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Biosynthesis of Nitric Oxide: An Overview

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Role of Nitric Oxide in Sepsis and ADRS

Part of the book series: Update in Intensive Care and Emergency Medicine ((UICM,volume 24))

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Abstract

Soon after the first reports on mammalian nitric oxide (NO) synthesis in 1987 [1, 2], cytosols of cytokine-activated macrophages were shown to contain an enzymatic activity catalyzing an NADPH-dependent conversion of the amino acid L-arginine to NO [3]. Subsequently, enzymatic NO formation was described for a variety of tissues. Consistent with the apparent involvement of Ca2+ in NO-mediated signal transduction in blood vessels [4] and neurons [5], NO synthesis turned out to require micromolar concentrations of free Ca2+ in endothelial cells [6] and brain [7, 8], whereas enzymatic NO formation occurred in a Ca2+-independent manner in cytokine-activated macrophages [3]. In the meantime our knowledge about this novel biochemical pathway has rapidly grown. The present chapter briefly reviews molecular mechanisms and regulation of NO biosynthesis with special focus on the enzymology of NO-synthesizing enzymes, the NO synthases (NOS).

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References

  1. Palmer RMJ, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526

    Article  PubMed  CAS  Google Scholar 

  2. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G (1987) Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 84:9265–9269

    Article  PubMed  CAS  Google Scholar 

  3. Marletta MA, Yoon PS, Iyengar R, Leaf CD, Wishnok JS (1988) Macrophage oxidation of L-arginine to nitrite and nitrate: Nitric oxide is an intermediate. Biochemistry 27:8706–8711

    Article  PubMed  CAS  Google Scholar 

  4. Moncada S, Palmer RM, Higgs EA (1989) Biosynthesis of nitric oxide from L-arginine: A pathway for the regulation of cell function and communication. Biochem Pharmacol 38:1709–1715

    Article  PubMed  CAS  Google Scholar 

  5. Garthwaite J, Charles SL, Chess-Williams R (1988) Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 336:385–388

    Article  PubMed  CAS  Google Scholar 

  6. Mayer B, Böhme E (1989) Ca2+-dependent formation of an L-arginine-derived activator of soluble guanylyl cyclase in bovine lung. FEBS Lett 256:211–214

    Article  PubMed  CAS  Google Scholar 

  7. Bredt DS, Snyder SH (1989) Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc Natl Acad Sci USA 86:9030–9033

    Article  PubMed  CAS  Google Scholar 

  8. Knowles RG, Palacios M, Palmer RMJ, Moncada S (1989) Formation of nitric oxide from L-arginine in the central nervous system: A transduction mechanism for stimulation of the soluble guanylate cyclase. Proc Natl Acad Sci USA 86:5159–5162

    Article  PubMed  CAS  Google Scholar 

  9. Marletta MA (1993) Nitric oxide synthase structure and mechanism. J Biol Chem 268: 12231–12234

    PubMed  CAS  Google Scholar 

  10. Mayer B (1993) Molecular characteristics and enzymology of nitric oxide synthase and soluble guanylyl cyclase in the CNS. Semin Neurosci 5:197–205

    Article  CAS  Google Scholar 

  11. Knowles RG, Moncada S (1994) Nitric oxide synthases in mammals. Biochem J 298: 249–258

    PubMed  CAS  Google Scholar 

  12. Nathan C, Xie QW (1994) Regulation of biosynthesis of nitric oxide. J Biol Chem 269:13725–13728

    PubMed  CAS  Google Scholar 

  13. Förstermann U, Closs EI, Pollock JS, et al (1994) Nitric oxide synthase isozymes Characterization, purification, molecular cloning, and functions. Hypertension 23: 1121–1131

    PubMed  Google Scholar 

  14. Cho HJ, Xie QW, Calaycay J, et al (1992) Calmodulin is a subunit of nitric oxide synthase from macrophages. J Exp Med 176:599–604

    Article  PubMed  CAS  Google Scholar 

  15. Stuehr DJ, Kwon NS, Nathan CF, Griffith OW, Feldman PL, Wiseman J (1991) N omega-hydroxy-L-arginine is an intermediate in the biosynthesis of nitric oxide from L-arginine. J Biol Chem 266:6259–6263

    PubMed  CAS  Google Scholar 

  16. Klatt P, Schmidt K, Uray G, Mayer B (1993) Multiple catalytic functions of brain nitric oxide synthase. Biochemical characterization, cofactor requirement and role of NG-hydroxy-L-arginine as an intermediate. J Biol Chem 268:14781–14787

    PubMed  CAS  Google Scholar 

  17. Kwon NS, Nathan CF, Gilker C, Griffith OW, Matthews DE, Stuehr DJ (1990) L-citrulline production from L-arginine by macrophage nitric oxide synthase. The ureido oxygen derives from dioxygen. J Biol Chem 265:13442–13445

    PubMed  CAS  Google Scholar 

  18. Leone AM, Palmer RMJ, Knowles RG, Francis PL, Ashton DS, Moncada S (1991) Constitutive and inducible nitric oxide synthases incorporate molecular oxygen into both nitric oxide and citrulline. J Biol Chem 266:23790–23795

    PubMed  CAS  Google Scholar 

  19. Feldman PL, Griffith OW, Stuehr DJ (1993) The surprising life of nitric oxide. Chem Eng News 71:26–38

    CAS  Google Scholar 

  20. Korth HG, Sustmann R, Thater C, Butler AR, Ingold KU (1994) On the mechanism of the nitric oxide synthase-catalyzed conversion of N-omega-hydroxy-L-arginine to citrulline and nitric oxide. J Biol Chem 269:17776–17779

    PubMed  CAS  Google Scholar 

  21. Marletta MA (1994) Nitric oxide synthase: Aspects concerning structure and catalysis. Cell 78:927–930

    Article  PubMed  CAS  Google Scholar 

  22. Mayer B, John M, Heinzel B, et al (1991) Brain nitric oxide synthase is a biopterin- and flavin-containing multifunctional oxido-reductase. FEBS Lett 288:187–191

    Article  PubMed  CAS  Google Scholar 

  23. Stuehr DJ, Cho HJ, Kwon NS, Weise MF, Nathan CF (1991) Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: An FAD- and FMN-containing flavoprotein. Proc Natl Acad Sci USA 88:7773–7777

    Article  PubMed  CAS  Google Scholar 

  24. Hevel JM, White KA, Marletta MA (1991) Purification of the inducible murine macrophage nitric oxide synthase Identification as a flavoprotein. J Biol Chem 266: 22789–22791

    PubMed  CAS  Google Scholar 

  25. White KA, Marletta MA (1992) Nitric oxide synthase is a cytochrome-P-450 type hemoprotein. Biochemistry 31:6627–6631

    Article  PubMed  CAS  Google Scholar 

  26. Stuehr DJ, Ikeda-Saito M (1992) Spectral characterization of brain and macrophage nitric oxide synthases: Cytochrome-P-450-like heme proteins that contain a flavin semiquinone radical. J Biol Chem 267:20547–20550

    PubMed  CAS  Google Scholar 

  27. McMillan K, Bredt DS, Hirsch DJ, Snyder SH, Clark, JE, Masters BSS (1992) Cloned, expressed rat cerebellar nitric oxide synthase contains stoichiometric amounts of heme, which binds carbon monoxide. Proc Natl Acad Sci USA 89:11141–11145

    Article  PubMed  CAS  Google Scholar 

  28. Klatt P, Schmidt K, Mayer B (1992) Brain nitric oxide synthase is a haemoprotein. Bio chem J 288:15–17

    CAS  Google Scholar 

  29. Pollock JS, Werner ER, Mitchell JA, Förstermann U (1993) Particulate endothelial nitric oxide synthase: Requirement and content of tetrahydrobiopterin, FAD, and FMN. Endothelium 1:147–152

    Article  CAS  Google Scholar 

  30. Wolff DJ, Datto GA, Samatovicz RA, Tempsick RA (1993) Calmodulin-dependent nitric oxide synthase: Mechanism of inhibition by imidazole and phenylimidazoles. J Biol Chem 268:9425–9429

    PubMed  CAS  Google Scholar 

  31. McMillan K, Masters BSS (1993) Optical difference spectrophotometry as a probe of rat brain nitric oxide synthase heme-substrate interaction. Biochemistry 32:9875–9880

    Article  PubMed  CAS  Google Scholar 

  32. Klatt P, Heinzel B, John M, Kastner M, Böhme E, Mayer B (1992) Ca2+/calmodulin dependent cytochrome c reductase activity of brain nitric oxide synthase. J Biol Chem 267:11374–11378

    PubMed  CAS  Google Scholar 

  33. Abu-Soud HM, Stuehr DJ (1993) Nitric oxide synthases reveal a novel role for calmodulin in controlling electron transfer. Proc Natl Acad Sci USA 90:10769–10772

    Article  PubMed  CAS  Google Scholar 

  34. Guengerich FP (1991) Reactions and significance of cytochrome P-450 enzymes. J Biol Chem 266:10019–10022

    PubMed  CAS  Google Scholar 

  35. Degtyarenko KN, Archakov AI (1993) Molecular evolution of P-450 superfamily and P-450-containing monooxygenase systems. FEBS Lett 332:1–8

    Article  PubMed  CAS  Google Scholar 

  36. Bredt DS, Hwang PM, Glatt CE, Lowenstein C, Reed RR, Snyder SH (1991) Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature 351:714–718

    Article  PubMed  CAS  Google Scholar 

  37. Sheta EA, McMillan K, Masters BSS (1994) Evidence for a bidomain structure of constitutive cerebellar nitric oxide synthase. J Biol Chem 269:15147–15153

    PubMed  CAS  Google Scholar 

  38. Narhi LO, Fulco AJ (1986) Characterization of a catalytically self-sufficient 119,000 dalton cytochrome P-450 monoxygenase induced by barbiturates in bacillus megaterium. J Biol Chem 261:7160–7169

    PubMed  CAS  Google Scholar 

  39. Fulco AJ (1991) P-450-BM-3 and other inducible bacterial P-450 cytochromes: Biochemistry and regulation. Annu Rev Pharmacol Toxicol 31:177–203

    Article  PubMed  CAS  Google Scholar 

  40. Nakayama N, Shoun H (1994) Fatty acid hydroxylase of the fungus Fusarium oxysporum is possibly a fused protein of cytochrome P-450 and its reductase. Biochem Biophys Res Commun 202:586–590

    Article  PubMed  CAS  Google Scholar 

  41. Nichol CA, Smith GK, Duch DS (1985) Biosynthesis and metabolism of tetrahydrobiopterin and molybdopterin. Annu Rev Biochem 54:729–764

    Article  PubMed  CAS  Google Scholar 

  42. Kaufman S (1993) New tetrahydrobiopterin-dependent systems. Annu Rev Nutr 13: 261–286

    Article  PubMed  CAS  Google Scholar 

  43. Tayeh MA, Marletta MA (1989) Macrophage oxidation of L-arginine to nitric oxide, nitrite, and nitrate. Tetrahydrobiopterin is required as a cofactor. J Biol Chem 264: 19654–19658

    PubMed  CAS  Google Scholar 

  44. Kwon NS, Nathan CF, Stuehr DJ (1989) Reduced biopterin as a cofactor in the generation of nitrogen oxides by murine macrophages. J Biol Chem 264:20496–20501

    PubMed  CAS  Google Scholar 

  45. Mayer B, John M, Böhme E (1990) Purification of a Ca2+/calmodulin-dependent nitric oxide synthase from porcine cerebellum. Cofactor-role of tetrahydrobiopterin. FEBS Lett 277:215–219

    Article  PubMed  CAS  Google Scholar 

  46. Bredt DS, Snyder SH (1990) Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 87:682–685

    Article  PubMed  CAS  Google Scholar 

  47. Knowles RG, Palacios M, Palmer RM, Moncada S (1990) Kinetic characteristics of nitric oxide synthase from rat brain. Biochem J 269:207–210

    PubMed  CAS  Google Scholar 

  48. Dwyer MA, Bredt DS, Snyder SH (1991) Nitric oxide synthase. Irreversible inhibition by L-NG-nitroarginine in brain in vitro and in vivo. Biochem Biophys Res Commun 176:1136–1141

    Article  PubMed  CAS  Google Scholar 

  49. Schmidt HHHW, Smith RM, Nakane M, Murad F (1992) Ca2+/calmodulin-dependent NO synthase type-I: A biopteroflavoprotein with Ca2+/calmodulin-independent diaphorase and reductase activities. Biochemistry 31:3243–3249

    Article  PubMed  CAS  Google Scholar 

  50. Klatt P, Heinzel B, Mayer B, et al (1992) Stimulation of human nitric oxide synthase by tetrahydrobiopterin and selective binding of the cofactor. FEBS Lett 305:160–162

    Article  PubMed  CAS  Google Scholar 

  51. Hevel JM, Marletta MA (1992) Macrophage nitric oxide synthase: Relationship between enzyme-bound tetrahydrobiopterin and synthase activity. Biochemistry 31: 7160–7165

    Article  PubMed  CAS  Google Scholar 

  52. Baek KJ, Thiel BA, Lucas S, Stuehr DJ (1993) Macrophage nitric oxide synthase subunits: Purification, characterization, and role of prosthetic groups and substrate in regulating their association into a dimeric enzyme. J Biol Chem 268:21120–21129

    PubMed  CAS  Google Scholar 

  53. Harteneck C, Klatt P, Schmidt K, Mayer B (1994) Baculovirus-mediated expression of rat brain nitric oxide synthase and characterization of the purified enzyme. Biochem J 304:683–686

    PubMed  CAS  Google Scholar 

  54. Werner-Felmayer G, Golderer G, Werner ER, Gröbner P, Wächter H (1994) Pteridine biosynthesis and nitric oxide synthase in Physarum Polycephalum. Biochem J 304: 105–111

    PubMed  CAS  Google Scholar 

  55. Klatt P, Schmid M, Leopold E, Schmidt K, Werner ER, Mayer B (1994) The pteridine binding site of brain nitric oxide synthase Tetrahydrobiopterin binding kinetics, specificity, and allosteric interaction with the substrate domain. J Biol Chem 269: 13861–13866

    PubMed  CAS  Google Scholar 

  56. Mayer B, Klatt P, Werner ER, Schmidt K (1994) Molecular mechanism of inhibition of porcine brain nitric oxide synthase by the antinociceptive drug 7-nitroindazole. Neuropharmacology 33:1253–1259

    Article  PubMed  CAS  Google Scholar 

  57. Heinzel B, John M, Klatt P, Böhme E, Mayer B (1992) Ca2+/calmodulin-dependent formation of hydrogen peroxide by brain nitric oxide synthase. Biochem J 281:627–630

    PubMed  CAS  Google Scholar 

  58. Pou S, Pou WS, Bredt DS, Snyder SH, Rosen GM (1992) Generation of superoxide by purified brain nitric oxide synthase. J Biol Chem 267:24173–24176

    PubMed  CAS  Google Scholar 

  59. Mayer B, Heinzel B, Klatt P, John M, Schmidt K, Böhme E (1992) Nitric oxide synthase-catalyzed activation of oxygen and reduction of cytochromes: Reaction mechanisms and possible physiological implications. J Cardiovasc Pharmacol 20: S54-S56

    PubMed  CAS  Google Scholar 

  60. Culcasi M, Lafoncazal M, Pietri S, Bockaert J (1994) Glutamate receptors induce a burst of superoxide via activation of nitric oxide synthase in arginine-depleted neurons. J Biol Chem 269:12589–12593

    PubMed  CAS  Google Scholar 

  61. Aoki E, Sembar R, Mikoshiba K, Kashiwamata S (1991) Predominant localization in glial cells of free L-arginine. Immunocytochemical evidence. Brain Res 547:190–192

    Article  PubMed  CAS  Google Scholar 

  62. Pow DV (1994) Immunocytochemical evidence for a glial localisation of arginine, and a neuronal localisation of citrulline in the rat neurohypophysis: Implications for nitrergic transmission. Neurosci Lett 181:141–144

    Article  PubMed  CAS  Google Scholar 

  63. Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–695

    Article  PubMed  CAS  Google Scholar 

  64. Lipton SA, Choi YB, Pan ZH, et al (1993) A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364:626–632

    Article  PubMed  CAS  Google Scholar 

  65. Cosentino F, Katusic ZS (1995) Tetrahydrobiopterin and dysfunction of endothelial nitric oxide synthase in coronary arteries. Circulation 91:139–144

    PubMed  CAS  Google Scholar 

  66. Ignarro LJ (1991) Heme-dependent activation of guanylate cyclase by nitric oxide: A novel signal transduction mechanism. Blood Vessels 28:67–73

    PubMed  CAS  Google Scholar 

  67. Wedel B, Humbert P, Harteneck C, et al (1994) Mutation of His-105 of the βl-subunit yields a nitric oxide-insensitive form of soluble guanylyl cyclase. Proc Natl Acad Sci USA 91:2592–2596

    Article  PubMed  CAS  Google Scholar 

  68. Henry Y, Lepoivre M, Drapier J-C, Ducrocq C, Boucher J-L, Guissani A (1993) EPR characterization of molecular targets for NO in mammalian cells and organelles. FASEB 17:1124–1134

    Google Scholar 

  69. Wink DA, Osawa Y, Darbyshire JF, Jones CR, Eshenaur SC, Nims RW (1993) Inhibition of cytochromes-P450 by nitric oxide and a nitric oxide-releasing agent. Arch Biochem Biophys 300:115–123

    Article  PubMed  CAS  Google Scholar 

  70. Khatsenko OG, Gross SS, Rifkind AB, Vane JR (1993) Nitric oxide is a mediator of the decrease in cytochrome-P450-dependent metabolism caused by immunostimulants. Proc Natl Acad Sci USA 90:11147–11151

    Article  PubMed  CAS  Google Scholar 

  71. Stadler J, Trockfeld J, Schmalix WA, et al (1994) Inhibition of cytochromes P-450–1A by nitric oxide. Proc Natl Acad Sci USA 91:3559–3563

    Article  PubMed  CAS  Google Scholar 

  72. Rogers NE, Ignarro LJ (1992) Constitutive nitric oxide synthase from cerebellum is reversibly inhibited by nitric oxide formed from L-arginine. Biochem Biophys Res Commun 189:242–249

    Article  PubMed  CAS  Google Scholar 

  73. Buga GM, Griscavage JM, Rogers NE, Ignarro LJ (1993) Negative feedback regulation of endothelial cell function by nitric oxide. Circ Res 73:808–812

    PubMed  CAS  Google Scholar 

  74. Griscavage JM, Rogers NE, Sherman MP, Ignarro LJ (1993) Inducible nitric oxide synthase from a rat alveolar macrophage cell line is inhibited by nitric oxide. J Immunol 151:6329–6337

    PubMed  CAS  Google Scholar 

  75. Assreuy J, Cunha FQ, Liew FY, Moncada S (1993) Feedback inhibition of nitric oxide synthase activity by nitric oxide. Br J Pharmacol 108:833–837

    PubMed  CAS  Google Scholar 

  76. Rengasamy A, Johns RA (1993) Regulation of nitric oxide synthase by nitric oxide. Mol Pharmacol 44:124–128

    PubMed  CAS  Google Scholar 

  77. Wang JL, Rousseau DL, Abu-Soud HM, Stuehr DJ (1994) Heme coordination of NO in NO synthase. Proc Natl Acad Sci USA 91:10512–10516

    Article  PubMed  CAS  Google Scholar 

  78. Griscavage JM, Fukuto JM, Komori Y, Ignarro LJ (1994) Nitric oxide inhibits neuronal nitric oxide synthase by interacting with the heme prosthetic group: Role of tetrahydrobiopterin in modulating the inhibitory action of nitric oxide. J Biol Chem 269:21644–21649

    PubMed  CAS  Google Scholar 

  79. Mayer B, Klatt P, Werner ER, Schmidt K (1995) Kinetics and mechanism of tetrahy-drobiopterin-induced oxidation of nitric oxide. J Biol Chem 270:655–659

    Article  PubMed  CAS  Google Scholar 

  80. Mayer B, Schmid M, Klatt P, Schmidt K (1993) Reversible inactivation of endothelial nitric oxide synthase by NG-nitro-L-arginine. FEBS Lett 333:203–206

    Article  PubMed  CAS  Google Scholar 

  81. Klatt P, Schmidt K, Brunner F, Mayer B (1994) Inhibitors of brain nitric oxide synthase. Binding kinetics, metabolism, and enzyme inactivation. J Biol Chem 269:1674–1680

    PubMed  CAS  Google Scholar 

  82. Abu-Soud HM, Feldman PL, Clark P, Stuehr DJ (1994) Electron transfer in the nitric-oxide synthases: Characterization of L-arginine analogs that block heme iron reduction. J Biol Chem 269:32318–32326

    PubMed  CAS  Google Scholar 

  83. Frey C, Narayanan K, McMillan K, et al (1994) L-thiocitrulline: A stereospecific, heme-binding inhibitor of nitric-oxide synthases. J Biol Chem 269:26083–26091

    PubMed  CAS  Google Scholar 

  84. Mayer B, Klatt P, Werner ER, Schmidt K (1994) Identification of imidazole as L-arginine-competitive inhibitor of porcine brain nitric oxide synthase. FEBS Lett 350: 199–202

    Article  PubMed  CAS  Google Scholar 

  85. Moore PK, Wallace P, Gaffen Z, Hart SL, Babbedge RC (1993) Characterization of the novel nitric oxide synthase inhibitor 7-nitroindazole and related indazoles: Antinociceptive and cardiovascular effects. Br J Pharmacol 110:219–224

    PubMed  CAS  Google Scholar 

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Mayer, B. (1995). Biosynthesis of Nitric Oxide: An Overview. In: Fink, M.P., Payen, D. (eds) Role of Nitric Oxide in Sepsis and ADRS. Update in Intensive Care and Emergency Medicine, vol 24. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-79920-4_1

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