Tetrahydrobiopterin is functionally distinguishable from tetrahydrodictyopterin in Dictyostelium discoideum Ax2

Dictyostelium discoideum Ax2 produces both l-erythro-tetrahydrobiopterin (BH4) and its stereoisomer d-threo-BH4 (DH4). The putative cofactor function of them for phenylalanine hydroxylase (PAH) was investigated through genetic manipulation and quantitative determination of pteridines. In addition to establishing that dihydropteridine reductase (DHPR) and dihydrofolate reductase (DHFR) constitute the regeneration pathway of both BH4 and DH4, the results suggested that BH4 is a preferential cofactor for PAH in vivo, not a secondary product of DH4, which functions mainly as an antioxidant. Our result also demonstrated that PAH may be essential for Dictyostelium growth in nature, and thus it appears that the organism has evolved a strategy to maintain BH4 level via regeneration pathway at the expense of DH4 under oxidative stress conditions.

► Functional study on the two isomers of tetrahydropteridines coexisting in D. discoideum Ax2.
► Genetic manipulation and quantitative determination of the reduced and oxidized pteridines.
► Dihydropteridine reductase and dihydrofolate reductase regenerate the reduced pteridines.
► Tetrahydrobiopterin is preferred as a cofactor for phenylalanine hydroxylase in vivo.
► Tetrahydrodictyopterin is consumed as an antioxidant under oxidative stress conditions.