A cofactor for production of aromatic amino acids, neurotransmitters, and nitric oxide
(6R)-5,6,7,8-tetrahydro-L-Biopterin (hydrochloride) (BH4) is a cofactor that, in the presence of enzyme site iron, binds to phenylalanine hydroxylase, tryptophan or tyrosine hydroxylase, and nitric oxide synthase (NOS), to facilitate the production of aromatic amino acids, neurotransmitters, and nitric oxide (NO), respectively.1,2,3 It is formed de novo from GTP with GTP cyclohydrolase-1 (GCH1) catalyzing the rate limiting conversion of GTP to 7,8-dihydroneopterin (NH2TP) followed by subsequent processing by TS and SPR to convert NH2TP to BH4.4,3 BH4 acts as a radical-trapping antioxidant that inhibits phospholipid oxidation in lipid membranes.4 It inhibits IKE- or RSL3-induced ferroptosis in HT-1080 cells (EC50s = 21 and 69 ?M), as well as ferroptosis induced by knockout of glutathione peroxidase (Gpx4-/-) in immortalized mouse fibroblasts.3 BH4 also reduces RLS3-induced lipid peroxidation in murine fibroblasts and HT-1080 cells when used at a concentration of 50 ?M.
1.Kappock, T.J., and Caradonna, J.P.Pterin-dependent amino acid hydroxylasesChem. Rev.96(7)2659-2756(1996) 2.Mayer, B., and Werner, E.R.In search of a function for tetrahydrobiopterin in the biosynthesis of nitric oxideN.-S. Arch. Pharmacol.351(5)453-463(1995) 3.Kraft, V.A.N., Bezjian, C.T., Pfeiffer, S., et al.GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodelingACS Cent. Sci.6(1)41-53(2020) 4.Soula, M., Weber, R.A., Zilka, O., et al.Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducersNat. Chem. Biol.16(12)1351-1360(2020)
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