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Nitric Oxide Pathway & Oxidative Stress Tomorrow’s Reagents Manufactured Today® International Version Nitric Oxide Pathway & Oxidative Stress Nitric Oxide Synthases (NOS) NOS Cofactors, Regulators & Activators Nitric Oxide Inducing Compounds Antibodies to NOS SPECIAL FEATURE: Oxidative Stress Assay Kits NOS Inhibitors ADMA & SDMA Catalog & Handbook Catalog Arginase & Related SPECIAL FEATURE: Products Spin Traps & Spin Probes Nitric Oxide Donors Nitric Oxide Detection Kits Includes Many Scientific NOSTRIN & NOSIP Technical Notes Soluble Guanylyl Cyclase Over 350 Products! www.alexis-biochemicals.com 2 NITRIC OXIDE PATHWAY Contents Introduction 3 Nitric Oxide and Viral Signalling 29 Physiological Effects of Nitric Oxide 4 Novel Function of RANKL – eNOS Activator 29 Nitric Oxide & Cell Death 5 NOSTRIN & NOSIP – 30 & 31 Mediators of eNOS Redistribution Nitric Oxide Synthase (NOS) Proteins 6 New Antibodies to NOSTRIN & NOSIP Bradykinin & Bradykinin Receptors NOS Cofactors, Regulators & Activators 7 Antibodies to Caveolins & Related Products BH4 – A Key Cofactor of NOS NOS Domain Binding Cofactors Nitric Oxide Detection Kits & Reagents 32 & 33 Fluorescent Probes for NO Detection in Cells Calmodulin & Nitric Oxide Synthases 8 New & Improved Assay Kits for NO Research Detection of Nitrite and Nitric Oxide Nitric Oxide Inducing Compounds 9 Highlight – Peroxynitrite Ultrapure LPS Soluble Guanylyl Cyclase [sGC] 34 – 37 Antibodies to Nitric Oxide Synthases 10 Proteins and Antibodies Activators & Inhibitors Inhibitors of Nitric Oxide Synthases 11 – 13 BAY 41-2272: NO-independent Activator of sGC Vasodilator Phosphoprotein [VASP] Phosphodiesterases – PDE5 Overview Table Purine and Pyrimidine Nucleotides 4-Hydroxynonenal [HNE] & 38 & 39 Selected Key Inhibitors of NOS 14 Lipid Peroxidation Protein NOS Inhibitors HNE – New Stable Form New HNE-Histidine FINE ELISA Kit New NOS Inhibitors – 15 Lipid Hydroperoxide [LPO] Assay Kits From The Leader In The Field Lipid Peroxidation Inhibitors New iNOS Inhibitors Latest Additions High Purity & Stable Spin Traps 40 BMPO, DEPMPO, DIPPMPO & EMPO Asymmetric (ADMA) & Symmetric (SDMA) 16 & 17 Ultrapure DMPO Dimethylarginine PBN Antibodies to Dynein Light Chain 1 17 Immuno-spin Trapping 41 Antibody to DMPO Nitric Oxide Synthase Modulators 18 – 20 Ceruloplasmin – A Nitric Oxide Oxidase & Nitrite Synthase Nitric Oxide Spin-trapping Reagents 42 Nitric Oxide & Nitric Oxide Synthase Related 21 Spin Probes 42 & 43 Products Antioxidant Spin Probe – TEMPOL Fluorinated Spin Probe – FDMPO Arginine & Arginase Related Products 22 & 23 pH-sensitive Spin Probe – DEDPI Arginine & Nitric Oxide Production Efficient Cystein-specific Spin Labelling Compound – MTSSL Arginase Specific Inhibitors Mitochondria-targeted Antioxidant – Mito-TEMPO Nitric Oxide (NO) Donors – 24 – 28 Alphabetical Product Index 44 – 47 The Widest Range NONOates Featured Kits 48 NOR Compounds Carbonyl ELISA Kit GEA Compounds Kit for Monitoring Lipid Peroxidation/Oxidative Stress Glyco-NO Donors Technical Overview Superoxide Dismutase [SOD] Activity Assay Kit Other NO Donors ADMA ELISA Kit For updated prices and additional information visit www.alexis-biochemicals.com or contact your local distributor. NITRIC OXIDE PATHWAY 3 Introduction • Nitric Oxide (NO ) sion in neurons [25], GAPDH-mediated apoptosis [26, 27] (see also Nitric oxide (NO•) is a gaseous, electrically free radical which dis- page 5), and blocking of the neuroprotective effect of protein-di- • plays bioactivity. Because of its chemical properties it can easily sulphide isomerase (PDI) during ER stress [28]. Thirdly, NO reacts •- diffuse across cell membranes and between cells. In this way it with superoxide anion (O2 ), a reactive oxygen species (ROS) to functions as an intracellular and intercellular signalling molecule. form peroxynitrite, which exists under physiological conditions Evidence for the biological activity of NO• was first described in both in the protonated (ONOOH) and anionic (ONOO-) form. Per- 1980 when Furchgott and Zawadski reported the existence of oxynitrite modifies biomolecules either directly, or indirectly by an endothelium-dependent relaxing factor for smooth muscles radicals formed after its decomposition. Diverse damages by oxi- [1], which was identified seven years later as NO• [2-4]. Once con- dation of proteins, lipids, and DNA, as well as damages of enzymes sidered to be a toxic by-product, today it is clear that NO• is im- by nitration have been reported. High levels of peroxynitrite lead portant for a wide range of physiological processes, including to NADH and energy depletion, swelling, calcium release, and fi- the functionality of neurons and the immune response. NO• also nally necrotic cell death (see also page 5). contributes to certain pathophysiologies. Nitric Oxide Synthases (NOS) Nitric oxide synthases (NOS, EC 1.14.13.39) [5] catalyze the bio- synthesis of NO• and L-citrulline from the amino acid L-arginine [5, 6]. The overall reaction occurs in two defined steps and overall involves a five-electron oxidation of L-arginine requiring NADPH •- and O2 as co-substrates in each step. All NOS isoforms are ho- modimeric and bind FAD, FMN [7, 8] and protoporphyrin IX heme [9, 10]. One bound tetrahydrobiopterin (BH4) per monomer is also required for full activity [7, 11]. Three members of the NOS family are well characterized. These isoforms are known as neuronal NOS (nNOS; NOS I) [12, 13], en- Literature References: dothelial NOS (eNOS; NOS III) [14, 15] and inducible NOS (iNOS; 1 The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetyl- NOS II) [16-18]. The role and existence of mitochondrial NOS (mt- choline: R. F. Furchgott & J. V. Zawadzki; Nature 288, 373 (1980) 2 Endothelium-derived relax- NOS) [19, 20], an isoform of nNOS, is a matter of debate. While ing factor produced and released from artery and vein is nitric oxide: L. J. Ignarro, et al.; PNAS 84, 9265 (1987) 3 Endothelium-derived relaxing factor from pulmonary artery and vein possesses nNOS is predominantly expressed in neurons of the brain and pe- pharmacologic and chemical properties identical to those of nitric oxide radical: L. J. Ignarro, et ripheral nervous system, eNOS is mainly found in endothelial cells. al.; Circ. Res. 61, 866 (1987) 4 Nitric oxide release accounts for the biological activity of en- 2+ dothelium-derived relaxing factor: R. M. Palmer, et al.; Nature 327, 524 (1987) 5 Nitric oxide as Both isoforms are constitutively expressed but Ca -calmodulin- a secretory product of mammalian cells: C. Nathan; FASEB J. 6, 3051 (1992) 6 Catalysis by nitric dependent. Thus, nNOS and eNOS produce transient and short oxide synthase: M.A. Marletta, et al.; Curr. Opin. Chem. Biol. 2, 656 (1998) 7 Purification of the living levels of active NO•. In contrast, iNOS expression is induc- inducible murine macrophage nitric oxide synthase. Identification as a flavoprotein: J.M. Hevel, et al.; J. Biol. Chem. 266, 22789 (1991) 8 Purification and characterization of the cytokine-in- 2+ ible but Ca -calmodulin-independent [21]. Hence, iNOS can con- duced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein: D.J. Stuehr, stantly produce high levels of NO• to sustain physiological duties et al.; PNAS 88, 7773 (1991) 9 Cloned, expressed rat cerebellar nitric oxide synthase contains stoichiometric amounts of heme, which binds carbon monoxide: K. McMillan, et al.; PNAS 89, and to contribute to certain pathologies. Murine and human iNOS 11141 (1992) 10 Nitric oxide synthase is a cytochrome P-450 type hemoprotein: K.A. White & are both thought to be regulated primarily on the transcriptional M.A. Marletta; Biochemistry 31, 6627 (1992) 11 Ca2+/calmodulin-dependent NO synthase type I: a biopteroflavoprotein with Ca2+/calmodulin-independent diaphorase and reductase activi- level, while their expression respond differently to stimuli such as ties: H.H. Schmidt, et al.; Biochemistry 31, 3243 (1992) 12 Structural organization of the human proinflammatory cytokines, microbial lipopolysaccharides (LPS), neuronal nitric oxide synthase gene (NOS1): A. V. Hall, et al.; J. Biol. Chem. 269, 33082 (1994) 13 dsRNA, and hypoxia. Cloned human brain nitric oxide synthase is highly expressed in skeletal muscle: M. Nakane, et al.; FEBS Lett. 316, 175 (1993) 14 Cloning and expression of a cDNA encoding human endothe- lium-derived relaxing factor/nitric oxide synthase: S. P. Janssens, et al.; J. Biol. Chem. 267, 14519 (1992) 15 Molecular cloning and characterization of human endothelial nitric oxide synthase: P. A. Marsden, et al.; FEBS Lett. 307, 287 (1992) 16 Molecular cloning and expression of induc- ible nitric oxide synthase from human hepatocytes: D. A. Geller, et al.; PNAS 90, 3491 (1993) 17 Purification and cDNA sequence of an inducible nitric oxide synthase from a human tumor cell line: P. A. Sherman, et al.; Biochemistry 32, 11600 (1993) 18 Cloning, characterization, and ex- pression of a cDNA encoding an inducible nitric oxide synthase from the human chondrocyte: I. G. Charles, et al.; PNAS 90, 11419 (1993) 19 Purification and characterization of a nitric-oxide synthase from rat liver mitochondria: A. Tatoyan & C. Giulivi; J. Biol. Chem. 273, 11044 (1998) 20 Immunocytochemical evidence for a mitochondrially located nitric oxide synthase in brain and liver: T. E. Bates, et al.; BBRC 213, 896 (1995) 21 Calcium-dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin: R. Busse & A. Mulsch; FEBS Lett. 265, 133 (1990) 22 S-nitrosylation of Hsp90 promotes
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