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Three Classes of Tetrahydrobiopterin-Dependent Enzymes

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Three Classes of Tetrahydrobiopterin-Dependent Enzymes DOI 10.1515/pterid-2013-0003 Pteridines 2013; 24(1): 7–11 Review Ernst R. Werner* Three classes of tetrahydrobiopterin-dependent enzymes Abstract: Current knowledge distinguishes three classes in Antalya, Turkey. For a more detailed review on bio- of tetrahydrobiopterin-dependent enzymes as based on chemistry and pathophysiology of tetrahydrobio pterin, protein sequence similarity. These three protein sequence the reader is referred to Ref. [ 1 ]. Here, a short historical clusters hydroxylate three types of substrate atoms and overview of the discovery of tetrahydrobiopterin-depend- use three different forms of iron for catalysis. The first ent enzymes is presented, followed by a summary of the class to be discovered was the aromatic amino acid biochemical properties of these enzymes. The reactions hydroxylases, which, in mammals, include phenylalanine catalyzed by the three classes of tetrahydrobiopterin- hydroxylase, tyrosine hydroxylase, and two isoforms of dependent enzymes are detailed in Figure 1 . tryptophan hydroxylases. The protein sequences of these tetrahydrobiopterin-dependent aromatic amino acid hydroxylases are significantly similar, and all mammalian Discovery of tetrahydrobiopterin- aromatic amino acid hydroxylases require a non-heme- dependent enzymes bound iron atom in the active site of the enzyme for cataly- sis. The second classes of tetrahydrobiopterin-dependent enzymes to be characterized were the nitric oxide syn- Aromatic amino acid hydroxylases thases, which in mammals occur as three isoforms. Nitric oxide synthase protein sequences form a separate cluster Phenylalanine hydroxylase was the first enzyme charac- of homologous sequences with no similarity to aromatic terized to be dependent on a tetrahydropterin [ 2 ]. It then amino acid hydroxylase protein sequences. In contrast to took five more years to identify the nature of the endo- aromatic amino acid hydroxylases, nitric oxide synthases genous cofactor as tetrahydrobiopterin [ 3 ]. Soon after, require a heme-bound iron for catalysis. The alkylglycerol the two other tetrahydrobiopterin-dependent aromatic monooxygenase protein sequence was the most recent to amino acid hydroxylases, i.e., tyrosine hydroxylase (EC be characterized. This sequence shares no similarity with 1.14.16.2) [ 4 ] and tryptophan hydroxylase (EC 1.14.16.4) aromatic amino acid hydroxylases and nitric oxide syn- [ 5 ], were characterized to depend on tetrahydrobiopterin. thases. Motifs contained in the alkylglycerol monooxyge- These enzymes are required for the degradation of phenyl- nase protein sequence suggest that this enzyme may use a alanine as well as for the biosynthesis of catecholamine di-iron center for catalysis. and serotonin neurotransmitters. Studying the formation of serotonin in tryptophan hydroxylase (TPH1) knock- Keywords: alkylglycerol monooxygenase; nitric oxide syn- out mice led to the discovery of the second isoform of thase; phenylalanine hydroxylase; tetrahydrobio pterin; tryptophan hydroxylase (TPH2) in 2003 [ 6 ]. The analysis of tyrosine hydroxylase. the protein sequences of the enzymes showed significant homologies between these tetrahydrobiopterin-dependent aromatic amino acid hydroxylases, and structural and *Corresponding author: Ernst R. Werner, Division of Biological mechanistic studies revealed a general similarity of these Chemistry, Biocentre, Innsbruck Medical University, Innrain 80-82, A-6020 Innsbruck, Austria, E-mail: [email protected] enzymes with only subtle differences [ 7 , 8 ]. Introduction Alkylglycerol monooxygenase The present article is based on the Gowland Hopkins In 1964, a tetrahydropteridine-dependent enzyme system Award lecture given by the author on the 15th Interna- for the cleavage of glyceryl ethers was first described [ 9 ]. tional Symposium on Pterins and Folates, May 9 – 13, 2012, The responsible enzyme, alkylglycerol monooxygenase 8 Werner: Tetrahydrobiopterin-dependent enzymes + - phenyalanine COOH O2 + 2H + 2e COOH hydroxylase NH NH (PAH) 2 HO 2 phenylalanine H2O tyrosine + - tyrosine COOH O2 + 2H + 2e HO COOH aromatic hydroxylase NH NH amino acid HO 2 2 (TH) tyrosine H2O HO hydroxylases DOPA COOH O + 2H+ + 2e- HO COOH tryptophan 2 hydroxylases NH NH 2 H O 2 (TPH1, TPH2) N 2 N H H tryptophan 5-hydroxytryptophan OH CH CH O 3 + - O 3 OH n O2 + 2H + 2e n H alkylglycerol monooxygenase OH OH OH +O CH3 (AGMO) n OH H2O OH OH alkylglycerol primary product glycerol + aldehyde n = 10 - 18 (unstable) H N H2N 2 H2N NH N OH O HN + - HN O + H+ + e- HN nitric oxide synthases O2 + 2H + 2e 2 (NOS1, NOS2, NOS3) +NO H2O H2O H2N H2N H2N COOH COOH COOH arginine NG-hydroxyarginine citrulline Figure 1 Chemical reactions catalyzed by the three classes of tetrahydrobiopterin-dependent enzymes. The respective gene symbols in humans are in parentheses. The intermediate semiacetal as initial reaction product of the alkylglycerol monooxygenase is assumed to occur by plausibility, an experimental proof of it as well as knowledge on whether or not its rearrangement is assisted by an additional enzyme is currently missing. The figure was modified from Ref. [ 1 ]. (EC 1.14.16.5.), is a very labile integral membrane protein view, behaves quite differently from the currently known that could not be purified up to now. Sequence assign- tetrahydrobiopterin-dependent enzymes (see below). ment was achieved in 2010 by bioinformatic selection of Nitric oxide synthases occur in mammals in three iso- candidate genes and recombinant expression in Chinese forms encoded by three different genes. They serve a hamster ovary cells [ 10 ]. This sequence turned out to be variety of important functions, including neurotransmis- unrelated to the other groups of tetrahydrobiopterin- sion, vasorelaxation, and host defense to pathogens and dependent enzymes, the aromatic amino acid hydroxy- tumors [ 15 – 17 ]. Their protein sequences share significant lases and the nitric oxide synthases (EC 1.14.19.39). sequence homology but are unrelated to the two other Alkylglycerol monooxygenase is the only enzyme known sequence clusters of tetrahydrobiopterin-dependent to cleave the ether bond of alkylglycerols, which are major enzymes, the aromatic amino acid hydroxylases and the membrane constituents, e.g., in the brain. The platelet- alkylglycerol monooxygenase. The role of tetrahydrobio- activating factor, a very potent inflammatory mediator, is pterin in the three isoforms is very similar, with only also an alkylglycerol derivative. The precise physiological subtle differences [ 18 , 19 ]. role of alkylglycerol monooxygenase remains to be eluci- dated. Current knowledge on alkylglycerol monooxyge- nase is summarized in Ref. [ 11 ]. Biochemical characteristics of the three classes of tetrahydrobiop- Nitric oxide synthases terin-dependent enzymes In the late 1980s, a new class of tetrahydrobiopterin- A summary of the current knowledge on the bio- dependent enzymes, the nitric oxide synthases, was chemistry of the three classes of tetrahydrobiopterin- discovered [ 12 – 14 ], which, from a biochemical point of dependent enzymes is presented in Table 1 ; for a more Werner: Tetrahydrobiopterin-dependent enzymes 9 detailed description, the reader is referred to Ref. [ 1 ]. The entries for the alkylglycerol monooxygenase are based on current knowledge, but they should be treated with caution because no pure enzyme has been prepared so far to study the biochemical parameters. These were observed mainly in rat liver microsomal preparations or in homogenates of transiently transfected Chinese hamster ovary cells. and palmitoylated) palmitoylated) and oxygenase of Crystal structures available domains The three classes of tetrahydrobiopterin-dependent enzymes all catalyze a mixed-function oxygenase reac- tion, i.e., one oxygen atom of the oxygen molecule is incorporated into the substrate, whereas the other one is converted to water ( Figure 1 ). However, the nature of the substrate atom hydroxylated is different for each class of tetrahydrobiopterin-dependent enzymes. It is an aro- matic carbon atom in the aromatic amino acid hydroxy- s in rat liver microsomes or in homogenates of transfected transfected of liver microsomes or in homogenates s in rat lases, a guanidino nitrogen in nitric oxide synthases, and an aliphatic carbon atom in alkylglycerol monooxy- genase. The affinity for the tetrahydrobiopterin cofac- tor varies over two orders of magnitude, being highest in the nitric oxide synthases and lowest in the aromatic the protein available the protein available Alkylglycerol monooxygenase (AGMO) (AGMO) monooxygenase Alkylglycerol (NOS1) NOS Neuronal amino acid hydroxylases. In addition to the highest affin- ity for tetrahydrobiopterin, nitric oxide synthases are also the class of enzymes with the highest selectivity for the 6 R -1 ′ ,2 ′ -dihydroxypropyl side chain of tetrahyd- robiopterin. Although nitric oxide synthases are almost exclusively stimulated by tetrahydrobiopterin, with the action of other tetrahydropterins only at orders-of- magnitude-higher concentrations, aromatic amino acid hydroxylases and alkylglycerol monooxygenase can be stimulated with some other tetrahydropterins to a more comparable extent. Aromatic amino acid hydroxylases and presumably also alkylglycerol monooxygenase use tetrahydrobiopterin for oxygen activation. This is not the case for nitric oxide synthases [ 20 ]. The tetrahydrobio- pterin cofactor leaves the enzymatic reaction of aromatic are shown by their gene symbols in the table. in the table. their gene symbols are shown by amino
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