Reduced Biopterin as a Cofactor in the Generation of Nitrogen Oxides by Murine Macrophages
Open accessAbstract
Generation of nitric oxide (NO.), an autacoid with vasorelaxant and cytotoxic properties, requires at least three cytosolic components in mouse macrophages besides L-arginine and NADPH. One or more components appear after induction by immunologic stimuli; two or more are present in both activated and non-activated macrophages. The constitutive factors can be separated on a Mr approximately 30,000 cut-off filter into high Mr fraction (HF) and low Mr fraction (LF) (Stuehr, D. J., Kwon, N. S., Gross, S. S., Thiel, B. A., Levi, R., and Nathan, C. F. (1989) Biochem. Biophys. Res. Commun. 161, 420-426). Herein we characterize the major active component in LF. The active component was dialyzable (Mr less than approximately 1,000), water soluble, and cationic at acidic to neutral pH. Fractionation on a C18 column in an acetonitrile/water gradient yielded one broad peak of activity, most of which corresponded to a fluorophore with the excitation/emission spectra of biopterins. Gas chromatography isolated a species in this peak with the mass spectrum of biopterin. Of 14 pteridines tested, only 7,8-dihydrobiopterin (H2biopterin) or 5,6,7,8-tetrahydrobiopterin (H4biopterin) could replace LF in synergizing with HF and the inducible component(s) to generate NO-2 and NO-3, the accumulating oxidation products of NO.. Half-maximal activity required 20-30 nM reduced biopterins. LFs from three cell lines were active in proportion to their content of biopterins; addition of reduced biopterins restored activity to LF from biopterin-deficient cells. Enhancement of NO-2 generation in the presence of H2biopterin but not H4biopterin was abolished by methotrexate and aminopterin, inhibitors of dihydrofolate reductase. These findings implicate a redox cycle in which the generation of NO. is facilitated by catalytic amounts of H4biopterin.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Peroxynitrite can in turn oxidize BH4 to BH2, further promoting eNOS uncoupling.
“Peroxynitrite can in turn oxidize BH4 to BH2, further promoting eNOS uncoupling (543).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [543]
Cites
Bradford, M. M. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90527-3 · Cited by 255,302 · see citing works
Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids
Green, L. C., Wagner, D. A., Glogowski, J. A., Skipper, P. L., Wishnok, J. S., & Tannenbaum, S. R. (1982) · Analytical Biochemistry · doi:10.1016/0003-2697(82)90118-x · Cited by 12,089 · see citing works
Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor
Palmer, R. M. J., Ferrige, A. G., & Moncada, S. (1987) · Nature · doi:10.1038/327524a0 · Cited by 10,704 · see citing works
Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.
Ignarro, L. J., Buga, G. M., Wood, K. S., Byrns, R. E., & Chaudhuri, G. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.24.9265 · Cited by 5,074 · see citing works
Vascular endothelial cells synthesize nitric oxide from L-arginine
Palmer, R. M. J., Ashton, D., & Moncada, S. (1988) · Nature · doi:10.1038/333664a0 · Cited by 4,745 · see citing works
Ding, A. H., Nathan, C., & Stuehr, D. J. (1988) · The Journal of Immunology · doi:10.4049/jimmunol.141.7.2407 · Cited by 2,840 · see citing works
Self-citationNitric oxide: A cytotoxic activated macrophage effector molecule
Hibbs, J. B., Taintor, R. R., Vavrin, Z., & Rachlin, E. M. (1988) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(88)80015-9 · Cited by 2,030 · see citing works
Stuehr, D. J., & Nathan, C. F. (1989) · The Journal of Experimental Medicine · doi:10.1084/jem.169.5.1543 · Cited by 1,744 · see citing works
Self-citationMacrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate
Marletta, M. A., Yoon, P. S., Iyengar, R., Leaf, C. D., & Wishnok, J. S. (1988) · Biochemistry · doi:10.1021/bi00424a003 · Cited by 1,601 · see citing works
Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite
Hibbs, J. B., Taintor, R. R., & Vavrin, Z. (1987) · Science · doi:10.1126/science.2432665 · Cited by 1,527 · see citing works
Stuehr, D. J., & Marletta, M. A. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.22.7738 · Cited by 1,126 · see citing works
Self-citationThe role of nitric oxide and cGMP in platelet adhesion to vascular endothelium
Radomski, M. W., Palmer, R. M. J., & Moncada, S. (1987) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(87)80299-1 · Cited by 746 · see citing works
Stuehr, D. J., & Marletta, M. A. (1987) · The Journal of Immunology · doi:10.4049/jimmunol.139.2.518 · Cited by 713 · see citing works
Self-citationAnalysis of reduced forms of biopterin in biological tissues and fluids
Fukushima, T., & Nixon, J. C. (1980) · Analytical Biochemistry · doi:10.1016/0003-2697(80)90336-x · Cited by 712 · see citing works
Green, L. C., Ruiz de Luzuriaga, K., Wagner, D. A., Rand, W., Istfan, N., Young, V. R., & Tannenbaum, S. R. (1981) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.78.12.7764 · Cited by 665 · see citing works
Iyengar, R., Stuehr, D. J., & Marletta, M. A. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.18.6369 · Cited by 664 · see citing works
Self-citationPartial Purification and Characterization of Tryptophan Hydroxylase from Rabbit Hindbrain
Friedman, P. A., Kappelman, A. H., & Kaufman, S. (1972) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)45055-2 · Cited by 446 · see citing works
Identification of arginine as a precursor of endothelium-derived relaxing factor.
Sakuma, I., Stuehr, D. J., Gross, S. S., Nathan, C., & Levi, R. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.22.8664 · Cited by 401 · see citing works
Self-citationTHE STRUCTURE OF THE PHENYLALANINE-HYDROXYLATION COFACTOR
Kaufman, S. (1963) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.50.6.1085 · Cited by 379 · see citing works
Synthesis of nitrite and nitrate in murine macrophage cell lines.
Stuehr, D. J., & Marletta, M. A. (1987) · PubMed · Cited by 335 · see citing works
Self-citationBilliar, T., Curran, R., Stuehr, D. J., West, M. A., Bentz, B., & Simmons, R. L. (1989) · The Journal of Experimental Medicine · doi:10.1084/jem.169.4.1467 · Cited by 311 · see citing works
Self-citationA New Pteridine-requiring Enzyme System for the Oxidation of Glyceryl Ethers
Tietz, A., Lindberg, M., & Kennedy, E. P. (1964) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)91137-3 · Cited by 297 · see citing works
Generation of nitric oxide by human neutrophils
Wright, C. D., Mülsch, A., Busse, R., & Oßwald, H. (1989) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(89)92506-0 · Cited by 292 · see citing works
The Isolation and Characterization of Dihydropteridine Reductase from Sheep Liver
Craine, J. E., Hall, E. S., & Kaufman, S. (1972) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)44767-4 · Cited by 253 · see citing works
Schmidt, H. H. H. W., Seifert, R., & Böhme, E. (1989) · FEBS Letters · doi:10.1016/0014-5793(89)80562-9 · Cited by 239 · see citing works
Kaufman, S. (1964) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)51786-5 · Cited by 213 · see citing works
Werner, E. R., Werner‐Felmayer, G., Fuchs, D., Hausen, A., Reibnegger, G. J., & WACHTER, H. (1989) · Biochemical Journal · doi:10.1042/bj2620861 · Cited by 200 · see citing works
Brenneman, A., & Kaufman, S. (1964) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(64)90141-x · Cited by 192 · see citing works
Further Studies on the Phenylalanine-hydroxylation Cofactor
Kaufman, S., & Levenberg, B. (1959) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)69759-5 · Cited by 180 · see citing works
Metabolism of the Phenylalanine Hydroxylation Cofactor
Kaufman, S. (1967) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)95837-0 · Cited by 180 · see citing works
Stuehr, D. J., Kwon, N. S., Gross, S. S., Thiel, B., Levi, R., & Nathan, C. (1989) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(89)92615-6 · Cited by 149 · see citing works
Self-citationSchoedon, G., Troppmair, J., FONTANA, A., Huber, C., Curtius, H., & Niederwieser, A. (1987) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1987.tb13515.x · Cited by 130 · see citing works
SHORT COMMUNICATION: Cytokines Induce an L-Arginine-Dependent Effector System in Nonmacrophage Cells
Amber, I. J., Hibbs, J. B., Taintor, R. R., & Vavrin, Z. (1988) · Journal of Leukocyte Biology · doi:10.1002/jlb.44.1.58 · Cited by 129 · see citing works
Duch, D. S., Bowers, S. W., Woolf, J. H., & Nichol, C. A. (1984) · Life Sciences · doi:10.1016/0024-3205(84)90541-1 · Cited by 106 · see citing works
The auto‐oxidation of tetrahydrobiopterin
DAVIS, M. D., Kaufman, S., & Milstien, S. (1988) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1988.tb14004.x · Cited by 94 · see citing works
Specificity of amino acids as activators and substrates for phenylalanine hydroxylase.
Kaufman, S., & Mason, K. T. (1982) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)33333-7 · Cited by 85 · see citing works
Mechanism of oxygen activation by tyrosine hydroxylase
Dix, T. A., Kuhn, D. M., & Benkovic, S. J. (1987) · Biochemistry · doi:10.1021/bi00386a016 · Cited by 84 · see citing works
Synthese und chromatographische Trennung von [8a‐14C]Biopterin und [8a‐14C]7‐Biopterin
Rembold, H., & Metzger, H. (1963) · Chemische Berichte · doi:10.1002/cber.19630960531 · Cited by 72 · see citing works
Mechanism of action of phenylalanine hydroxylase
Lazarus, R. A., Dietrich, R. F., Wallick, D. E., et al. (1981) · Biochemistry · doi:10.1021/bi00527a015 · Cited by 68 · see citing works
Davis, M. D., & Kaufman, S. (1989) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)81832-4 · Cited by 67 · see citing works
Dix, T. A., Bollag, G. E., Domanico, P. L., & Benkovic, S. J. (1985) · Biochemistry · doi:10.1021/bi00333a022 · Cited by 59 · see citing works
The biosynthesis of tetrahydrobiopterin in rat brain
Milstien, S., & Kaufman, S. (1989) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)83151-9 · Cited by 55 · see citing works
Gas chromatography—mass spectrometry of trimethylsilyl pteridines
Küster, T., & Niederwieser, A. (1983) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/s0378-4347(00)84783-0 · Cited by 22 · see citing works
Incorporation of molecular oxygen into pyrimidine cofactors by phenylalanine hydroxylase.
Bailey, S., Weintraub, S. T., Hamilton, S. M., et al. (1982) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)34325-4 · Cited by 21 · see citing works
Mammalian brain dihydrofolate reductase1
LYNN, R. B., Rueter, M. E., & Guynn, R. W. (1977) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1977.tb06523.x · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Nitric oxide as a secretory product of mammalian cells
Nathan, C. (1992) · The FASEB Journal · doi:10.1096/fasebj.6.12.1381691 · Cited by 4,350 · see citing works
Self-citationInterferon-γ: an overview of signals, mechanisms and functions
Schroder, K., Hertzog, P. J., Ravasi, T., & Hume, D. A. (2004) · Journal of Leukocyte Biology · doi:10.1189/jlb.0603252 · Cited by 4,120 · see citing works
Nitric oxide synthases in mammals
Knowles, R. G., & Moncada, S. (1994) · Biochemical Journal · doi:10.1042/bj2980249 · Cited by 2,752 · see citing works
Role of nitric oxide synthesis in macrophage antimicrobial activity
Nathan, C. F., & Hibbs, J. B. (1991) · Current Opinion in Immunology · doi:10.1016/0952-7915(91)90079-g · Cited by 1,523 · see citing works
Self-citationAn L-arginine/nitric oxide pathway present in human platelets regulates aggregation.
Radomski, M. W., Palmer, R. M., & Moncada, S. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.13.5193 · Cited by 1,208 · see citing works
Gases as biological messengers: nitric oxide and carbon monoxide in the brain
Dawson, T., & Snyder, S. (1994) · The Journal of Neuroscience · doi:10.1523/jneurosci.14-09-05147.1994 · Cited by 1,043 · see citing works
Mammalian nitric oxide synthases
Stuehr, D. J. (1999) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/s0005-2728(99)00016-x · Cited by 996 · see citing works
Self-citationStuehr, D. J., Cho, H. J., Kwon, N. S., Weise, M. F., & Nathan, C. F. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.17.7773 · Cited by 816 · see citing works
Self-citationGeneration of superoxide by purified brain nitric oxide synthase
Pou, S., Pou, W. S., Bredt, D. S., Snyder, S. H., & Rosen, G. M. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)35745-4 · Cited by 750 · see citing works
Clancy, R. M., Leszczynska-Piziak, J., & Abramson, S. B. (1992) · Journal of Clinical Investigation · doi:10.1172/jci115929 · Cited by 686 · see citing works
Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541 · see citing works
Tetrahydrobiopterin: biochemistry and pathophysiology
Werner, E. R., Blau, N., & Thöny, B. (2011) · Biochemical Journal · doi:10.1042/bj20110293 · Cited by 493 · see citing works
Translational regulation via iron‐responsive elements by the nitric oxide/NO‐synthase pathway.
Weiss, G., Goossen, B., Doppler, W., Fuchs, D., Pantopoulos, K., Werner‐Felmayer, G., Wachter, H., & Hentze, M. W. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb06039.x · Cited by 389 · see citing works
Baek, K. J., Thiel, B. A., Lucas, S., & Stuehr, D. J. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)36901-7 · Cited by 389 · see citing works
Self-citationRosenkranz-Weiss, P., Sessa, W. C., Milstien, S., Kaufman, S., Watson, C. A., & Pober, J. S. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117221 · Cited by 362 · see citing works
Schmidt, H. H. H. W., Hofmann, H., Schindler, U., Shutenko, Z. S., Cunningham, D. D., & Feelisch, M. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.25.14492 · Cited by 353 · see citing works
Structure–function studies on nitric oxide synthases
LI, H., & POULOS, T. (2005) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2004.10.016 · Cited by 302 · see citing works
Klatt, P., Schmidt, K., Lehner, D., Glatter, O., Bächinger, H. P., & Mayer, B. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb00038.x · Cited by 292 · see citing works
Werner-Felmayer, G., Werner, E. R., Fuchs, D., Hausen, A., Reibnegger, G., Schmidt, K., Weiss, G., & Wachter, H. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)53931-4 · Cited by 263 · see citing works
Hobbs, A. J., Fukuto, J. M., & Ignarro, L. J. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.23.10992 · Cited by 244 · see citing works
Tetrahydrobiopterin in Cardiovascular Health and Disease
Bendall, J. K., Douglas, G., McNeill, E., Channon, K. M., & Crabtree, M. J. (2014) · Antioxidants & Redox Signaling · doi:10.1089/ars.2013.5566 · Cited by 231 · see citing works
Klatt, P., Schmid, M., Leopold, E., Schmidt, K., Werner, E. R., & Mayer, B. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)36726-1 · Cited by 219 · see citing works
Crabtree, M. J., Smith, C. L., Lam, G., Goligorsky, M. S., & Gross, S. S. (2008) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00823.2007 · Cited by 213 · see citing works
Tetrahydrobioterin (BH4) pathway: from metabolism to neuropsychiatry
Fanet, H., Capuron, L., Castanon, N., Calon, F., & Vancassel, S. (2021) · Current Neuropharmacology · doi:10.2174/1570159x18666200729103529 · Cited by 134 · see citing works
Tetrahydrobiopterin, superoxide, and vascular dysfunction
Vásquez-Vivar, J. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.07.024 · Cited by 84 · see citing works
Tetrahydrobiopterin in nitric oxide synthase
Tejero, J., & Stuehr, D. (2013) · IUBMB Life · doi:10.1002/iub.1136 · Cited by 75 · see citing works
Self-citationOxygen metabolism by neuronal nitric-oxide synthase
Gao, Y. T., Panda, S. P., Roman, L. J., Martásek, P., Ishimura, Y., & Masters, B. S. S. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m609814200 · Cited by 30 · see citing works
Urano, F., Hayashi, N., Arisaka, F., Kurita, H., Murata, S., & Ichinose, H. (2006) · The Journal of Biochemistry · doi:10.1093/jb/mvj073 · Cited by 30 · see citing works
- Authors
- Kwon, N. S., Nathan, C. F., & Stuehr, D. J.
- Affiliations
- Cornell University (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1989-12
- Volume
- 264
- Issue
- 34
- Pages
- 20496-20501
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1533126574
- Cited by
- 570
- References
- 45
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 6 · 2020: 2 · 2019: 6 · 2018: 6 · 2017: 6 · 2016: 4 · 2015: 4 · 2014: 9 · 2013: 10 · 2012: 8
- FWCI
- 30.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA-43610)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- nitric oxide, macrophages, 7,8-dihydrobiopterin, pteridines, dihydrofolate reductase inhibition, methotrexate, aminopterin, redox cycling, L-arginine
- MeSH terms
- Aminopterin, Animals, Biopterins, Cell Line, Cytosol, Kinetics, Macrophages, Gas Chromatography-Mass Spectrometry, Methotrexate, Nitrogen Oxides, Spectrometry, Fluorescence, Structure-Activity Relationship, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
