Nitric oxide (NO) is an important signaling molecule in a large variety of physiological and pathological processes. Besides the important and various functions of the classical three NO synthases there is growing evidence that nitrite plays a critical role in controlling NO homeostasis and mediated long-lasting effects in a variety of processes such as blood pressure, hypoxic vasodilation, and cellular cytoprotection.
During the previous funding period we established mitochondrial sulfite oxidase (SOX) as novel nitrite reductase in vitro and in cellulo (Wang et al. ARS 2015). We demonstrated that nitrite-dependent NO synthesis requires the molybdenum domain of SOX and identified MoIV as reactive species of the enzyme. By direct NO detection we determined kinetic parameters for NO synthesis and were able to run the enzyme with all three substrates (sulfite, nitrite, cytochrome cox) in a catalytic manner producing sulfate, cytochrome cred and NO in a 1:1:1 ratio. Our mechanistic studies further disclosed an inverse relationship between the rate of electron transfer from MoIV to the heme iron and the rate of NO synthesis.
This project aims to demonstrate the importance of SOX-dependent NO synthesis in vivo. We propose that SOX-dependent NO synthesis provides a missing link in the regulation of mitochondrial respiration by nitrite and NO. Animal models with altered NO activity will be used to demonstrate SOX-dependent control of blood pressure by nitrite reduction. Finally, we aim to screen for substances that increase NO synthesis.
Ischemia/reperfusion injury underlies the progression of pathologies in various organs and is a significant cause of morbidity and mortality. Management of cardiovascular disorders critically dependents on blood pressure control by NO. With SOX, as novel NO-synthase, we found an entirely new target for pharmacological targeting of nitrite-dependent NO release. Given our previous experience in drug development, we aim to find now compounds for the treatment of hypertension disorders.
Bender, D., Kaczmarek, A.T., Santamaria-Araujo, J.A., Stueve, B., Waltz, S., Bartsch, D., Kurian, L., Cirak, S., and Schwarz, G. (2019). Impaired mitochondrial maturation of sulfite oxidase in a patient with severe sulfite oxidase deficiency. Hum Mol Genet10.1093/hmg/ddz109.
Bender, D., Tobias Kaczmarek, A., Niks, D., Hille, R., and Schwarz, G. (2019). Mechanism of nitrite-dependent NO synthesis by human sulfite oxidase. Biochem J 476, 1805-15.
Kaczmarek, A.T., Strampraad, M.J.F., Hagedoorn, P.L., and Schwarz, G. (2019). Reciprocal regulation of sulfite oxidation and nitrite reduction by mitochondrial sulfite oxidase. Nitric Oxide 89, 22-31.
Kohl, J.B., Mellis, A.T., and Schwarz, G. (2019). Homeostatic impact of sulfite and hydrogen sulfide on cysteine catabolism. Br J Pharmacol 176, 554-70.
Grunewald N, Jan A, Salvatico C, Kress V, Renner M, Triller A, Specht CG, and Schwarz G (2018). Sequences Flanking the Gephyrin-Binding Site of GlyRbeta Tune Receptor Stabilization at Synapses. eNeuro 5.
Lubout CMA, Derks TGJ, Meiners L, Erwich JJ, Bergman KA, Lunsing RJ, Schwarz G, Veldman A, and van Spronsen FJ (2018). Molybdenum cofactor deficiency type A: Prenatal monitoring using MRI. Eur J Paediatr Neurol 22, 536-540.
Bender D, and Schwarz G (2018). Nitrite-dependent nitric oxide synthesis by molybdenum enzymes. FEBS Lett10.1002/1873-3468.13089.
Kohl JB, Mellis AT, and Schwarz G (2018). Homeostatic impact of sulfite and hydrogen sulfide on cysteine catabolism. Br J Pharmacol10.1111/bph.14464
Kalimuthu P, Belaidi AA, Schwarz G, and Bernhardt PV (2017a). Chitosan-Promoted Direct Electrochemistry of Human Sulfite Oxidase. J Phys Chem B 121, 9149-59.
Kalimuthu P, Belaidi AA, Schwarz G, and Bernhardt PV (2017b). Mediated Catalytic Voltammetry of Holo and Heme-Free Human Sulfite Oxidases. Chemelectrochem 4, 947-56.
Kumar A, Dejanovic B, Hetsch F, Semtner M, Fusca D, Arjune S, Santamaria-Araujo JA, Winkelmann A, Ayton S, Bush AI, Kloppenburg P, Meier JC, Schwarz G, and Belaidi AA (2017). S-sulfocysteine/NMDA receptor-dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency. J Clin Invest10.1172/JCI89885.
Information from this funding period will not be updated anymore. New research related information is available here.