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

Abstract

Tetrahydrobiopterin (BH 4 ) is a cofactor for aromatic amino acid hydroxylases and nitric oxide synthase. The biosynthetic pathway of BH 4 from 6-pyruvoyl-tetrahydropterin (PPH 4 ) includes two reduction steps catalyzed by sepiapterin rcductasc (SPR). PP1I 4 is reduced to 6-( 1 '-oxo-2'-hydroxypiOpyl)-tetrahydropterin (l'-OXPH 4 ) or 6-( r-hydroxy-2'-oxopropyl)-tetrahydropterin (2'-OXPH 4 ), which is further converted to BH 4 . However, patients with SPR deficiency show normal urinary excretion of pterins without hyperphenylalaninemia, suggesting the existence of another BH 4 biosynthetic pathway, which is not concerned with SPR in humans. Blau et al. proposed a BH 4 biosynthetic salvage pathway containing nonenzymatic conversion of l'-OXPH 4 to sepiapterin. In this study, the possibility of the nonenzymatic conversion of l'-OXPH 4 to sepiapterin was examined by using silkworm carbonyl reductase (CR 1) and human monomeric carbonyl reductase. Since l'-OXPH 4 has been suggested to be nonenzymatically converted into sepiapterin, in an incubation mixture containing PPH 4 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'-OXPH 4 , was further incubated at 37°C for 2 h in darkness. This result suggests that the rate of nonenzymatic formation of sepiapterin from l'-OXPH 4 is quite low. The findings obtained here indicate that the proposed pathway in which a nonenzymatic conversion of l'-OXPH 4 to sepiapterin occurs may be difficult or unlikely to proceed in humans.

Peripheralized sepiapterin reductase inhibition as a safe analgesic therapy

“…The most efficient salvage pathway appears to be mediated by AKR1C3 then AKR1B1, while BH4 production through sepiapterin and DHFR appears to be quite slow (Iino et al, 2003;Sawada et al, 2005). The relative tissue distribution of these enzymes will therefore determine how much BH4 can be produced when SPR is blocked.…”