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Research Topics, Institute of Biological Chemistry, Biocentre, Medical University of Innsbruck
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 glycerylether monooxygenase - a little studied enzyme with 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.
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).
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 doi: 10.1073/pnas.1002404107