Functional analysis of sepiapterin reductase in Drosophila melanogaster

Abstract

<jats:title>Abstract</jats:title><jats:p>Sepiapterin reductase (SR) is a key enzyme involved in the biosynthesis of tetrahydrobiopterin (BH<jats:sub>4</jats:sub>), an essential cofactor for the synthesis of important biogenic amines, including catecholamines and serotonin. BH<jats:sub>4</jats:sub> deficiencies have been implicated in several neurological disorders. Here, we characterized <jats:italic>sepiapterin reductase</jats:italic> (<jats:italic>SR</jats:italic>) loss-of-function mutants in <jats:italic>Drosophila melanogaster</jats:italic> and demonstrated that <jats:italic>SR</jats:italic> mutations are responsible for hyposensitivity to oxidative stress. Biochemical analysis further revealed that SR activity and BH<jats:sub>4</jats:sub> levels in <jats:italic>SR</jats:italic> mutants were significantly reduced. Furthermore, we showed that the levels of phosphorylated Akt and total Akt protein were increased in <jats:italic>SR</jats:italic> mutants. Our findings indicate that SR plays an important role in the Akt pathway and that <jats:italic>SR</jats:italic> mutants will be a valuable tool for investigating the physiological functions of BH<jats:sub>4</jats:sub>.</jats:p>

Biosynthesis of Pteridines in Insects: A Review

“…The de novo pathway involves the enzymes pyruvoyl-tetrahydropterin reductase and sepiapterin reductase [33]. However, the participation of another enzyme cannot be discounted, since in a study carried out in D. melanogaster in which sepiapterin reductase was almost completely depleted, the levels of 5,6,7,8-tetrahydropterin were only decreased to 50%, suggesting the participation of other enzymes in 5,6,7,8-tetrahydrobiopterin biosynthesis [65]. In mammals, it was shown that, in addition to sepiapterin reductase, the synthesis of 5,6,7,8-tetrahydrobiopterin can be accomplished by an enzyme of the aldose reductase family (to which pyruvoyl-tetrahydropterin reductase belongs) and a carbonyl reductase [66,67].…”