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In search of a function for tetrahydrobiopterin in the biosynthesis of nitric oxide

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Abstract

(6R)-5,6,7,8-Tetrahydro-l,-biopterin(H4biopterin) is well known as a cofactor of enzymes that hydroxylate aromatic amino acids. More recent work has revealed an essential role of H4biopterin in the biosynthesis of nitric oxide (NO), an intercellular messenger molecule synthesized from l-arginine by different NO synthase isozymes in many species and tissues. While the function of H4biopterin in aromatic amino acid hydroxylation is well established, the role of this pteridine in NO synthesis is, as yet, elusive. Current experimental evidence hints at a dual mode of action of H4biopterin, involving both an allosteric effect on the NO synthase protein and participation as a reactant in l,-arginine oxidation. As discussed in detail in the present article, the latter effect of this pteridine may be related to the protection of NO synthase from feedback inhibition by NO.

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Abbreviations

H4biopterin:

(6R)-5,6,7,8-tetrahydro-l-biopterin

H2biopterin:

6,7(8H)-dihydro-l-biopterin

NOS:

NO synthase

nNOS:

neuronal NO synthase

eNOS:

endothelial NO synthase

iNOS:

inducible NO synthase

SOD:

superoxide dismutase

References

  • 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

    Google Scholar 

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

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • Bailey SW, Dillard SB, Ayling JE (1991) Role of C6 chiraiity of tetrahydropterin cofactor in catalysis and regulation of tyrosine and phenylalanine hydroxylases. Biochemistry 30:10226–10235

    Google Scholar 

  • Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:1620–1624

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  • 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

    Google Scholar 

  • Bredt DS, Snyder SH (1994) Nitric oxide: A physiologic messenger molecule. Annu Rev Biochem 63:175–195

    Google Scholar 

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

    Google Scholar 

  • Cho HJ, Xie QW Calaycay J, Murnford RA, Swiderek KM, Lee TD, Nathan C (1992) Calmodulin is a subunit of nitric oxide synthase from macrophages. J Exp Med 176:599–604

    Google Scholar 

  • Citron BA, Davis MD, Milstien S, Gutierrez J, Mendel DB, Crabtree GE, Kaufman S (1992) Identity of 4a-carbinolamine dehydratase, a component of the phenylalanine hydroxylation system, and DCoH, a transregulator of homeodomain proteins. Biochemistry 89:11891–11894

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Culcasi M, Lafon-Cazal 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

    Google Scholar 

  • Curtius HC, Adler C, Rebrin I, Heizmann C, Ghisla S (1990) 7-substituted pterins: formation during phenylalanine hydroxylation in the absence of dehydratase. Biochem Biophys Res Commun 172:1060–1066

    Google Scholar 

  • Davies MD, Kaufman S (1993) Products of the tyrosine-dependent oxidation of tetrahydrobiopterin by rat liver phenylalanine hydroxylase. Arch Biochem Biophys 304:9–16

    Google Scholar 

  • Davis MD, Kaufman S, Milstien S (1991) Conversion of 6-substituted tetrahydropterins to 7-isomers via phenylalanine hydroxylase-generated intermediates. Proc Nail Acad Sci USA 88:385389

    Google Scholar 

  • Degtyarenko KN, Archakov AI (1993) Molecular evolution of P450 superfamily and P450-containing monooxygenase systems. FEES Lett 332:1–8

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  • Ford PC, Wink DA, Stanbury DM (1993) Autoxidation kinetics of aqueous nitric oxide. FEBS Lett 326:1–3

    Google Scholar 

  • Fulco AJ (1991) P450BM-3 and other inducible bacterial P450 cytochromes: Biochemistry and regulation. Annu Rev Pharmacol Toxicol 31:177–203

    Google Scholar 

  • Garthwaite J (1993) Nitric oxide signalling in the nervous system. Semin Neurosci 5:171–180

    Google Scholar 

  • Gibbs BS, Wojchowski D, Benkovic SJ (1993) Expression of rat liver phenylalanine hydroxylase in insect cells and site-directed mutagenesis of putative non-heme iron binding sites. J Biol Chem 268:8046–8052

    Google Scholar 

  • Giovanelli J, Campos KL, Kaufman S (1991) Tetrahydrobiopterin, a cofactor for rat cerebellar nitric oxide synthase, does not function as a reactant in the oxygenation of arginine. Proc Natl Acad Sci USA 88:7091–7095

    Google Scholar 

  • 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

    Google Scholar 

  • 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 269:2164421649

    Google Scholar 

  • Gross SS, Levi R (1992) Tetrahydrobiopterin synthesis — an absolute requirement for cytokine-induced nitric oxide generation by vascular smooth muscle. J Biol Chem 267:25722–25729

    Google Scholar 

  • Gross SS, Jaffe EA, Levi R, Kilbourn RG (1991) Cytokine-activated endothelial cells express an isotype of nitric oxide synthase which is tetrahydrobiopterin-dependent, calmodulin-independent and inhibited by arginine analogs with a rank-order of potency characteristic of activated macrophages. Biochem Biophys Res Commun 178:823–829

    Google Scholar 

  • Guengerich FP (1991) Reactions and significance of cytochrome P450 enzymes. J Biol Chem 266:10019–10022

    Google Scholar 

  • Haavik J, Martinez A, Olafsdottir S, Mallet J, Flatmark T (1992) The incorporation of divalent metal ions into recombinant human tyrosine hydroxylase apoenzymes studied by intrinsic fluorescence and 1H-NMR spectroscopy. Fur J Biochem 210:23–31

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  • 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 J 7:1124–1134

    CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

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

    Google Scholar 

  • Huie RE, Padmaja S (1993) The reaction of NO with superoxide. Free Radic Res Commun 18:195–199

    Google Scholar 

  • Kaufman S (1961) The nature of the primary oxidation product formed from tetrahydropteridines during phenylalanine hydroxylation. J Biol Chem 236:804–810

    Google Scholar 

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

    Google Scholar 

  • Kharitonov VG, Sundquist AR, Sharma VS (1994) Kinetics of nitric oxide autoxidation in aqueous solution. J Biol Chem 269:5881–5883

    Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Klatt P, Heinzel B, Mayer B, Ambach E, Werner-Felmayer G, Wachter H, Werner ER (1992c) Stimulation of human nitric oxide synthase by tetrahydrobiopterin and selective binding of the cofactor. FEBS Lett 305:160–162

    Google Scholar 

  • 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

    Google Scholar 

  • Klatt P, Schmid M, Leopold E, Schmidt K, Wemer ER, Mayer B (1994a) 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

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  • Kooy NW, Royall JA (1994) Agonist-induced peroxynitrite production from endothelial cells. Arch Biochem Biophys 310:352–359

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • Lipton SA, Choi YB, Pan ZH, Lei SZZ, Chen HSV, Sucher NJ, Loscalzo J, Singel DJ, Stamler JS (1993) A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364:626–632

    Article  CAS  PubMed  Google Scholar 

  • Liu S, Beckman JS, Ku DD (1994) Peroxynitrite, a product of superoxide and nitric oxide, produces coronary vasorelaxation in dogs. J Pharmacol Exp Ther 268:1114–1121

    Google Scholar 

  • Malinski T, Taha Z (1992) Nitric oxide release from a single cell measured in situ by a porphyrinic-based microsensor. Nature 358:676–678

    Google Scholar 

  • Malinski T, Bailey F, Zhang ZG, Chopp M (1993) Nitric oxide measured by a porphyrinic microsensor in rat brain after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 13:355–358

    Google Scholar 

  • Marletta MA (1993) Nitric oxide synthase structure and mechanism. J Biol Chem 268:121231–121234

    Google Scholar 

  • Marletta MA (1994) Approaches toward selective inhibition of nitric oxide synthase. J Med Chem 37:1899–1907

    Google Scholar 

  • Martinez A, Olafsdottir S, Haavik J, Flatmark T (1992) Inactivation of purified phenylalanine hydroxylase by dithiothreitol. Biochem Biophys Res Commun 182:92–98

    Google Scholar 

  • Martinez A, Abeygunawardana C, Haavik J, Flatmark T, Mildvan AS (1993) Conformation and interaction of phenylalanine with the divalent cation at the active site of human recombinant tyrosine hydroxylase as determined by proton NMR. Biochemistry 32: 6381–6390

    Google Scholar 

  • Masters BSS (1994) Nitric oxide synthases: Why so complex? Annu Rev Nutr 14:131–145

    Google Scholar 

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

    Google Scholar 

  • Mayer B, John M, Böhme E (1990) Purification of a Ca 2+/calmodu-lin-dependent nitric oxide synthase from porcine cerebellum. Cofactor-role of tetrahydrobiopterin. FEES Lett 277:215–219

    Google Scholar 

  • Mayer B, John M, Heinzel B, Werner ER, Wachter H, Schultz G, Böhme E (1991) Brain nitric oxide synthase is a biopterin- and flavin-containing multi-functional oxido-reductase. FEBS Lett 288:187–191

    Google Scholar 

  • 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 20:554–556

    Google Scholar 

  • Mayer B, Brunner F, Schmidt K (1993) Inhibition of nitric oxide synthesis by methylene blue. Biochem Pharmacol 45:367–374

    Article  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

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

    Google Scholar 

  • 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

    Google Scholar 

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

    Google Scholar 

  • Mellouk S, Hoffmann SL, Lui ZZ, Delavega P, Billiar TR, Nüssler AK (1994) Nitric oxide-mediated antiplasmodial activity in human and murine hepatocytes induced by gamma-interferon and the parasite itself: Enhancement by exogenous tetrahydrobiopterin. Infect Immun 62:4043–4046

    Google Scholar 

  • Moncada S, Palmer RMJ, Higgs EA (1991) Nitric oxide — physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109–142

    CAS  PubMed  Google Scholar 

  • Moncada S, Higgs A (1993) Mechanisms of disease — the l-arginine nitric oxide pathway. New Engl J Med 329:2002–2012

    Google Scholar 

  • Morikawa E, Huang Z, Moskowitz MA (1992) l-Arginine decreases infarct size caused by middle cerebral arterial occlusion in SHR. Am J Physiol 263:111632–111635

    Google Scholar 

  • Morikawa E, Moskowitz MA, Huang ZH, Yoshida T, Irikura K, Dalkara T (1994) l-Arginine infusion promotes nitric oxide-dependent vasodilation, increases regional cerebral blood flow, and reduces infarction volume in the rat. Stroke 25:429–435

    Google Scholar 

  • Moro MA, Darley-Usmar VM, Goodwin DA, Read NG, Zamorapino R, Feelisch M, Radomski MW Moncada S (1994) Paradoxical fate and biological action of peroxynitrite on human platelets. Proc Natl Acad Sci USA 91:6702–6706

    Google Scholar 

  • Nakayama N, Shoun H (1994) Fatty acid hydroxylase of the fungus Fusarium oxysporum is possibly a fused protein of cytochrome P450 and its reductase. Biochem Biophys Res Commun 202:586–590

    Google Scholar 

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

    Google Scholar 

  • Nathan CF, Hibbs JB (1991) Role of nitric oxide synthesis in macrophage antimicrobial activity. CurT Opin Immunol 3:65–70

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  • Nishikimi M (1975) A function of tetrahydropteridines as cofactor for indoleamine 2,3-dioxygenase. Biochem Biophys Res Commun 63:92–98

    Google Scholar 

  • Olken NM, Marletta MA (1993) NG-Methyl-l-arginine functions as an alternate substrate and mechanism-based inhibitor of nitric oxide synthase. Biochemistry 32:9677–9685

    Google Scholar 

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

    Google Scholar 

  • Pou S, Pou WS, Bredt DS, Snyder SH, Rosen GM (1992) Generation of superoxide by purified brain nitric oxide synthase. J Biol Chem 267:241173–241176

    Google Scholar 

  • Radomski MW, Rees DD, Dutra A, Moncada S (1992) S-Nitrosoglutathione inhibits platelet activation in vitro and in vivo. Br J Pharmacol 107:745–749

    Google Scholar 

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

    Google Scholar 

  • 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

    Google Scholar 

  • Rosenkranz-Weiss P, Sessa WC, Milstien S, Kaufman S, Watson CA, Pober JS (1994) Regulation of nitric oxide synthesis by proinflammatory cytokines in human umbilical vein endothelial cells — elevations in tetrahydrobiopterin levels enhance endothelial nitric oxide synthase specific activity. J Clin Invest 93:2236–2243

    Google Scholar 

  • Sakai N, Kaufman S, Milstien S (1993a) Tetrahydrobiopterin is required for cytokine-induced nitric oxide production in a murine macrophage cell line (RAW-264). Mol Pharmacol 43:6–10

    Google Scholar 

  • Sakai N, Saito K, Kaufman S, Heyes MP, Milstien S (1993b) Induction of pterin synthesis is not required for cytokine-stimulated tryptophan metabolism. Biochem J 295:543–547

    Google Scholar 

  • 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

    Google Scholar 

  • Schmidt K, Werner ER, Mayer B, Wachter H, Kukovetz WR (1992) Tetrahydrobiopterin-dependent formation of endothelium-derived relaxing factor (nitric oxide) in aortic endothelial cells. Biochem J 281:297–300

    Google Scholar 

  • Schmidt K, Klatt P, Mayer B (1994) Reaction of peroxynitrite with oxyhaemoglobin: interference with photometrical determination of nitric oxide. Biochem J 301:645–647

    Google Scholar 

  • Sheta EA, McMillan K, Masters BSS (1994) Evidence for a bidomain structure of constitutive cerebellar nitric oxide synthase. J Biol Chem 269:151147–151153

    Google Scholar 

  • Stadler J, Trockfeld J, Schmalix WA, Brill T, Siewert JR, Greim H, Doehmer J (1994) Inhibition of cytochromes P4501A by nitric oxide. Proc Natl Acad Sci USA 91:3559–3563

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  • Stuehr DJ, Cho HJ, Kwon NS, Weise MF, Nathan CF (1991b) 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

    Google Scholar 

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

    Google Scholar 

  • 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

    Google Scholar 

  • Thöny B, Neuheiser F, Hauer CR, Heizmann CW (1993) Molecular cloning and recombinant expression of the human liver phenylalanine hydroxylase stimulating factor revealed structural and functional identity to the dimerization cofactor for the nuclear transcription factor HNF-1 alpha. Adv Exp Med Biol 338:103–106

    Google Scholar 

  • Wachter H, Fuchs D, Hausen A, Reibnegger G, Werner ER (1989) Neopterin as a marker for activation of cellular immunity: immunologic basis and clinical application. Adv Clin Chem 27:81–141

    Google Scholar 

  • Wedel B, Humbert P, Harteneck C, Foerster J, Malkewitz J, Böhme E, Schultz G, Koesling D (1994) Mutation of His-105 of the β1-subunit yields a nitric oxide-insensitive form of soluble guanylyl cyclase. Proc Natl Acad Sci USA 91:2592–2596

    Google Scholar 

  • Weiss G, Goossen B, Doppler W, Fuchs D, Pantopoulos K, Werner-Felmayer G, Wachter H, Hentze MW (1993) Translational regulation via iron-responsive elements by the nitric oxide/NO synthase pathway. EMBO J 12:3651–3657

    Google Scholar 

  • Werner ER, Werner-Felmayer G, Wachter H (1993) Tetrahydrobiopterin and cytokines. Proc Soc Exp Biol Med 203:1–12

    Google Scholar 

  • Werner ER, Werner-Felmayer G, Fuchs D, Hausen A, Reibnegger G, Yim JJ, Wachter H (1991) Pteridine synthesis in cytokine-treated cells. In: Blau N, Curtius C, Levine R (eds) Pterins and Biogenic Amines in Neurology, Pediatrics and Immunology. Lakeshore Publishing, Grosse Pointe, Mich., USA, pp 213–224

    Google Scholar 

  • Werner-Felmayer G, Werner ER, Fuchs D, Hausen A, Reibnegger G, Wachter H (1990) Tetrahydrobiopterin-dependent formation of nitrite and nitrate in murine fibroblasts. J Exp Med 172:1599–1607

    Google Scholar 

  • Werner-Felmayer G, Werner ER, Fuchs D, Hausen A, Mayer B, Reibnegger G, Weiss G, Wachter H (1993a) Calcium/calmodulin-dependent nitric oxide synthase in the human cervical carcinoma cell line ME-180. Biochem J 289:357–361

    Google Scholar 

  • Werner-Felmayer G, Werner ER, Fuchs D, Hausen A, Reibnegger G, Schmidt K, Weiss G, Wachter H (1993b) Pteridine biosynthesis in human endothelial cells. Impact on nitric oxide-mediated formation of cyclic GMP. J Biol Chem 268:1842–1846

    Google Scholar 

  • Werner-Felmayer G, Golderer G, Werner ER, Grobner P, Wachter H (1994) Pteridine biosynthesis and nitric oxide synthase in Physarum polycephalum. Biochem J 304:105–111

    Google Scholar 

  • Werner-Felmayer G, Werner ER, Wachter H, Gross SS (1995) Analysis of tetrahydrobiopterin and its role in nitric oxide synthesis. In: Feelisch M, Stamler JS (eds) Methods in nitric oxide research. Wiley, Chichester, UK (in press)

    Google Scholar 

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

    Google Scholar 

  • Wink DA, Darbyshire JF, Nims RW, Saavedra JE, Ford PC (1993a) Reactions of the bioregulatory agent nitric oxide in oxygenated aqueous media — determination of the kinetics for oxidation and nitrosation by intermediates generated in the NO/O2 reaction. Chem Res Toxicol 6:23–27

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • Wolff DJ, Gribin BJ (1994) The inhibition of the constitutive and inducible nitric oxide synthase isoforms by indazole agents. Arch Biochem Biophys 311:300–306

    Google Scholar 

  • Wu MD, Pritchard KA, Kaminski PM, Fayngersh RP, Hintze TH, Wolin MS (1994) Involvement of nitric oxide and nitrosothiols in relaxation of pulmonary arteries to peroxynitrite. Am J Physiol 2660:H2108-H2113

    Google Scholar 

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  1. Institut für Pharmakologie und Toxikologie, Karl-Franzens-Universität Graz, Universitätsplatz, 2, A-8010, Graz, Austria

    Bernd Mayer

  2. Institut für Medizinische Chemie and Biochemie, Universität Innsbruck, Fritz-Pregl-Straße 3, A-6020, Innsbruck, Austria

    Ernst R. Werner

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This article is dedicated to Prof. Dr. Helmut Wachter on the occasion of his 65th birthday

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Mayer, B., Werner, E.R. In search of a function for tetrahydrobiopterin in the biosynthesis of nitric oxide. Naunyn-Schmiedeberg's Arch Pharmacol 351, 453–463 (1995). https://doi.org/10.1007/BF00171035

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