindlimb vascular beds of the male rat. 1130 42