BH4 (tetrahydrobiopterin) is the obligate cofactor for the aromatic amino acid hydroxylases — TYROSINE HYDROXYLASE (TH, catecholamine synthesis), TRYPTOPHAN HYDROXYLASE (TPH, serotonin synthesis), PHENYLALANINE HYDROXYLASE (PAH, PKU enzyme) — and for all three NITRIC OXIDE SYNTHASE isoforms (NOS1/2/3). De novo synthesis: GTP → 7,8-dihydroneopterin triphosphate (GTPCH1, rate-limiting + tightly regulated) → multi-step → BH4. Salvage: 7,8-dihydrobiopterin → BH4 via DHFR. After each hydroxylation reaction BH4 is oxidized to BH2; recycled by DHPR (dihydropteridine reductase). DHPR deficiency causes a PKU-like phenotype because functional PAH activity fails despite intact enzyme protein. SAPROPTERIN = synthetic BH4 used to rescue mild PAH deficiency. BH4 deficiency also causes monoamine deficiency syndromes — treated with L-DOPA + 5-HTP supplementation.
Organ Systems
nervous
endocrine
Pathway Steps
gtp → 7-8-dihydroneopterin-triphosphate — via GTP cyclohydrolase 1 (GTPCH1) — RATE-LIMITING. GTP cyclohydrolase 1 is the rate-limiting, feedback-regulated step of de-novo BH4 synthesis. BH4 is the obligate cofactor for the aromatic amino-acid hydroxylases (PAH, TH, TPH) and all NOS isoforms, so GTPCH1 deficiency causes dopa-responsive dystonia and hyperphenylalaninemia.
7-8-dihydroneopterin-triphosphate → bh4 — via multi-step (PTPS + SR). PTPS then sepiapterin reductase finish de-novo BH4. Because BH4 supplies phenylalanine hydroxylase, BH4-responsive PKU (and synthetic BH4, sapropterin) lowers phenylalanine — and BH4 is studied to “re-couple” eNOS.
bh2 → bh4 — via DHPR (dihydropteridine reductase) — recycles cofactor after hydroxylation. Each hydroxylation oxidizes BH4 to BH2; dihydropteridine reductase regenerates BH4 using NADH. DHPR deficiency is a malignant PKU variant that also starves dopamine/serotonin synthesis of the cofactor despite a low-phenylalanine diet.