Research Interests, Ernst R. Werner, Division of Biological Chemistry, Biocentre, Innsbruck Medical University
Localisation of Alkylgylcerol monooxygenase in transfected CHO cells.
See ref. 4 for details and text below for more information. Photo by Martin Hermann
Biosynthesis and metabolic roles of tetrahydrobiopterin
5,6,7,8-Tetrahydrobiopterin (H4biopterin) is a compound related to the vitamins folic acid and riboflavin which are all characterised by the common pteridine heterocycle. In contrast to folic acid and riboflavin, however, mammals (including humans) synthesise H4biopterin from guanosine triphosphate (GTP). H4-biopterin is a cofactor for hydroxylating aromatic amino acids – and is hence of crucial importance for neurotransmitter formation –, for nitric oxide (NO) formation from L-arginine – a key molecule for neurotransmission, blood pressure regulation and immune function –, and for alkylgylcerol monooxygenase (glycerylether monooxygenase) - a little studied enzyme with (until 2010) unknown sequence (Figure 1).
In previous work we
studied the regulation of tetrahydrobiopterin biosynthesis by
cytokines, pharmacological effects of tetrahydrobiopterin
derivatives, and the role of H4biopterin in the nitric
oxide synthase reaction (see >> Research topics Biological Chemistry and >> Selected key findings, Ernst R. Werner)
Current focus
A main goal of the group is currently to characterise alkylgylcerol monooxygenase (glyceryl ether monooxygenase). We have developed a novel assay for this enzyme, which is 5 orders of magnitude more sensitive than previously used absorbance-based assays (1) We have characterised some properties of the enzyme (2), and have developed means to monitor the fate of the product of the reaction, toxic fatty aldehydes (3). We managed to assign a sequence to alkylglycerol monooxygenase by expressing candidate genes in CHO cells (4), and we now try to study the biochemistry and physiological role of this enzyme.
In cooperation with the Center of Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, we plan to explore the mechanism and the potential of tetrahydrobiopterin derivatives to attenuate the ischemia-reperfusion injury harming transplanted organs (5).
References
1. Werner, E. R., Hermetter, A., Prast, H., Golderer, G., Werner-Felmayer, G. (2007) Widespread occurrence of glyceryl ether monooxygenase activity in rat tissues detected by a novel assay. J.Lipid Res. 48, 1422-1427
2. Watschinger, K., Keller, M. A., Hermetter, A., Golderer, G., Werner-Felmayer, G., Werner, E. R. (2009) Glyceryl ether monooxygenase resembles aromatic amino acid hydroxylases in metal ion and tetrahydrobiopterin dependence. Biol.Chem. 390, 3-10
3. Keller, M. A., Watschinger, K., Golderer, G., Maglione, M., Sarg, B., Lindner, H., Werner-Felmayer, G., Terrinoni, A., Wanders, R. J., Werner, E. R. (2010) Monitoring of fatty aldehyde dehydrogenase by formation of pyrenedecanoic acid from pyrenedecanal. J.Lipid.Res.51: 1554-1559
4. Watschinger, K., Keller, M. A., Golderer, G., Hermann, M., Maglione, M., Sarg, B., Lindner, H. H., Hermetter, A., Werner-Felmayer, G., Konrat, R., Hulo, N., Werner, E. R. (2010) Identification of the gene encoding alkylglycerol monooxygenase defines a third class of tetrahydrobiopterin-dependent enzymes. Proc.Natl.Acad.Sci.U.S.A 107: 13672-13677
5. Maglione, M., Oberhuber, R., Cardini, B., Watschinger, K., Hermann, M., Obrist, P., Hengster, P., Mark, W., Schneeberger, S., Werner-Felmayer, G., Pratschke, J., Margreiter, R., Werner, E. R., Brandacher, G. (2010) Donor pretreatment with tetrahydrobiopterin saves pancreatic isografts from ischemia reperfusion injury in a mouse model. Am.J.Transplant. 10, 2231-2240
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