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(Circulation Research. 2005;96:141.)
© 2005 American Heart Association, Inc.

Editorials

Transcribing the Cross-Talk of Cytokine-Induced Tetrahydrobiopterin Synthesis in Endothelial Cells

Timothy E. Peterson, Zvonimir S. Katusic

From the Department of Anesthesiology, Mayo Clinic, Rochester, Minn.

Correspondence to Zvonimir S Katusic, Mayo Clinic, Department of Anesthesiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail katusic.zvonimir@mayo.edu

See related article, pages 164–171

Key Words: nitric oxide • nitric oxide synthase • tumor necrosis factor- • interferon-

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Tetrahydrobiopterin (BH4) is an essential cofactor required for the production of nitric oxide by each of the nitric oxide synthase (NOS) isoforms (see review¹). Synthesis of BH4 involves a multistep process in which GTP cyclohydrolase I (GTPCH I) is the rate-limiting enzyme required for the initial step in conversion of guanosine-5'-triphosphate (GTP) to BH4. The importance of BH4 has been even more appreciated ever since it was discovered that in its absence, NOS uncoupling could occur, resulting in the production of superoxide anion and hydrogen peroxide rather than nitric oxide.^2,3 Loss of endothelial nitric oxide attributable to impairment of BH4 metabolism appears to be an important mechanism in pathogenesis of vascular endothelial dysfunction.^1,4 Indeed, existing evidence indicate that pharmacological or genetic supplementation of BH4 protects against endothelial dysfunction induced by hypercholesterolemia, diabetes, hypertension, and smoking.^5–12 Based on these observations, it has been suggested that BH4 metabolism could be an attractive therapeutic target for prevention and treatment of vascular disease.¹³

More recent studies have provided insights into the molecular mechanisms underlying regulation of GTPCH I.¹⁴ X-ray crystallography has revealed that GTPCH I exists as a dimer of pentamers (thereby creating a decamer), composed of 25 to 30 kDa subunits. GTPCH I activity is controlled at the posttranslational level by interaction with GTPCH I Feedback Regulatory Protein (GFRP) which, in the presence of excess BH4, has been shown to induce a conformational change in the protein resulting in feedback inhibition of enzymatic activity. This inhibition of GTPCH I activity can be . . . [Full Text of this Article]

Related Article:

Cytokine-Stimulated GTP Cyclohydrolase I Expression in Endothelial Cells Requires Coordinated Activation of Nuclear Factor-B and Stat1/Stat3

Annong Huang, Ying-Yi Zhang, Kai Chen, Kazuyuki Hatakeyama, and John F. Keaney, Jr
Circ. Res. 2005 96: 164-171. [Abstract] [Full Text] [PDF]