Thrombin-catalyzed hydrolysis of p-nitrophenyl esters

Lóránd, L.; Brannen, William; Rule, N. G.

doi:10.1016/0003-9861(62)90463-0

Cited by 46 publications

(14 citation statements)

References 6 publications

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“…Unlike trypsin, however, thrombin can efficiently cleave chymotrypsin specific substrates carrying Phe at the P1 position , as documented more than 40 years ago from studies on ester substrates (Martin et al, 1959;Lorand et al, 1962;Kezdy et al, 1965). This peculiar property of thrombin has obviously been overlooked when devising ''general" rules for the conversion of specificity in serine proteases (Hedstrom et al, 1992;Perona and Craik, 1995;Hedstrom, 2002).…”

Section: Thrombin Structurementioning

confidence: 99%

Thrombin

2008

Molecular Aspects of Medicine

308

330

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Thrombin is a Na+-activated, allosteric serine protease that plays opposing functional roles in blood coagulation. Binding of Na+ is the major driving force behind the procoagulant, prothrombotic and signaling functions of the enzyme, but is dispensable for cleavage of the anticoagulant protein C. The anticoagulant function of thrombin is under the allosteric control of the cofactor thrombomodulin. Much has been learned on the mechanism of Na+ binding and recognition of natural substrates by thrombin. Recent structural advances have shed light on the remarkable molecular plasticity of this enzyme and the molecular underpinnings of thrombin allostery mediated by binding to exosite I and the Na+ site. This review summarizes our current understanding of the molecular basis of thrombin function and allosteric regulation. The basic information emerging from recent structural, mutagenesis and kinetic investigation of this important enzyme is that thrombin exists in three forms, E*, E and E:Na+, that interconvert under the influence of ligand binding to distinct domains. The transition between the Na+ -free slow from E and the Na+ -bound fast form E:Na+ involves the structure of the enzyme as a whole, and so does the interconversion between the two Na+ -free forms E* and E. E* is most likely an inactive form of thrombin, unable to interact with Na + and substrate. The complexity of thrombin function and regulation has gained this enzyme pre-eminence as the prototypic allosteric serine protease. Thrombin is now looked upon as a model system for the quantitative analysis of biologically important enzymes.

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Section: Thrombin Structurementioning

confidence: 99%

Thrombin

2008

Molecular Aspects of Medicine

308

330

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“…substrates [14]). The present paper arises from our observation that Z-D-Phe-Pro-methylpropylboroglycine (boroMpg) pinanediol ester (Scheme 1 below; IV), in which the boroMpg residue is a C-terminal P1 amino acid analogue with a neutral side chain, is a potent thrombin inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Benzyloxycarbonyl-d-Phe-Pro-methoxypropylboroglycine: a novel inhibitor of thrombin with high selectivity containing a neutral side chain at the P1 position

Claeson

Philipp

Agner³

et al. 1993

Biochemical Journal

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Thrombin, the blood-clotting enzyme, is a serine proteinase with trypsin-like specificity and is able to cleave Arg-Xaa peptide bonds but only in a very limited number of substrates (and sites therein). For the prevention and treatment of thrombosis the control of thrombin activity is a key target, and a variety of synthetic inhibitors have been introduced recently, all of which have a positive charge at the P1 site. We report the synthesis of the first example of a new class of inhibitor containing a neutral side chain at the P1 site, the peptide benzyloxycarbonyl-D-Phe-Pro- methoxypropylboroglycine. The peptide is a potent inhibitor of thrombin [Ki (limiting) = 7 nM] and is highly selective for its target enzyme in respect of other serine proteinases. This may be expected to confer considerable advantage in terms of specificity of action and reduced toxicity over conventional, positively charged, inhibitors.

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“…Unlike trypsin, however, thrombin can efficiently cleave chymotrypsin specific substrates carrying Phe at the P1 position, 36 as documented more than 40 years ago from studies on ester substrates. [37][38][39] This peculiar property of thrombin has obviously been overlooked when devising ''general'' rules for the conversion of specificity in serine proteases. 9,40,41 Thrombin has a preference for small and hydrophobic side chains at P2 that pack tightly against the hydrophobic wall of the S2 site defined by residues Y60a-P60b-P60c-W60d of the 60-loop.…”

Section: Thrombin Structurementioning

confidence: 99%

Thrombin allostery

Page

Bah

et al. 2007

Phys. Chem. Chem. Phys.

100

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Thrombin is a Na(+)-activated, allosteric serine protease that plays multiple functional roles in blood pathophysiology. Binding of Na(+) is the major driving force behind the procoagulant, prothrombotic and signaling functions of the enzyme. This review summarizes our current understanding of the molecular basis of thrombin allostery with special emphasis on the kinetic aspects of Na(+) activation. The molecular mechanism of thrombin allostery is a remarkable example of long-range communication that offers a paradigm for many other biological systems.

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Thrombin-catalyzed hydrolysis of p-nitrophenyl esters

Cited by 46 publications

References 6 publications

Thrombin

Thrombin

Benzyloxycarbonyl-d-Phe-Pro-methoxypropylboroglycine: a novel inhibitor of thrombin with high selectivity containing a neutral side chain at the P1 position

Thrombin allostery

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