Tetrahydrobiopterin

Tetrahydrobiopterin, sapropterin, or BH₄ is a naturally occurring essential cofactor of the three aromatic amino acid hydroxylases; phenylalanine-4-hydroxylase for conversion of phenylalanine to tyrosine, tyrosine-3-hydroxylase for the conversion of tyrosine to L-dopa, and tryptophan-5-hydroxylase for the conversion of tryptophan to 5-hydroxytryptophan. It is also essential for the synthesis of nitric oxide by nitric oxide synthase (NOS).

Clinical significance

A defect in BH₄ synthesis and/or regeneration causes phenylketonuria type IV, as well as neurotransmitter (dopamine and serotonin) deficiency. Prolonged elevations in blood Phe levels in patients with PKU can result in severe neurologic damage, including severe mental retardation, microcephaly, delayed speech, seizures, and behavioral abnormalities.

Sapropterin, under the tradename Kuvan, is a synthetic preparation of the dihydrochloride salt of tetrahydrobiopterin. It was developed by BioMarin and approved by the US Food and Drug Administration on December 13, 2007. It is sold as tablets containing 100 mg. Sapropterin is the only drug approved for the treatment of phenylketonuria (PKU). Kuvan is indicated to reduce blood phenylalanine (Phe) levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive Phenylketonuria (PKU). Kuvan is to be used in conjunction with a Phe-restricted diet.

Synthesis

Tetrahydrobiopterin is synthesized from GTP by three enzymatic reactions (GTP cyclohydrolase I, 6-pyruvoyltetrahydropterin synthase, and sepiapterin reductase).

History

Tetrahydrobiopterin has been discovered to play a role as biological cofactor by Seymour Kaufman. The first enzyme found to use tetrahydrobiopterin was phenylalanine hydroxylase.