On the role of sepiapterin reductase in the biosynthesis of tetrahydrobiopterin.
Rat erythrocyte sepiapterin reductase can catalyze the NADPH-dependent reduction of tetrahydropterin substrates with relative velocities of sepiapterin greater than lactoyltetrahydropterin greater than or equal to pyruvoyltetrahydropterin greater than 1'-hydroxy-2'-oxopropyltetrahydropterin; L-erythrotetrahydrobiopterin is the product of the reduction of all three tetrahydropterins. The 1' position of the 1',2'-diketone, pyruvoyltetrahydropterin, is reduced first; the product of this first reduction is 1'-hydroxy-2'-oxopropyltetrahydropterin. Both steps are inhibited by N-acetylserotonin. An antibody to sepiapterin reductase purified from rat erythrocytes was produced in rabbits, and the purified antibody is highly specific for sepiapterin reductase. This antibody is an inhibitor of both sepiapterin reductase activity and tetrahydrobiopterin biosynthesis in crude extracts of rat adrenal and brain. The antibody inhibits the production of both the biosynthetic intermediate, 1'-hydroxy-2'-oxopropyltetrahydropterin, and tetrahydrobiopterin. The results indicate that sepiapterin reductase is on the biosynthetic pathway to tetrahydrobiopterin, and catalyzes the complete reduction of pyruvoyltetrahydropterin to tetrahydrobiopterin. In contrast, homogenates of whole rat adrenal also produce large quantities of lactoyltetrahydropterin which suggests that in some tissues this compound may also be an intermediate in tetrahydrobiopterin biosynthesis. The synthesis of lactoyltetrahydropterin is not inhibited by the antibody to sepiapterin reductase and therefore does not appear to be catalyzed by sepiapterin reductase. However, sepiapterin reductase is responsible for the conversion of lactoyltetrahydropterin to tetrahydrobiopterin. The source of sepiapterin in biosynthetic reactions was found to be oxidative decomposition of lactoyltetrahydropterin.
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D000429:Alcohol Oxidoreductases / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D000936:Antigen-Antibody Complex; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis; D004912:Erythrocytes / Q000201:enzymology; D007700:Kinetics; D008297:Male; D008970:Molecular Weight; D011621:Pteridines / Q000378:metabolism; D011622:Pterins; D051381:Rats; D013379:Substrate Specificity; D014018:Tissue Distribution
D000936:Antigen-Antibody Complex; D011621:Pteridines; D011622:Pterins; D001708:Biopterins; C016727:sepiapterin; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase; C003402:sapropterin