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| {{STRUCTURE_1afe| PDB=1afe | SCENE= }} | | {{STRUCTURE_1afe| PDB=1afe | SCENE= }} |
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| '''HUMAN ALPHA-THROMBIN INHIBITION BY CBZ-PRO-AZALYS-ONP'''
| | ===HUMAN ALPHA-THROMBIN INHIBITION BY CBZ-PRO-AZALYS-ONP=== |
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| ==Overview==
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| Kinetics, thermodynamics and structural aspects of human alpha-thrombin (thrombin) inhibition by newly synthesized low molecular weight derivatives of alpha-azalysine have been investigated. The thrombin catalyzed hydrolysis of N-ethoxycarbonyl-D-Phe-Pro-alpha-azaLys p-nitrophenyl ester (Eoc-D-Phe-Pro-azaLys-ONp) and N-carbobenzoxy-Pro-alpha-azaLys p-nitrophenyl ester (Cbz-Pro-azaLys-ONp) was investigated at pH 6.2 and 21.0 degrees C, and analyzed in parallel with that of N-alpha-(N,N-dimethylcarbamoyl)-alpha-azalysine p-nitrophenyl ester (Dmc-azaLys-ONp). Decarboxylation following the enzymatic hydrolysis of these p-nitrophenyl esters gave the corresponding 1-peptidyl-2(4-aminobutyl) hydrazines (peptidyl-Abh) showing properties of thrombin competitive inhibitors. Therefore, thermodynamics for the reversible binding of D-Phe-Pro-Abh, Cbz-Pro-Abh and Dmc-Abh to thrombin was examined. These results are consistent with the minimum four-step catalytic mechanism for product inhibition of serine proteinases. Eoc-D-Phe-Pro-azaLys-ONp and Eoc-D-Phe-Pro-Abh display a sub-micromolar affinity for thrombin together with a high selectivity versus homologous plasmatic and pancreatic serine proteinases acting on cationic substrates. The three-dimensional structures of the reversible non-covalent thrombin:Eoc-D-Phe-Pro-Abh and thrombin:Cbz-Pro-Abh complexes have been determined by X-ray crystallography at 2.0 A resolution (R-factor = 0.169 and 0.179, respectively), and analyzed in parallel with that of the thrombin:Dmc-azaLys acyl-enzyme adduct. Both Eoc-D-Phe-Pro-Abh and Cbz-Pro-Abh competitive inhibitors are accommodated in the thrombin active center, spanning the region between the aryl binding site and the S1 primary specificity subsite.
| | The line below this paragraph, {{ABSTRACT_PUBMED_9217260}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 9217260 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_9217260}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: N-carbobenzoxy-pro-alfa-azalys-p-nitrophenylester]] | | [[Category: N-carbobenzoxy-pro-alfa-azalys-p-nitrophenylester]] |
| [[Category: Serine proteinase inhibition]] | | [[Category: Serine proteinase inhibition]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 10:11:52 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 16:44:09 2008'' |
