Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.37 (neutrophil elastase)
 4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The degradation of the coagulation cofactors Va and VIIIa by activated protein C (APC), is dependent on calcium, a suitable surface and protein S. The latter is a vitamin K-dependent protein which functions as a cofactor in the reaction. In this study we investigated the role of neutrophils in regulating the activity of protein S. Protein S specifically bound to neutrophils pretreated with di-isopropyl fluorophosphate (DFP) in a time-dependent and saturable reaction. Double reciprocal plot analysis indicated 5 x 10(6) protein S binding sites per neutrophil with half saturable binding occurring at a protein S concentration of 18 nM. Binding was unaffected by the presence of APC, factor V or factor Va. Failure to preincubate the cells with DFP allowed a surface protease to rapidly cleave protein S resulting in its dissociation from its binding site. The cleavage was associated with loss of protein S cofactor activity. The major neutrophil surface associated enzyme that caused this cleavage was identified as elastase. Exposure of neutrophils to ionophore A23187, soluble heat aggregated IgG and serum opsonized zymosan caused the release of a protease/s which cleaved and inactivated protein S. Purification of the protease revealed that it was elastase. This was verified by incubating the neutrophil releasate with anti-neutrophil elastase antibody which inhibited protein S cleavage. Purified neutrophil elastase in concentrations observed under physiological conditions resulted in rapid cleavage and inactivation of protein S. We propose that neutrophils by binding and inactivating protein S serve as an important control for the activity of this natural anticoagulant.
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PMID:The binding and regulation of protein S by neutrophils. 183 84

Protein S (PS) is a vitamin K-dependent anticoagulant that acts as a cofactor to activated protein C (APC). To date PS has not been shown to possess anticoagulant activity in the absence of APC. In this study, we have developed monoclonal antibody to protein S and used to purify the protein to homogeneity from plasma. Affinity purified protein S (PSM), although identical to the conventionally purified protein as judged by SDS-PAGE, had significant anticoagulant activity in the absence of APC when measured in a factor Xa recalcification time. Using SDS-PAGE we have demonstrated that prothrombin cleavage by factor Xa was inhibited in the presence of PSM. Kinetic analysis of the reaction revealed that PSM competitively inhibited factor Xa mediated cleavage of prothrombin. PS preincubated with the monoclonal antibody, acquired similar anticoagulant properties. These results suggest that the interaction of the monoclonal antibody with PS results in an alteration in the protein exposing sites that mediate the observed anticoagulant effect. Support that the protein was altered was derived from the observation that PSM was eight fold more sensitive to cleavage by thrombin and human neutrophil elastase than conventionally purified protein S. These observations suggest that PS can be modified in vitro to a protein with APC-independent anticoagulant activity and raise the possibility that a similar alteration could occur in vivo through the binding protein S to a cellular or plasma protein.
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PMID:The anticoagulant properties of a modified form of protein S. 297 8

Human protein S is degraded by neutrophil elastase. The characteristics of cleavage are compared in a purified protein S preparation, a concentrate of vitamin K-dependent proteins (PPSB) and in normal plasma as well as in alpha-proteinase inhibitor (alpha PI)- deficient plasma. Elastase incubation of purified human protein S (molar enzyme-to-substrate-ratio 1:5500-1:55) reduces the molar mass of the native protein S (81-83 kDa) to about 79 kDa by cleavage of a small peptide. Incubation with very high elastase concentrations (molar enzyme-to-substrate-ratio 1:5.5) completely degrades protein S into small fragments. The elastase incubated protein S has a higher isoelectric point than the native form (Ip 5.9 vs. 5.3). Protein S in a PPSB coagulation factor concentrate is degraded in the same way as isolated protein S. By immunoblotting also smaller split products of molar masses between 34 and 70 kDa are demonstrated. In normal plasma protein S is not degraded by elastase concentrations up to 14 mumol l-1. In plasma of a patient with alpha 1-proteinase inhibitor deficiency protein S can be degraded by elastase. The native 82 kDa protein is degraded to a 72 kDa protein. PEG precipitation of the protein S- C4b- binding protein-complex shows that elastase predominantly splits the free protein S.
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PMID:Protein S degradation in vitro by neutrophil elastase. 831 56