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

Current focus

Tryptophan degradation is still in focus of our experimental and clinical studies. In an intense collaboration with the NCI/Bethesda, the role of IDO and its relationship to regulatory T-cells and dendritic cells in the development of immunodeficiency in states of chronic immune activation (1,2). The influence of tryptophan degradation on the course of neuropsychiatric symptoms is investigated in patients with HIV infection (e.g. in collaboration with UCSF) and with cancer. To further characterize the role of immune activation and inflammation in cardiovascular diseases, the relationship between metabolism of homocysteine (3) and asymmetric dimethylarginine (ADMA, 4) is investigated in vitro and in vivo. For investigating a potential influence of immune activation and oxidative stress on the metabolism of phenylalanine (5), a new HPLC method is to be developed and clinical collaboration studies are under way. The relationship between tryptophan metabolism and allergy development is investigated in patients and in vitro (6). Special attention is given to antioxidant compounds like vitamins, cannabinoids and food preservatives (7,8) and experimental studies are devoted to the influence of these compounds on activated peripheral blood mononuclear cells in vitro.

In the animal models investigated in collaboration with the General and Transplantation Surgery group, we intend to optimize treatment conditions of tetrahydrobiopterin in attenuating ischemia reperfusion injury (9) with the aim to develop a novel therapeutic strategy also applicable in humans.

In our biochemical work, we focus on the molecular characterization of alkylglycerol monooxygenase (glyceryl-ether monooxygenase), an enzyme that may contribute to metabolic actions of tetrahydrobiopterin, the sequence of which had been unknown. We have developed a 5 orders of magnitude more sensitive assay for this enzyme (10), assigned a sequence to this activity (11) and aim at characterising the physiological significance of this protein. Related with this project, we study the metabolic fate of long chain fatty aldehydes using a novel, fluorescence labelled compound (12).

References

1. Cecchinato V, Tryniszewska E, Ma ZM, Vaccari M, Boasso A, Tsai WP, Petrovas C, Fuchs D, Heraud JM, Venzon D, Shearer GM, Koup RA, Lowy I, Miller CJ, Franchini G (2008) Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection.  J Immunol 180, 5439-5447.( >>PubMed). 

2. Jürgens B, Hainz U, Fuchs D, Felzmann T, Heitger A (2009) Interferon-gamma-triggered indoleamine 2,3-dioxygenase competence in human monocyte-derived dendritic cells induces regulatory activity in allogeneic T cells. Blood 114, 3235-43.(>>PubMed).

3. Ploder M, Schroecksnadel K, Spittler A, Neurauter G, Roth E, Fuchs D (2010) Moderate hyperhomocysteinemia in patients with multiple trauma and with sepsis predicts poor survival.  Mol Med doi: 10.2119/molmed.2010.00008. (>>PubMed).

4. Kurz K, Teerlink T, Sarcletti M, Weiss G, Zangerle R, Fuchs D (2009) Plasma concentrations of the cardiovascular risk factor asymmetric dimethylarginine (ADMA) are increased in patients with HIV-1 infection and correlate with immune activation markers. Pharmacol Res 60, 508-514. (>>PubMed).

5. Neurauter G, Schröcksnadel K, Scholl-Bürgi S, Sperner-Unterweger B, Schubert C, Ledochowski M, Fuchs D (2008) Chronic immune stimulation correlates with reduced phenylalanine turn-over.  Curr Drug Metabol 9,622-627. (>>PubMed).

6. Ciprandi G, Amici M, Tosca M, Fuchs D (2010) Tryptophan metabolism in allergic rhinitis: the effect of pollen allergen exposure.  Hum Immunol doi:10.1016/j.humimm.2010.05.017 (>>PubMed). 

7. Maier E, Kurz K, Jenny M, Schennach H, Ueberall F, Fuchs D (2010) Food preservatives sodium benzoate and propionic acid and colorant curcumin suppress Th1-type immune response in vitro. Food Chem Toxicol doi:10.1016/j.fct.2010.04.042. (>>PubMed) .

8. Jenny M, Santer E, Pirich E, Schennach H, Fuchs D (2009) D9-Tetrahydrocannabinol and cannabidiol modulate mitogen-induced tryptophan degradation and neopterin formation in peripheral blood mononuclear cells in vitro. J Neuroimmunol 207, 75-82. >>PubMed. 

9. Maglione M, Hermann M, Hengster P, Schneeberger S, Mark W, Obrist P, Werner-Felmayer G, Werner E.R, Margreiter R, Brandacher G (2006) Tetrahydrobiopterin attenuates microvascular reperfusion injury following murine pankreas transplantation. Am J Transplant 6, 1551-1559. (>> PubMed).

10. Werner ER, 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. (>>PubMed)

11. 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. (>>PubMed)

12. 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. (>>PubMed)