tetrahydropteridines

Tetrahydropteridines are a class of pteridine derivatives in which the heterocyclic rings of the pteridine core are fully reduced, i.e., saturated with additional hydrogens. The most prominent member is tetrahydrobiopterin (BH4), an essential cofactor in several enzymatic reactions. In chemical terms, they belong to bicyclic pteridine systems that can exist in several redox states, with the tetrahydro form serving as a key electron carrier in various oxidation-reduction reactions.

Biological synthesis and recycling: In humans, BH4 is synthesized de novo from GTP via a pathway that includes GTP cyclohydrolase I, 6-pyruvoyltetrahydropterin synthase, and sepiapterin reductase. BH4 is oxidized to quinonoid dihydropterin during catalysis and must be regenerated to the tetrahydro form by dihydropteridine reductase with NADPH. Defects in these steps can cause tetrahydropteridine deficiency, leading to hyperphenylalaninemia and impaired production of neurotransmitters.

Function and clinical relevance: BH4 serves as a cofactor for phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase, enabling the synthesis of catecholamines and serotonin. It is also a cofactor for nitric oxide synthase in certain tissues. Other tetrahydropteridines, such as neopterin and biopterin, are related oxidation products that occur under physiological conditions. Genetic defects in BH4 synthesis or regeneration are associated with early-onset hyperphenylalaninemia and neurological movement disorders; treatment may include BH4 supplementation and precursors for neurotransmitters.