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The high specificity for a targeted enzyme with these inhibitors arises predominantly from a combination of the differentials in noncovalent interactions and those for the influences of microscopic rate constants for the incremental steps in the process of enzyme inhibition (Silverman, R. In Mechanism-Based Enzyme Inactivation: Chemistry and Enzymology: CRC Press: Boca Raton, FL, 1988).
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0343950782
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note
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This enzyme has not been crystallized to date. However, a computational model based on three-dimensional homology modeling for this enzyme is at hand in our laboratory (see citations 10b and 11).
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23
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0343950774
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note
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Homogeneous preparations of MMPs were used in our studies. Recombinant human MMP-2 and MMP-9 were prepared as described previously (see Supporting Information). Representative members of the other classes of MMPs, such as stromelysin 1 (MMP-3), matrilysin (MMP-7), and collagenase-1 (MMP-1), were used in our studies.
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24
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0343950775
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note
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The partition ratio indicates that there is turnover of the thiirane for each covalent inhibition of the enzyme. The partition ratios were relatively low, such that given the quantities of the enzymes available to us, we were not able to isolate and characterize the product of this turnover.
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26
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0342644763
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note
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1/2) is calculated at just under 6 min. The fact that 50% of activity still did not recover after dialysis over 3 days strongly argues for the covalency of enzyme modification.
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27
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0030669224
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