Tetrahydrobiopterin Synthesis is Induced by LPS in Vascular Smooth Muscle and is Rate-Limiting for Nitric Oxide Production

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Abstract
Cells produce tetrahydrobiopterin (BH4) by two distinct pathways; a de novo synthetic pathway which uses GTP as a precursor and a salvage pathway which uses preexisting dihydropterins1 (see Fig. 1). GTP cyclohydrolase I (GTPCH1; EC 3.5.4.16) is the first and rate-limiting enzyme for the de novo BH4 synthetic pathway, leading to synthesis of dihydroneopterin triphosphate (NH2 PPP). GTPCH1 has been shown to be selectively inhibited by pterins, most potently by reduced pterins, including BH42,3. Thus, it is likely that de novo BH4 synthesis can be regulated by end-product inhibition. Additionally, 2,4-diamino-6-hydroxypyrimadine (DAHP) selectively inhibits this enzyme in vitro4 and in vivo5. Subsequent metabolism of NH2PPP to BH4 is catalyzed by 6-pyruvoyl tetrahydropterin synthase, producing 6-pyruvoyl tetrahydropterin (6-PT). 6-PT is finally converted to BH4 by two successive NADPH-dependent hydroxylations catalyzed by sepiapterin reductase. While the dihydropterins, BH2 and sepiapterin, are not substrates for the de novo synthetic pathway, they are converted to BH4 via the pterin salvage pathway which utilizes dihydrofolate reductase (DHFR; EC 1.5.1.3) for its final step1.

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