Peter Schmidt

Publications of Peter Schmidt

• Nitric oxide-independent vasodilator rescues heme-oxidized soluble guanylate cyclase from proteosomal degradation

  Authors: Sabine Meurer, Sylke Pioch, Tatjana Pabst, Nils Opitz, Peter Schmidt, Tobias Beckhaus, Kristina Wagner, Simone Matt, Kristina Gegenbauer, Sandra Geschka, Michael Karas, Johannes-Peter Stasch, Harald Schmidt, Werner Müller-Esterl

  BMC Pharmacology. 01/2009;

• Distinct molecular requirements for activation or stabilization of soluble guanylyl cyclase upon haem oxidation-induced degradation

  Authors: Linda Hoffmann, Peter Schmidt, Yvonne Keim, Stefan Schaefer, Harald Schmidt, Johannes-Peter Stasch

  BMC Pharmacology. 01/2009;

• Insights into activation and dimerization of soluble guanylate cyclase

  Authors: Christiane Rothkegel, Peter Schmidt, Derek-John Atkins, Friederike Stoll, Henning Schröder, Harald Schmidt, Johannes-Peter Stasch

  BMC Pharmacology. 01/2007;

• Oxidative stress induces CHIP-mediated ubiquitination and roteasomal degradation of soluble guanylyl cyclase

  Authors: Sabine Meurer, Tatjana Pabst, Sylke Pioch, Nils Opitz, Peter Schmidt, Kristina Wagner, Simone Matt, Harald Schmidt, Werner Müller-Esterl

  BMC Pharmacology. 01/2007;

• Beyond NO and heme: biochemical and pharmacological opportunities

  Authors: Christiane Rothkegel, Peter Schmidt, Arun HS, Friederike Stoll, Harald Lapp, Frank Wunder, Henning Schröder, Matthias Rinke, Harald Schmidt, Johannes-Peter Stasch

  BMC Pharmacology. 01/2005;

• Residues stabilizing the heme moiety of the NO sensor soluble guanylate cyclase

  Authors: Peter Schmidt, Christiane Rothkegel, Frank Wunder, Friederike Stoll, Henning Schröder, Johannes-Peter Stasch

  BMC Pharmacology. 01/2005;

• Formation of quasi-covalent sGC α₁/β₁-heterodimers by ODQ-induced oxidation of the prosthetic heme moiety

  Authors: Tatiana Nedvetskaya, Pavel Nedvetsky, Sanchaita Sonar, Helmut Müller, Albert Sickmann, Peter Schmidt, Petra Kronich, Johannes-Peter Stasch, Harald Schmidt

  BMC Pharmacology. 01/2005;

• Preparation of heme-free soluble guanylate cyclase.

  Authors: Peter Schmidt, Matthias Schramm, Henning Schröder, Johannes-Peter Stasch

  Protein expression and purification. 10/2003; 31(1):42-6.

  Soluble guanylate cyclase (sGC), a heterodimer consisting of alpha- and beta-subunit, is the key enzyme of the NO/cGMP signaling pathway. The heme moiety ligated to the beta-subunit via His(105) isSoluble guanylate cyclase (sGC), a heterodimer consisting of alpha- and beta-subunit, is the key enzyme of the NO/cGMP signaling pathway. The heme moiety ligated to the beta-subunit via His(105) is crucial for the activation of the enzyme by NO. In addition to this NO binding capability, the heme status of the enzyme influences the activity of non-NO sGC activators and sGC inhibitors. Different sGC activity profiles were observed in the presence, absence, or the oxidized form of heme. Modulating the heme status is therefore crucial for the investigation of the mechanism of sGC activation. Here, we present a simple and reliable procedure for the removal of the heme moiety of sGC that is capable of eliminating any traces of unbound heme and detergent from the sample mixture in one single step. Samples containing 15 microg sGC and the non-ionic detergent Tween 20 (2%) were incubated at 37 degrees C for 10 min and loaded onto centrifugal ion exchange columns. After centrifugation, heme was bound entirely to the ion exchanger and could not be eluted, even after incubation with 1M NaCl. Tween 20 was found completely within the flowthrough. Heme-free sGC was eluted from the ion exchanger after application of 300 mM NaCl. The absence of the heme moiety was confirmed by UV/Vis spectra and determination of the enzymatic activity. In summary, the described procedure is suitable for the preparation of very small amounts of highly purified heme-free sGC for the investigation of the mechanism of action of different types of sGC activators.

• Mechanisms of nitric oxide independent activation of soluble guanylyl cyclase.

  Authors: Peter Schmidt, Matthias Schramm, Henning Schröder, Johannes-Peter Stasch

  European journal of pharmacology. 06/2003; 468(3):167-74.

  The heterodimeric heme-protein soluble guanylyl cyclase (sGC) is the only proven receptor for nitric oxide (NO). Recently, two different types of NO-independent soluble guanylyl cyclase stimulatorsThe heterodimeric heme-protein soluble guanylyl cyclase (sGC) is the only proven receptor for nitric oxide (NO). Recently, two different types of NO-independent soluble guanylyl cyclase stimulators have been discovered. The heme-dependent stimulator 2-[1-[2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5(4-morpholinyl)-4,6-pyrimidinediamine (BAY 41-8543) stimulates the enzyme in a synergistic fashion when combined with NO, requires the presence of the heme group and can be blocked by the soluble guanylyl cyclase inhibitor 1H-(1,2,4)-Oxadiazole-(4,3-a)-quinoxalin-1-one (ODQ). The heme-independent activator 4-[((4-carboxybutyl)[2-[(4-phenethylbenzol) oxy]phenethyl]amino)methyl[benzoic]acid (BAY 58-2667) activates soluble guanylyl cyclase even in the presence of ODQ or rendered heme-deficient. In the present study, BAY 41-8543, BAY 58-2667 and NO strongly increased V(max). Combination of BAY 58-2667 and NO increased V(max) in an additive manner, whereas the synergistic effect of BAY 41-8543 and NO on enzyme activation was reflected in an overadditive increase of V(max). ODQ potentiated V(max) of BAY 58-2667-stimulated soluble guanylyl cyclase. BAY 41-8543 prolonged the half-life of the nitrosyl-heme complex of NO-activated enzyme, an effect that was not observed with BAY 58-2667. These results show the different activation patterns of both compounds and demonstrate their value as tools to investigate the mechanisms that underlie soluble guanylyl cyclase activation.

• Receptor binding assay for nitric oxide- and heme-independent activators of soluble guanylate cyclase.

  Authors: Peter Schmidt, Matthias Schramm, Henning Schröder, Johannes-Peter Stasch

  Analytical biochemistry. 04/2003; 314(1):162-5.

• NO- and haem-independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle.

  Authors: Johannes-Peter Stasch, Peter Schmidt, Cristina Alonso-Alija, Heiner Apeler, Klaus Dembowsky, Michael Haerter, Markus Heil, Torsten Minuth, Elisabeth Perzborn, Ulrich Pleiss, Matthias Schramm, Werner Schroeder, Henning Schröder, Elke Stahl, Wolfram Steinke, Frank Wunder

  British journal of pharmacology. 08/2002; 136(5):773-83.

  1. Soluble guanylyl cyclase (sGC) is the only proven receptor for the ubiquitous biological messenger nitric oxide (NO) and is intimately involved in many signal transduction pathways, most notably1. Soluble guanylyl cyclase (sGC) is the only proven receptor for the ubiquitous biological messenger nitric oxide (NO) and is intimately involved in many signal transduction pathways, most notably in regulating vascular tone and platelet function. sGC is a heterodimeric (alpha/ss) protein that converts GTP to cyclic GMP; NO binds to its prosthetic haem group. Here, we report the discovery of a novel sGC activating compound, its interaction with a previously unrecognized regulatory site and its therapeutic implications. 2. Through a high-throughput screen we identified BAY 58-2667, an amino dicarboxylic acid which potently activates sGC in an NO-independent manner. In contrast to NO, YC-1 and BAY 41-2272, the sGC stimulators described recently, BAY 58-2667 activates the enzyme even after it has been oxidized by the sGC inhibitor ODQ or rendered haem deficient. 3. Binding studies with radiolabelled BAY 58-2667 show a high affinity site on the enzyme. 4. Using photoaffinity labelling studies we identified the amino acids 371 (alpha-subunit) and 231 - 310 (ss-subunit) as target regions for BAY 58-2667. 5. sGC activation by BAY 58-2667 results in an antiplatelet activity both in vitro and in vivo and a potent vasorelaxation which is not influenced by nitrate tolerance. 6. BAY 58-2667 shows a potent antihypertensive effect in conscious spontaneously hypertensive rats. In anaesthetized dogs the hemodynamic effects of BAY 58-2667 and GTN are very similar on the arterial and venous system. 7. This novel type of sGC activator is a valuable research tool and may offer a new approach for treating cardiovascular diseases.