Role for Tetrahydrobiopterin in the Fetoplacental Endothelial Dysfunction in Maternal Supraphysiological Hypercholesterolemia

Figure 1

Tetrahydrobiopterin metabolism and endothelial nitric oxide synthase uncoupling. (a) The first step in the de novo synthesis of tetrahydrobiopterin (BH₄) is the rate limiting reaction involving the enzyme GTP cyclohydrolase 1 (GTPCH1), whose substrate is GTP. An alternative salvage pathway for BH₄ synthesis is the reduction of 7,8-dihydrobiopterin (BH₂) to BH₄ by the enzyme dihydrofolate reductase (DHFR). BH₂ is generated from sepiapterin by the sepiapterin reductase enzyme (SR). Oxidative stress may be an environmental condition that promotes the oxidation of BH₄ to BH₂, decreasing the bioavailability of BH₄. (b) Under physiological conditions, nitric oxide synthases (NOS, coupled NOS) generate nitric oxide, following the metabolism of L-arginine into L-citrulline in the presence of BH₄. However, uncoupling NOS (uncoupled eNOS) with these enzymes may result in the generation of a superoxide anion (). This phenomenon results from a deficiency in BH₄ and an increased BH₂ bioavailability (from data in [6, 17, 30]).

(a)

(b)