NO-independent regulatory site on soluble guanylate cyclase
| Autor: | Wolfram Steinke, Heiner Apeler, Klaus Dembowsky, Henning Schröder, Matthias Schramm, Eva Maria Becker, Johannes-Peter Stasch, Werner Schroeder, Elisabeth Perzborn, Cristina Alonso-Alija, Achim Feurer, Torsten Minuth, Elke Stahl, Rupert Gerzer, Alexander Straub, Ulrich Pleiß |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Indazoles
GTP' Pyridines Molecular Sequence Data Blood Pressure Regulatory site Heme Photoaffinity Labels In Vitro Techniques Biology Nitric Oxide Nitric oxide Cyclic N-Oxides chemistry.chemical_compound Cinaciguat Mediator Pyrazolopyridine Animals Humans Amino Acid Sequence Cysteine Antihypertensive Agents Binding Sites Multidisciplinary GUCY1A3 Imidazoles Rats Enzyme Activation Disease Models Animal Solubility chemistry Biochemistry Guanylate Cyclase Pyrazoles Female Platelet Aggregation Inhibitors |
| Zdroj: | Nature. 410:212-215 |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | Nitric oxide (NO) is a widespread, potent, biological mediator that has many physiological and pathophysiological roles. Research in the field of NO appears to have followed a straightforward path, and the findings have been progressive: NO and cyclic GMP are involved in vasodilatation; glycerol trinitrate relaxes vascular smooth muscles by bioconversion to NO; mammalian cells synthesize NO; and last, NO mediates vasodilatation by stimulating the soluble guanylate cyclase (sGC), a heterodimeric (alpha/beta) haem protein that converts GTP to cGMP2-4. Here we report the discovery of a regulatory site on sGC. Using photoaffinity labelling, we have identified the cysteine 238 and cysteine 243 region in the alpha1-subunit of sGC as the target for a new type of sGC stimulator. Moreover, we present a pyrazolopyridine, BAY 41-2272, that potently stimulates sGC through this site by a mechanism that is independent of NO. This results in antiplatelet activity, a strong decrease in blood pressure and an increase in survival in a low-NO rat model of hypertension, and as such may offer an approach for treating cardiovascular diseases. |
| Databáze: | OpenAIRE |
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