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J. Biol. Chem., Vol. 259, Issue 3, 1447-1453, 02, 1984
ME Nesheim, RP Tracy and KG Mann
Prothrombinase is a Ca2+-dependent, 1:1, enzymatic complex of Factor Xa and
Factor Va that assembles on the surface of negatively charged phospholipid
vesicles or platelets. It catalyzes the proteolytic conversion of
prothrombin to the blood-clotting enzyme thrombin. Experimentally
determined kinetic parameters, plus Kd and n values for the interaction of
substrate, cofactor (Factor Va), and serine protease (Factor Xa) for both
phospholipid and each other, were used to develop a model that simulates
the functional properties of the enzymatic complex. Through the use of a
desk-top computer and a program designated "Clotspeed," the distribution of
enzymatic components and substrate between the bulk fluid and phospholipid
is determined for a given set of initial concentrations of reaction
components. Simulated reaction rates are then calculated from the
calculated distributions, fractional binding, and local and bulk
concentration of reactants. Predicted behavior includes formal
Michaelis-Mentenlike properties for the reaction, increasing apparent Km
with increased levels of phospholipid, and apparent inhibition by excess
substrate, enzyme, and phospholipid. Inhibition by excess enzyme and
phospholipid was demonstrated experimentally in quantitative agreement with
predicted results. The model is useful in that it rationalizes well the
seemingly unusual properties of prothrombinase in straightforward physical
terms, provides a means of rationally choosing experimental conditions to
both further test and refine the model, and explores the properties not
only of prothrombinase but also other blood-clotting or surface-bound
enzymatic complexes.
"Clotspeed," a mathematical simulation of the functional properties of prothrombinase
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