Possibility of the Nonenzymatic Conversion of 6-(1'-Oxo-2'-hydroxypropyl)- Tetrahydropterin to Sepiapterin

Abstract

Tetrahydrobiopterin (BH4) is a cofactor for aromatic amino acid hydroxylases and nitric oxide synthase. The biosynthetic pathway of BH4 from 6-pyruvoyl-tetrahydropterin (PPH4) includes two reduction steps catalyzed by sepiapterin rcductasc (SPR). PP1I4 is reduced to 6-( 1 '-oxo-2'-hydroxypiOpyl)-tetrahydropterin (l'-OXPH4 ) or 6- ( r-hydroxy-2'-oxopropyl)-tetrahydropterin (2'-OXPH4), which is further converted to BH4. However, patients with SPR deficiency show normal urinary excretion of pterins without hyperphenylalaninemia, suggesting the existence of another BH4 biosynthetic pathway, which is not concerned with SPR in humans. Blau et al. proposed a BH4 biosynthetic salvage pathway containing nonenzymatic conversion of l'-OXPH4 to sepiapterin. In this study, the possibility of the nonenzymatic conversion of l'-OXPH4 to sepiapterin was examined by using silkworm carbonyl reductase (CR 1) and human monomeric carbonyl reductase. Since l'-OXPH4 has been suggested to be nonenzymatically converted into sepiapterin, in an incubation mixture containing PPH4 and silkworm CR I, sepiapterin was determined by its derivative as biopterin. No sepiapterin was detected in the incubation mixture when the mixture, containing 800 pmol of l'-OXPH4, was further incubated at 37°C for 2 h in darkness. This result suggests that the rate of nonenzymatic formation of sepiapterin from l'-OXPH4 is quite low. The findings obtained here indicate that the proposed pathway in which a nonenzymatic conversion of l'-OXPH4 to sepiapterin occurs may be difficult or unlikely to proceed in humans.

Keywords

• tetrahydrobiopterin
• carbonyl reductase
• sepiapterin reductase
• biosynthesis of tetrahydrobiopterin
• tetrahydrobiopterin deficiency
• sepiapterin reductase deficiency