PMID: 3754812May 15, 1986Paper

Spectral studies on structure-activity relationships of thromboxane synthase inhibitors

European Journal of Biochemistry
M HeckerS Terao

Abstract

Thromboxane A2 synthase is a cytochrome P450-type enzyme and its interaction with imidazole or pyridine-based inhibitors could be studied by absolute and difference spectroscopy with the solubilized as well as the purified enzyme. Nitrogenous bases shift the 418-nm Soret absorption by 4-6 nm to the red and among them the best inhibitors of enzyme activity showed a stoichiometric binding to the enzyme. The structural and energetic prerequisites for such high binding affinities were primarily the liganding of the basic nitrogen to the hemin but also the attachment of a hydrophobic carboxylic side chain to the active site at an about 1 nm distance from the nitrogen. In addition, the side chain seemed to be oriented almost parallel to the plane of the heme. If this geometry was changed, a decrease in affinity was observed and if the ligand binding was sterically hindered, a spectral shift to a five-coordinated complex absorbing at 390 nm occurred. This is best explained by the displacement of an endogenous oxygen ligand, presumably water, from the sixth coordination position of the heme. From these results it can be concluded that the inhibitors mimic the binding of prostaglandin H2 (PGH2) with its carboxylic group at the carboxyl ...Continue Reading

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Citations

Sep 1, 1988·Biochemical Pharmacology·M Hecker, V Ullrich
Jan 1, 1995·Pharmacology & Therapeutics·H Vanden BosscheH Moereels
Oct 1, 1995·Journal of Lipid Mediators and Cell Signalling·T Tanabe, V Ullrich
Aug 16, 2003·Progress in Cardiovascular Diseases·Anne Burke, Garret A Fitzgerald
Nov 16, 1987·European Journal of Biochemistry·M HeckerC O Meese
Apr 27, 2001·Expert Opinion on Investigational Drugs·J Geiger
Jan 5, 1999·The Journal of Biological Chemistry·P Y HsuL H Wang
May 23, 2002·The Journal of Biological Chemistry·David B HawkesJames J De Voss
Jan 1, 1995·Journal of Enzyme Inhibition·D Ledergerber, R W Hartmann
Feb 18, 1992·Biochemical Pharmacology·H Vanden BosscheP A Janssen
Apr 10, 1999·Journal of Medicinal Chemistry·R SoykaT H Müller
Aug 1, 1990·Archives of Biochemistry and Biophysics·R NüsingV Ullrich

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