IngentaConnect Regulation of tetrahydrobiopterin synthesis and bioavailability i...

Authors: Shi, Wenjuan¹; Meininger, Cynthia²; Haynes, Tony¹; Hatakeyama, Kazuyuki³; Wu, Guoyao⁴

Source: Cell Biochemistry and Biophysics, Volume 41, Number 3, October 2004 , pp. 415-433(19)

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-γ, and tumor necrosis factor-α), 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]-β) 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 know ledge 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.

Keywords: Tetrahy drobiopterin; GTP cyclohydrolase-I; nitric oxide; endothelial cells

Document Type: Research article

DOI: 10.1385/CBB:41:3:415

Affiliations: 1: Faculty of Nutrition and Department of Animal Science, Texas A&M University, 77843, College Station, TX, 2: Department of Medical Physiology and Cardiovascular Research Institute, The Texas A&M University System Health Science Center, 77843, College Station, TX, 3: Department of Surgery, University of Pittsburgh, 15213, Pittsburgh, PA, 4: Faculty of Nutrition and Department of Animal Science, Texas A&M University, 77843, College Station, TX, Email: g-wu@tamu.edu

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Regulation of tetrahydrobiopterin synthesis and bioavailability in endothelial cells