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Pterins and related enzymes


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.

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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Item Type:Book Section, refereed, further contribution
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:31 May 2008
Deposited On:05 Dec 2008 10:51
Last Modified:05 Apr 2016 12:30
Publisher:Springer Verlag
ISBN:978-3-540-76697-1 (Print) 978-3-540-76698-8 (Online)
Publisher DOI:10.1007/978-3-540-76698-8_28
Related URLs:http://www.springerlink.com
http://opac.nebis.ch/F/?local_base=NEBIS&con_lng=GER&func=find-b&find_code=SYS&request=005677608
Permanent URL: http://doi.org/10.5167/uzh-4314

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