Boronic acids: Inhibition of thrombin and catalysis of imine formation.
Item
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Title
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Boronic acids: Inhibition of thrombin and catalysis of imine formation.
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Identifier
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AAI9405567
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identifier
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9405567
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Creator
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Niu, Linghao.
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Contributor
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Adviser: Manfred Philipp
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Date
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1993
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Language
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English
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Publisher
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City University of New York.
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Subject
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Chemistry, Biochemistry
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Abstract
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In part I of this study, peptide boronic acids have been used as transition state analog inhibitors for thrombin, a serine protease in the blood coagulation cascade. The pH profiles of these inhibitions have been studied in comparison with those of other compounds. These include a peptide carboxamide, a peptide aldehyde, a diamidinoketone and an arsonic acid.;One of the peptide boronic acids studied here, Ac- scD-Phe-Pro-boroArg, is a known slow binding inhibitor for thrombin. In an effort to investigate the origin of the slow inhibition, the inhibitory behavior of Ac- scD-Phe-Pro-boroArg was compared with its analogous inhibitors. One of these, Ac- scD-Phe-Pro-Arg does not contain the boronate group, the other, Z- scD-Phe-Pro-boroMPG contains a neutral side chain at the P{dollar}\sb1{dollar} position. (The boroMPG indicates methoxypropylboroglycine.).;The results demonstrate that the slow inhibition shown by Ac- scD-Phe-Pro-boroArg is also shown by Ac- scD-Phe-Pro-Arg. pH-dependent kinetics of the weak-to-tight binding transition are similar. In contrast, Z- scD-Phe-Pro-boroMPG only displays a prompt inhibition mode. Therefore, the slow inhibition depends on the peptide sequence used. The boronate moiety of the inhibitor is not essential for the formation of the tight-binding complex, but is required for the potent inhibitory effect.;In part II of this study, boron acids have been used as enzyme analogs. Their catalytic effects on the formation of salicylaldoxime and salicylaldehyde phenylhydrazones were studied using pH-dependent kinetics, linear free energy relationships and the solvent deuterium isotope effect. The oxime-boronate complexes were characterized by UV spectra. Their dissociation constants were determined.;The results indicate that catalytic effectiveness is improved by electron-withdrawing substituents on the boron acids. The Michaelis-Menten kinetics exhibited by diphenylborinic acid in salicylaldoxime formation allow the determination of K{dollar}\sb{lcub}\rm m{rcub}{dollar} and {dollar}k\sb{lcub}\rm cat{rcub}.{dollar} Based on these data, the possible catalytic mechanisms were proposed. Boron acids are perhaps the smallest enzyme-like catalysts found to date.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
