tetrahydropteridine

Tetrahydropteridine refers to a class of pteridine molecules in which the bicyclic ring system is fully reduced; the best known example is tetrahydrobiopterin (BH4), a cofactor in several hydroxylase enzymes and in nitric oxide synthase. Other tetrahydropteridines occur in nature but BH4 is the most studied due to its role in human metabolism.

Biosynthesis and cycling: In humans, BH4 is synthesized de novo from GTP through a pathway starting with GTP cyclohydrolase I, then 6-pyruvoyl tetrahydropterin synthase, and sepiapterin reductase; an alternate salvage pathway regenerates BH4 from BH2 via dihydropteridine reductase. Tetrahydropteridines can be oxidized to dihydro- or biopterin forms and recycled.

Biological role: BH4 serves as a critical cofactor for aromatic amino acid hydroxylases (phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase) enabling production of catecholamines and serotonin; it also acts as a cofactor for nitric oxide synthase and influences nitric oxide production. BH4 deficiency or impaired recycling can disrupt neurotransmitter synthesis and cause neurological symptoms.

Clinical relevance: Congenital BH4 deficiency, due to defects in GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase, dihydropteridine reductase, or related enzymes, leads to hyperphenylalaninemia and reduced monoamine neurotransmitters. Treatment may involve sapropterin dihydrochloride (a synthetic BH4), L-DOPA and 5-hydroxytryptophan or other neurotransmitter precursors, dietary management of phenylalanine, and clinical monitoring.

Occurrence and research: BH4 and related tetrahydropteridines are found in animals, plants, and microbes; BH4 is the most clinically relevant. Ongoing research explores their roles in metabolism, neurochemistry, and redox biology.