Blau, N; Thöny, B (2008). Pterins and related enzymes. In: Blau, N; Duran, M; Gibson, K M. Laboratory guide to the methods in biochemical genetics. Berlin Heidelberg, Germany: Springer Verlag, 665-701.
Abstract
Tetrahydrobiopterin(BH4)cofactor is essential for various enzyme activities, including phenylalanine-4-hydroxylase(PAH), tyrosine-3-hydroxylase(TH), tryptophan-5-hydroxylase(TPH), nitric oxide synthase(NOS), and glyceryl-ether monooxygen-ase(GEMO).The de novo biosynthesis pathway of BH4 from guanosine triphosphate (GTP) involves GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), and sepiapterin reductase (SR). Three additional enzymes catalyze the last two steps of reduction: aldose reductase (AR), carbonyl reductase (CR), and 3α-hydroxysteroid dehydrogenase type 2 (HSDH2). Cofactor regeneration requires pterin-4a-carbinolamine dehydratase(PCD)and dihydropteridine reductase (DHPR)[1]. The pteridines, a group to which BH4 also belongs, constitute naturally occurring compounds with a base structure of pyrazino [2,3d] pyrimidine (Fig. 6.1.1). Pteridines with the structure 2-amino-4-oxo are designated by the term “pterins,” and those with the structure 2,4-dioxo by the term“lumazines”(Fig.6.1.1). Two groups of pterins can be distinguished: the first have p-aminobenzoate and glutamate attached to the pterin.These pteridines are designated as conjugated pterins(e.g., folic acid). The second group consists of unconjugated pterins, which contain neither of these two substitutions; instead, substitutions occur at the 6-position of the pterin ring nucleus by the aliphatic side chain.The most important blue-fluorescing unconjugated pterins are neopterin, monapterin, biopterin, isoxanthopterin, primapterin, and pterin(Fig.6.1.1). Several other pterins,like xanthopterin, sepiapterin, and 3’-hydroxy-sepiepterin, are yellow-fluorescing species(Fig.6.1.2). Pterins can exist in different oxidation stages, but only fully reduced forms are biologically active.Biop-terin is present in biologicalsamples as biopterin, 7,8-dihydrobiopterin(BH2), and 5,6,7,8-tetrahydrobiopterin(BH4)(Fig.6.1.3). In man, BH4 is degraded either nonenzymatically by side-chain cleavage to pterin or is enzymatically metabolized in the gastrointestinal tract to become a lumazine [2]. Pterin and dihydropterin are converted by xanthine dehydrogenase to isoxanthopterin and xanthopterin, respectively[3,4]. It is assumed, however, that most of the ingested BH4 is used as a cofactor(mainly for PAH in the liver)and is catabolized to nonfluorescing compounds;it may even be degraded to CO2 and ammonia.
Abstract
Tetrahydrobiopterin(BH4)cofactor is essential for various enzyme activities, including phenylalanine-4-hydroxylase(PAH), tyrosine-3-hydroxylase(TH), tryptophan-5-hydroxylase(TPH), nitric oxide synthase(NOS), and glyceryl-ether monooxygen-ase(GEMO).The de novo biosynthesis pathway of BH4 from guanosine triphosphate (GTP) involves GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), and sepiapterin reductase (SR). Three additional enzymes catalyze the last two steps of reduction: aldose reductase (AR), carbonyl reductase (CR), and 3α-hydroxysteroid dehydrogenase type 2 (HSDH2). Cofactor regeneration requires pterin-4a-carbinolamine dehydratase(PCD)and dihydropteridine reductase (DHPR)[1]. The pteridines, a group to which BH4 also belongs, constitute naturally occurring compounds with a base structure of pyrazino [2,3d] pyrimidine (Fig. 6.1.1). Pteridines with the structure 2-amino-4-oxo are designated by the term “pterins,” and those with the structure 2,4-dioxo by the term“lumazines”(Fig.6.1.1). Two groups of pterins can be distinguished: the first have p-aminobenzoate and glutamate attached to the pterin.These pteridines are designated as conjugated pterins(e.g., folic acid). The second group consists of unconjugated pterins, which contain neither of these two substitutions; instead, substitutions occur at the 6-position of the pterin ring nucleus by the aliphatic side chain.The most important blue-fluorescing unconjugated pterins are neopterin, monapterin, biopterin, isoxanthopterin, primapterin, and pterin(Fig.6.1.1). Several other pterins,like xanthopterin, sepiapterin, and 3’-hydroxy-sepiepterin, are yellow-fluorescing species(Fig.6.1.2). Pterins can exist in different oxidation stages, but only fully reduced forms are biologically active.Biop-terin is present in biologicalsamples as biopterin, 7,8-dihydrobiopterin(BH2), and 5,6,7,8-tetrahydrobiopterin(BH4)(Fig.6.1.3). In man, BH4 is degraded either nonenzymatically by side-chain cleavage to pterin or is enzymatically metabolized in the gastrointestinal tract to become a lumazine [2]. Pterin and dihydropterin are converted by xanthine dehydrogenase to isoxanthopterin and xanthopterin, respectively[3,4]. It is assumed, however, that most of the ingested BH4 is used as a cofactor(mainly for PAH in the liver)and is catabolized to nonfluorescing compounds;it may even be degraded to CO2 and ammonia.
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Blau, N