title: Tetrahydrobiopterin is synthesized from 6-pyruvoyl-tetrahydropterin by the human aldo-keto reductase AKR1 family members.
abstract: Tetrahydrobiopterin (BH(4)) is a cofactor for aromatic amino acid hydroxylases and nitric oxide synthase. The biosynthesis includes two reduction steps catalyzed by sepiapterin reductase. An intermediate, 6-pyruvoyltetrahydropterin (PPH(4)) is reduced to 1(')-oxo-2(')-hydroxypropyl-tetrahydropterin (1(')-OXPH(4)) or 1(')-hydroxy-2(')-oxopropyl-tetrahydropterin (2(')-OXPH(4)), which is further converted to BH(4). However, patients with sepiapterin reductase deficiency show normal urinary excretion of pterins without hyperphenylalaninemia, suggesting that other enzymes catalyze the two reduction steps. In this study, the reductase activities for the tetrahydropterin intermediates were examined using several human recombinant enzymes belonging to the aldo-keto reductase (AKR) family and short-chain dehydrogenase/reductase (SDR) family. In the reduction of PPH(4) by AKR family enzymes, 2(')-OXPH(4) was formed by 3 alpha-hydroxysteroid dehydrogenase type 2, whereas 1(')-OXPH(4) was produced by aldose reductase, aldehyde reductase, and 20 alpha-hydroxysteroid dehydrogenase, and both 1(')-OXPH(4) and 2(')-OXPH(4) were detected as the major and minor products by 3 alpha-hydroxysteroid dehydrogenases (types 1 and 3). The activities of aldose reductase and 3 alpha-hydroxysteroid dehydrogenase type 2 (106 and 35 nmol/mg/min, respectively) were higher than those of the other enzymes (0.2-4.0 nmol/mg/min). Among the SDR family enzymes, monomeric carbonyl reductase exhibited low 1(')-OXPH(4)-forming activity of 5.0 nmol/mg/min, but L-xylulose reductase and peroxisomal tetrameric carbonyl reductase did not form any reduced product from PPH(4). Aldose reductase reduced 2(')-OXPH(4) to BH(4), but the other enzymes were inactive towards both 2(')-OXPH(4) and 1(')-OXPH(4). These results indicate that the tetrahydropterin intermediates are natural substrates of the human AKR family enzymes and suggest a novel alternative pathway from PPH(4) to BH(4), in which 3 alpha-hydroxysteroid dehydrogenase type 2 and aldose reductase work in concert.
authors.affiliation: Department of General Studies, Nihon University, Sakurajosui 3-25-40, Setagaya-ku, Tokyo 156-8550, Japan. iino@chs.nihon-u.ac.jp
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Iino
authors.forename: Mayuko
authors.initials: M
authors.lastname: Tabata
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Takikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sawada
authors.forename: Haruo
authors.initials: H
authors.lastname: Shintaku
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ishikura
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
mesh_terms: D000429:Alcohol Oxidoreductases / Q000737:chemistry*; D000449:Aldehyde Reductase; D000074408:Aldo-Keto Reductases; D001708:Biopterins / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D044943:Fatty Acid Desaturases / Q000737:chemistry*; D064429:Fatty Acid Synthases; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry; D009247:NADH, NADPH Oxidoreductases; D011622:Pterins / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry*
chemical_list: D007527:Isoenzymes; D011622:Pterins; D011994:Recombinant Proteins; D001708:Biopterins; C045652:dyspropterin; D000429:Alcohol Oxidoreductases; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; D044943:Fatty Acid Desaturases; C036543:short chain trans-2-enoyl-CoA reductase; D009247:NADH, NADPH Oxidoreductases; D064429:Fatty Acid Synthases; C003402:sapropterin