Tetrahydrobiopterin in Nitric Oxide Synthesis: A Novel Biological Role for Pteridines

Authors: Gorren A.C.F.; Mayer B.

Source: Current Drug Metabolism, Volume 3, Number 2, April 2002 , pp. 133-157(25)

Publisher: Bentham Science Publishers

Abstract:

Ever since the discovery that (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4) is a cofactor of NOS, its function has been the object of intense research and occasional controversy. Only in the last couple of years a consensus has been reached on what constitutes the main role of BH4 in NO synthesis. In this review we aim to provide an outline of the various ways in which BH4 affects NOS catalysis. First we give a brief general description of the structure and catalytic mechanism of NOS, with special emphasis on those aspects of catalysis that are actively debated, and that directly or indirectly involve BH4. Foremost among those issues is uncoupled catalysis, i.e. the NOS-catalyzed oxidation of NADPH in the absence of substrate or pterin that does not result in NO production. We also shortly discuss the ongoing debate on whether NO is the actual reaction product of NOS catalysis, as well as the phenomenon of NO-mediated autoinhibition. We describe the function of BH4 in aromatic amino acid hydroxylation, and discuss the allosteric and structural effects that BH4 exerts on NOS. Next we turn our attention to what is now becoming accepted as the central function of BH4: its capacity to act as a 1-electron donor during reductive activation of the oxyferrous complex of the heme. Finally, we illustrate how BH4 might transform the NOS dimer into an efficient S-nitrosoglutathione synthase, and briefly touch on some more speculative aspects of the role of BH4 in NO synthesis.

Keywords: Tetrahydrobiopterin; Nitric oxide synthesis; pteridines; Nitric oxide synthase; tetrahydrobiopterin; Aromatic amino acid hydroxylases; Bh analogues; 4-amino-tetrahydrobiopterin; tetrahydroneopterin; 7,8-dihydrobiopterin

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1389200024605154

Publication date: 2002-04-01

• Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
  
  In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.

• In this: publication
• By this: publisher
• In this Subject: Anatomy & Physiology ,  Pharmacology
• By this author: Gorren A.C.F. ;  Mayer B.

Website © Publishing Technology. Article copyright remains with the publisher, society or author(s) as specified within the article.

• Terms and conditions
• Privacy policy
• Information for advertisers