Regulation of Tetrahydrobiopterin Synthesis and Bioavailability in Endothelial Cells

Shi, Wenjuan; Meininger, Cynthia J.; Haynes, Tony E.; Hatakeyama, Kazuyuki; Wu, Guoyao

doi:10.1385/cbb:41:3:415

Cited by 137Nitric Oxide and Endothelin EffectsBiochemical and Molecular ResearchFolate and B Vitamins Research

The DOI matches its Crossref record; 122 of the 122 references it cites were found in a registry or an index.

Regulation of Tetrahydrobiopterin Synthesis and Bioavailability in Endothelial Cells

Shi, Wenjuan, Meininger, Cynthia J., Haynes, Tony E., Hatakeyama, Kazuyuki, Wu, Guoyao·2004·Cell Biochemistry and Biophysics

DOI 10.1385/cbb:41:3:415

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Abstract

Tetrahydrobiopterin (BH4) is a member of the pterin family that has a core structure of pyrazino-2,3-d-pyrimidine rings. Because BH4 is an essential cofactor for the biosynthesis of nitric oxide (a major vasodilator), there is growing interest in BH4 biochemistry in endothelial cells (the cells that line blood vessels). BH4 is synthesized via de novo and salvage pathways from guanosine 5'-triphosphate (GTP) and 7,8-dihydrobiopterin, respectively, in animal cells. GTP cyclohydrolase-I (GTP-CH) is the first and rate-controlling enzyme in the de novo pathway. Available evidence shows that endothelial GTP-CH expression and BH4 synthesis are stimulated by a wide array of nutritional (phenylalanine and arginine), hormonal (insulin and estrogen), immunological (inflammatory cytokines including interleukin [IL]-1, interferon-gamma, and tumor necrosis factor-alpha), therapeutic (statins and cyclosporin A), and endothelium-derived (basic fibroblast growth factor and H2O2) factors. In contrast, glucocorticoids and anti-inflammatory cytokines (IL-4, IL-10, and transforming growth factor [TGF]-beta) inhibit endothelial BH4 synthesis. Because BH4 is oxidized to 7,8-dihydrobiopterin and 7,8-dihydropterin at physiological pH, endothelial BH4 homeostasis is regulated by both BH4 synthesis and its oxidation. Vitamin C, folate, and other antioxidants enhance endothelial BH4 bioavailability through chemical stabilization or scavenging of reactive oxygen species, thereby contributing to the maintenance of physiological homeostasis in the endothelium. New knowledge about the cellular and molecular mechanisms for the regulation of endothelial BH4 synthesis and bioavailability is beneficial for developing effective means to prevent and treat cardiovascular disorders, the leading cause of death in developed nations.

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Folate regulates melanin production because it is required for synthesis of GTP, a substrate for de novo production of BH4 and 6BH4 in melanocytes and keratinocytes.
“folate regulates melanin production because it is required for the synthesis of GTP, which is a substrate for de novo production of tetrahydrobiopterin (BH4) and 6BH4 in melanocytes and keratinocytes (38,39).”
From Human skin pigmentation as an adaptation to UV radiation (2010) · cites this paper as [38]
Folate depletion would impact purine synthesis and onward metabolism to GTP and hence BH4.
“Folate depletion would impact purine synthesis and onward metabolism to GTP and hence BH4”
From The evolution of human skin pigmentation: A changing medley of vitamins, genetic variability, and UV radiation during human expansion (2023) · cites this paper as Shi et al., 2004

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Regulation of Endothelial Cell Tetrahydrobiopterin
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Authors: Shi, W., Meininger, C. J., Haynes, T. E., Hatakeyama, K., & Wu, G.
Affiliations: Texas A&M University (US)
Texas A&M Health Science Center (US)
University of Pittsburgh (US)
Corresponding author: Wu, Guoyao
ORCID: Shi, Wenjuan
Meininger, Cynthia J.
Wu, Guoyao
Venue: Cell Biochemistry and Biophysics
Publisher: Springer Science and Business Media LLC
Published: 2004
Volume: 41
Issue: 3
Pages: 415-434
ISSN: 1085-9195 (ISSN-L)
DOI: 10.1385/cbb:41:3:415
OpenAlex: W1970164806
Cited by: 137
References: 122
Citations by year: 2026: 1 · 2025: 2 · 2024: 2 · 2023: 6 · 2022: 9 · 2021: 11 · 2020: 4 · 2019: 7 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 10 · 2014: 2 · 2013: 8 · 2012: 6
FWCI: 4.53
Type: journal article
Language: en
Open access: closed
Locations: Cell Biochemistry and Biophysics (publishedVersion)
PubMed (publishedVersion)
Funders: American Heart Association
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
Keywords: tetrahydrobiopterin, endothelial cells, GTP cyclohydrolase I, 7,8-dihydrobiopterin, nitric oxide production, antioxidant vitamins, folic acid, reactive oxygen species, phenylalanine, L-arginine, cytokines, glucocorticoids, statins, cyclosporine, cardiovascular disease
MeSH terms: Animals, Biopterins, Estrogens, Gene Expression Regulation, Glucocorticoids, GTP Cyclohydrolase, Humans, Hydrogen-Ion Concentration, Models, Biological, Nitric Oxide, Oxygen, Phenylalanine, Cytokines, Endothelial Cells

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Regulation of Tetrahydrobiopterin Synthesis and Bioavailability in Endothelial Cells

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