Research Topics, Division of Biological Chemistry, Biocentre, Innsbruck Medical University
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