Identification of the Gene Encoding Alkylglycerol Monooxygenase Defines a Third Class of Tetrahydrobiopterin-Dependent Enzymes

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Identification of the Gene Encoding Alkylglycerol Monooxygenase Defines a Third Class of Tetrahydrobiopterin-Dependent Enzymes Identification of the gene encoding alkylglycerol monooxygenase defines a third class of tetrahydrobiopterin-dependent enzymes Katrin Watschingera, Markus A. Kellera, Georg Golderera, Martin Hermannb, Manuel Maglioneb, Bettina Sargc, Herbert H. Lindnerc, Albin Hermetterd, Gabriele Werner-Felmayera, Robert Konrate, Nicolas Hulof, and Ernst R. Wernera,1 aDivision of Biological Chemistry, Biocenter, Innsbruck Medical University, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria; bDepartment of Visceral-, Transplant-, and Thoracic Surgery, Daniel-Swarovski-Research Laboratory, Innsbruck Medical University, Innrain 66, A-6020 Innsbruck, Austria; cDivision of Clinical Biochemistry, Biocenter, Innsbruck Medical University, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria; dInstitute of Biochemistry, Graz University of Technology, Petersgasse 12/2, A-8010 Graz, Austria; eDepartment of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter Campus 5, A-1030 Vienna, Austria; and fCentre Medical Universitaire and Structural Biology and Bioinformatics Department, 1 Rue Michel-Servet, CH-1211 Geneva 4, Switzerland Edited by Stephen J. Benkovic, Pennsylvania State University, University Park, PA, and approved June 22, 2010 (received for review February 25, 2010) Alkylglycerol monooxygenase (glyceryl-ether monooxygenase, EC step, this reaction yields the radical gas nitric oxide and citrulline 1.14.16.5) is the only enzyme known to cleave the O-alkyl bond of (4, 5). Nitric oxide synthases are required for a number of ether lipids which are essential components of brain membranes, physiological processes such as blood pressure regulation, neuro- protect the eye from cataract, interfere or mediate signalling transmission, and host defense against pathogens (6–8). The fifth processes, and are required for spermatogenesis. Along with phe- tetrahydrobiopterin-dependent enzymatic reaction catalyzed by nylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydro- alkylglycerol monooxygenase (glyceryl-ether monooxygenase, xylase, and nitric oxide synthase, alkylglycerol monooxygenase EC 1.14.16.5, Fig. 1A) has been first described already in 1964 is one of five known enzymatic reactions which depend on tetra- (9). Despite several attempts to purify and characterize this hydrobiopterin. Although first described in 1964, no sequence membrane bound protein (10), it still belonged to the currently had been assigned to this enzyme so far since it lost activity upon 1,297 enzymes lacking sequence assignment which are called protein purification attempts. A functional library screen using orphan enzymes (11). Alkylglycerol monooxygenase is the only pools of plasmids of a rat liver expression library transfected to enzyme known to cleave the O-alkyl ether bond in alkylglycerols, CHO cells was also unsuccessful. We therefore selected human yielding an aldehyde and a glycerol derivative. The aldehyde is candidate genes by bioinformatic approaches and by proteomic detoxified by conversion to the corresponding acid by fatty analysis of partially purified enzyme and tested alkylglycerol aldehyde dehydrogenase (EC 1.2.1.48, gene symbol ALDH3A2, monooxygenase activity in CHO cells transfected with expression Fig. S1). Tetrahydrobiopterin leaves the reaction as “quinoid” 6,7 plasmids. Transmembrane protein 195, a predicted membrane pro- [8H]-dihydrobiopterin (10) and is recycled to tetrahydrobiopterin tein with unassigned function which occurs in bilateral animals, by quinoid dihydropteridine reductase (Fig. S1, EC 1.5.1.34, gene was found to encode for tetrahydrobiopterin-dependent alkylgly- symbol QDPR). The formation of 6,7[8H]-dihydrobiopterin from cerol monooxygenase. This sequence assignment was confirmed 4a-hydroxy-tetrahydrobiopterin, the initial enzymatic product by injection of transmembrane protein 195 cRNA into Xenopus formed from tetrahydrobiopterin, may be facilitated by 4a-carbi- laevis oocytes. Transmembrane protein 195 shows no sequence nolamine dehydratase (EC 4.2.1.96, PCBD1) like for aromatic homology to aromatic amino acid hydroxylases or nitric oxide amino acid hydroxylases (12), but this has not yet been demon- synthases, but contains the fatty acid hydroxylase motif. This motif strated for alkylglycerol monooxygenase. is found in enzymes which contain a diiron center and which carry out hydroxylations of lipids at aliphatic carbon atoms like alkylgly- Results cerol monooxygenase. This sequence assignment suggests that Protein Purification, Functional Expression Screening Attempts, and alkylglycerol monooxygenase forms a distinct third group among Bioinformatic Candidate Gene Selection. Although we used a robust, tetrahydrobiopterin-dependent enzymes. and sensitive assay for alkylglycerol monooxygenase activity (13), attempts to purify the protein from male rat liver, the source EC 1.14.16.5 ∣ glyceryl-ether monooxygenase ∣ nitric oxide synthase ∣ with the highest activity observed (10), failed due to the instability phenylalanine hydroxylase ∣ transmembrane protein 195 of the enzyme activity (Table S1), which could not be fully solubilized (Fig. S2). The necessity of HPLC analysis which etrahydrobiopterin is a metabolite structurally related to the has a capacity of about 40 assays a day precluded a full, single Tvitamins folic acid and riboflavin by sharing the common clone functional expression screen which would require testing pterin (pyrimido[4,5-b]pyrazine) backbone. In contrast to the of about 100,000 clones. We therefore tried an approach using two vitamins which have to be taken up by the diet, however, plasmid pools (14). Transfection of CHO cells with 196 plasmid tetrahydrobiopterin is synthesized in animals from guanosine pools containing about 2,500 individual clones each of a rat liver triphosphate by the consecutive action of three enzymes (1). Five enzymatic reactions are known to depend essentially on the Author contributions: K.W., M.A.K., G.G., M.H., M.M., G.W.-F., and E.R.W. designed tetrahydrobiopterin cofactor (2). In three of these reactions, a research; K.W., M.A.K., G.G., M.H., M.M., B.S., H.H.L., R.K., N.H., and E.R.W. performed hydroxy function is introduced into the aromatic ring of pheny- research; A.H. contributed new reagents/analytic tools; K.W., M.A.K., G.G., M.H., M.M., lalanine, tyrosine, and tryptophan by aromatic amino acid hydro- B.S., H.H.L., G.W.-F., R.K., N.H., and E.R.W. analyzed data; and E.R.W. wrote the paper. xylases, which are required for the degradation of phenylalanine The authors declare no conflict of interest. and for the biosynthesis of catecholamines and serotonin, impor- This article is a PNAS Direct Submission. tant neurotransmitters and metabolism regulators. The fourth Freely available online through the PNAS open access option. enzymatic reaction requiring tetrahydrobiopterin is catalyzed 1To whom correspondence should be addressed. E-mail: [email protected]. by nitric oxide synthases, which occur in three isoforms (3). After This article contains supporting information online at www.pnas.org/lookup/suppl/ hydroxylation of the guanidino nitrogen of L-arginine in a first doi:10.1073/pnas.1002404107/-/DCSupplemental. 13672–13677 ∣ PNAS ∣ August 3, 2010 ∣ vol. 107 ∣ no. 31 www.pnas.org/cgi/doi/10.1073/pnas.1002404107 Downloaded by guest on September 24, 2021 PAH human ABCH3 O ( )n PAH mouse PAH danre OH alkylglycerol TPH1 human TPH1 mouse aromatic OH TPH1 danre TPH2 human amino acid O tetrahydrobiopterin 2 TPH2 mouse hydroxylases alkylglycerol monooxygenase TPH2 danre (EC 1.14.16.5) TH human TH mouse H O 2 6,7[8H]-dihydrobiopterin TH danre NOS1 mouse OH NOS1 human OH NOS1 danre OH glycerol CH NOS3 human ( ) 3 nitric oxide O n NOS3 mouse synthases OH NOS2 human OH NOS2 mouse O NOS2a danre OH CH NOS2b danre H ( ) 3 n TMEM195 human alkylglycerol primary product fatty aldehyde TMEM195 mouse mono- (unstable) TMEM195 danre oxygenase 0.4 0.00.2 Fig. 1. Alkylglycerol monooxygenase. (A) The alkylglycerol monooxygenase reaction. Alkylglycerols are thought to be hydroxylated on the aliphatic carbon of the sn1 side chain adjacent to the ether bond in a tetrahydrobiopterin-dependent way in a mechanism sharing features with tetrahydrobiopterin-dependent enzymatic hydroxylation of aromatic amino acids. The resulting primary product, a hemiacetal, is thought to decay rapidly to the respective fatty aldehyde and glycerol (9, 10, 19). Alkylglycerol monooxygenase accepts a wide range of alkylglycerol lipids and phospholipids, and is currently the only enzyme known to cleave the O-alkyl ether bond in these compounds (see Fig. S1 for further details). Alkylglycerols with O-alkyl chain lengths of 12–20 carbon atoms are good substrates, thus n ranges from 10–18. (B) Phylogenetic tree of tetrahydrobiopterin-dependent enzymes. Protein sequences of genes for tetrahydrobiopterin- dependent enzymes from man, mouse, and zebrafish were selected from protein databases, aligned by ClustalW (Gonnet Matrix) and an UPMGA (unweighted pair group method using arithmetic averages) tree with Poisson correction drawn by MEGA4.0 using the default parameters (29). For details and accession numbers of protein sequences see Table S2. No sequence homology occurred across the three groups which differ in the form of iron required for catalysis. The scale bar gives a measure of the average fraction of amino acids exchanged between the sequences. expression library, however, did not yield activity above back- dehydrogenase) yielded a two orders of magnitude higher read-
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