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Selective Inhibition of Trypsin by (2R,4R)-4-Phenyl-1-[Nα-(7- methoxy-2-naphthalenesulfonyl)-l-arginyl]-2-piperidinecarboxylic Acid

Evidence is accumulating indicating that trypsin stimulates divergent cellular reactions through the proteinase-activated receptor, in addition to its role as the digestive enzyme. In this report, we introduce (2R,4R)- 4-phenyl-1-[Nα-(7-methoxy-2-naphthalenesulfonyl)-l-arginyl]-2-piperidinecarboxyli...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-06, Vol.275 (25), p.18995-18999
Main Authors: Hijikata-Okunomiya, Akiko, Tamao, Yoshikuni, Kikumoto, Ryoji, Okamoto, Shosuke
Format: Article
Language:English
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Summary:Evidence is accumulating indicating that trypsin stimulates divergent cellular reactions through the proteinase-activated receptor, in addition to its role as the digestive enzyme. In this report, we introduce (2R,4R)- 4-phenyl-1-[Nα-(7-methoxy-2-naphthalenesulfonyl)-l-arginyl]-2-piperidinecarboxylic acid as a potent and selective trypsin inhibitor. The agent inhibited trypsin competitively with the Ki value of 0.1 μm. It inhibited thrombin weakly (Ki = 2 μm) and did not inhibit plasmin, plasma kallikrein, urokinase, and mast cell tryptase (Ki values for these enzymes are >60 μm). Comparative studies with several established proteinase inhibitors revealed that the compound was the first small molecular weight trypsin inhibitor without tryptase inhibitory activity. A docking study has provided a plausible explanation for the molecular mechanism of the selective inhibition showing that the agent fits into the active site of trypsin without any severe collision but that it comes into clash at the 4-phenyl group of piperidine ring against the “60-insertion loop” of thrombin and at the 7-methoxy-2-naphthalenesulfonyl group against Gln98 of tryptase.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M908124199