Tetrahydrobiopterin

Tetrahydrobiopterin is a cofactor that carries electrons for REDOX reactions, as in the oxidation of phenylalanine to tyrosine. It is formed from dihydrobiopterin through the action of the enzyme dihydrofolate reductase, or from the quinonoid form of dihydrobiopterin through the action of dihydropteridine reductase.

Defects in the regeneration of the cofactor tetrahydobiopterin (BH4) account for a small fraction of PKU cases. Such cases are sometimes identified as "malignant" PKU, because of the progressive deterioration in neurological function which cannot be alleviated by simple dietary restriction in phenylalanine intake. These cases may be distinguished from the classical form of PKU which is due to a defect in the enzyme phenylalanine hydroxylase (PAH). There are several possible causes of a defect in biopterin metabolism, and the consequences of such a defect can be profound, extending beyond phenylketonuria to defects in neurotransmission. Such cases can be better understood by referring to the biosynthetic pathway of tetrahydrobiopterin:

DE NOVO BIOSYNTHESIS OF TETRAHYDROBIOPTERIN

In addition to a defect in the regeneration of BH4 there can be problems in the de novo synthesis of BH4. The pathway shown here has four enzymes. Among patients with hyperphenylalaninemia, defects in two of these enzymes have been identified, in GTP cyclohydrolase I (the first enzyme in the pathway) and in pyruvoyl tetrahydropterin synthase (the second enzyme in the pathway).

Defects in these enzymes result in many of the same symptoms that are seen in "classical" PKU (due to defective PAH). However, defects in regeneration or synthesis of BH4 account for only a small fraction of all patients with hyperphenylalaninemia.

Deficiencies in biopterin metabolism can be distinguished from the classical PKU disease by the profile of various pterins in serum, urine, and cerebrospinal fluid.

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