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Reversible modulation of human factor Xa activity with phosphonate esters: media effects
1Department of Chemistry, The Catholic University of America, Washington, DC 20064, USA.
Bioorganic & Medicinal Chemistry
|March 25, 2000
Summary
Enantiomers of methylphosphonate esters inactivate human factor Xa, with stereoselectivity favoring levorotatory forms. Phospholipids influence factor Xa reactivation, suggesting enzyme catalysis.
Area of Science:
- Biochemistry
- Enzymology
- Pharmacology
Background:
- Human factor Xa is a critical enzyme in the coagulation cascade.
- Methylphosphonate esters are investigated as potential modulators of enzyme activity.
- Understanding enzyme kinetics and inhibition is crucial for drug development.
Purpose of the Study:
- To investigate the inactivation of human factor Xa by enantiomers of 4-nitrophenyl 4-X-phenacyl methylphosphonate esters.
- To determine the stereoselectivity and pH-dependence of this inactivation process.
- To elucidate the mechanism and kinetics of factor Xa reactivation from phosphonyl adducts, and the role of phospholipids.
Main Methods:
- Enzyme kinetics assays to measure inactivation rate constants.
- pH-dependence studies to determine pKa values.
- Investigation of reactivation kinetics in the presence and absence of phospholipids.
Main Results:
- Enantiomers of methylphosphonate esters inactivated human factor Xa with rate constants of 8-86 M(-1)s(-1).
- Stereoselectivity was observed, favoring levorotatory enantiomers (2-10).
- Reactivation from phosphonyl adducts is influenced by phospholipids and exhibits pH-dependent sigmoidal kinetics, indicating enzyme catalysis.
Conclusions:
- The study demonstrates stereoselective inhibition of human factor Xa by methylphosphonate esters.
- Phospholipids play a significant role in modulating factor Xa reactivation, suggesting a catalytic role for the enzyme.
- The findings provide insights into the mechanism of factor Xa inactivation and reactivation.
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