Breaking down fat is not always a good thing. The storage of fat in fatty tissue protects the body against high blood fats and fat deposits in other organs. Too many free fatty acids in the blood due to increased breakdown of fat can lead to insulin resistance and subsequently to diabetes type 2 – also known as adult-onset diabetes. Excessive fat breakdown is also dangerous in the context of cancer since pathological emaciation or wasting, also known as cachexia, reduces chances of survival. Since the discovery of ATGL – the enzyme responsible for fat degradation – by researchers at the University of Graz and Graz University of Technology in 2004, more recent studies have shown that genetic inhibition of ATGL lowers fatty acids and triglycerides in the blood and promotes breakdown of glucose. This inhibition thus protects against diabetes type 2 as well as against undesirable fat breakdown in tumour-induced cachexia.
The long journey to Atglistatin
Based on these findings and over years of meticulous work, a team led by Robert Zimmermann at the University of Graz and Rolf Breinbauer at Graz University of Technology have developed a molecular tool which specifically inhibits ATGL and thus the breakdown of fat. It's called Atglistatin. "Such a molecule could prevent both diabetes type 2 and the pathological emaciation of cancer patients in the future", explain Zimmermann and Breinbauer. "This is very interesting since diabetes is one of the biggest widespread diseases, and the trend is increasing. Also, there is currently no real satisfactory treatment for cachexia".
The development of Atglistatin was challenging – both for the synthesis chemists at the Institute of Organic Chemistry at Graz University of Technology and the bioscientists at the University of Graz. There was no three-dimensional protein structure of ATGL which could be used for modern computer-supported modelling approaches. "We had no alternative but to use the classical approach of trial and error", adds Rolf Breinbauer. For the researchers of Graz University of Technology, this meant synthesising molecules, having their effectiveness tested by colleagues at the University of Graz, and developing new molecules from the data obtained. "The process is comparable to finding your way in a pitch-dark room. You can't avoid obstacles and dead ends but the more you move around, the better you develop your feeling for the right direction", explains Breinbauer. The Graz researchers "felt their way forward" for about four years and needed to develop more than 300 molecules before finally discovering one with the desired ATGL-inhibiting properties. The scientists are publishing the details of Atglistan for the first time in the journal "Nature Chemical Biology".
Current research work is embedded in a variety of projects funded by the Austrian Science Fund (FWF) and the doctoral programme "Molecular Enzymology" (Translational Program, Wittgenstein Award, GOLD, PLACEBO). At the same time the projects impressively prove the successful co-operation of Graz University of Technology, the University of Graz and the Medical University of Graz in the framework of the NAWI Graz co-operation project and the research initiative "BioTechMed-Graz".
Mayer, N.,Schweiger, M., Romauch, M., Grabner, G., Eichmann, T., Fuchs, E., Ivkovic, J., Heier, C., Mrak, I., Lass, A., Höfler, G., Fledelius, C., Zechner, R., Zimmermann, R. & Breinbauer, R.: Development of small-molecule inhibitors targeting adipose triglyceride lipase. Nature Chemical Biology, 2013. doi:10.1038/nchembio.1359
Univ.-Prof. Dipl.-Ing. Dr.rer.nat. Rolf Breinbauer
Institute of Organic Chemistry
Tel.: +43 (0) 316 873 32400
Assoz. Prof. Dr. Robert Zimmermann
Department of Molecular Biosciences
Tel.: +43 (0) 316 380 1914