Tetrahydrobiopterin

Abstract

See related article, pp 287–294 Tetrahydrobiopterin (BH4), an essential cofactor for diverse cellular processes, is present in almost every cell or tissue of higher organisms. BH4 has well-defined functions in terms of enzymatic activities (BH4 is a crucial cofactor for the aromatic amino acid hydroxylases and all isoforms of nitric oxide synthase [NOS]) but has other less-defined functions in cells. BH4 is a growth or proliferation factor for various mammalian cells, including hematopoietic and endothelial cells.1,2 Epidermal growth factor and nerve growth factor act to increase proliferation of rat PC12 cells by elevating BH4 levels.3 However, BH4 is also a powerful antioxidant4 and has scavenging capabilities, reacting with superoxide anion radicals peroxynitrite and hydrogen peroxide.5 BH4 bioavailability is, thus, potently influenced by oxidative stress in cells. GTP cyclohydrolase I (GTPCH), 6-pyruvoyltetrahydropterin synthase, and sepiapterin reductase act in sequence to generate BH4 de novo in endothelial cells.5 The first enzyme, GTPCH, is thought to be the rate-controlling enzyme. GTPCH activity can be controlled at the transcriptional level by a number of mediators, including nutritional (phenylalanine and arginine), hormonal (insulin and estrogen), immunologic (inflammatory cytokines including interleukin1, interferon-γ, and tumor necrosis factor-α), therapeutic (statins and cyclosporin A), and endothelium-derived (basic fibroblast growth factor and H2O2) factors.5 These agonists act via different mechanisms but all lead to the increased generation of BH4. BH4 regulates NO synthesis in both mature endothelial cells and endothelial progenitor cells (EPCs). Bone marrow–derived EPCs have the potential to give rise to circulating vascular …