Reactive chemicals cause toxicity and genotoxicity which can lead to cancer. The principal defence system from reactive chemicals is an enzyme system called glutathione transferase. These enzyme catalyse the conjugation of an endogenous nucleophilic tripeptide, glutathione, to electrophilic* reactive compounds (*the most common reactive intermediate formed during cellular metabolism of foreign compounds). It is of interest to determine the detailed mechanism of these enzymes to understand their protective function. We also develop systems to predict reactive intermediates and in silico modelling of their metabolism and toxicity. Microsomal glutathione transferase 1 is an enzyme that can protect tumor cells from cytostatic drugs and we are investigating inhibitors that could increase treatment efficiency.
Prostaglandin E (PGE) is very important in pathophysiology related to fever pain and inflammation. In collaboration with Per-Johan Jakobssons group we are investigating a membrane bound enzyme that catalyses the formation of PGE regarding active site location, chemical and kinetic mechanism. Recently the structure of MPGES1 was solved in collaboration with Professor Hans Heberts group at KI which forms the basis for studies on the molecular level. This information is vital to develop new and hopefully safer alternatives to NSAIDs like aspirin. Such development is underway in collaboration with NovaSaid, a company formed together with KI innovations.
Antioxidant supplements at high levels are increasingly recognised as harmful. The mechanism of the harmful effects have not been elucidated. We have proposed the hypothesis that antioxidants cause a redox dysregulation that lowers endogenous protective enzyme levels. We will investigate this hypothesis initially in cellular systems and later in more complex settings.
The Swedish Cancer Society / Cancerfonden
Five selected publications
Holm, P.J., Bhakat, P., Jegerschöld, C., Guybo, N., Mitsuoka, K., Fujiyoshi, Y., Morgenstern, R. and Hebert, H.
Structural basis for detoxication and oxidative stress protection in membranes
J. Mol. Biol. 360, 934-45.
Johansson, K., Ahlen, K., Rinaldi, R., Sahlander, K., Siritantikorn, A., Morgenstern, R. (2007)
Microsomal Glutathione Transferase 1 in anti-cancer drug resistance.
Carcinogenesis, 28, 465-70
Samuelsson, B., Morgenstern, R. and Jakobsson, P-J. (2007)
Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target.
Pharmacol. Rev. 59, 207-24.
Jegerschöld, C., Pawelzik, S., Purhonen, P., Bhakat, P., Gheorge, K., Gyobu, N., Mitsuoka, K., Morgenstern, R., Jakobsson, P-J and Hebert, H., (2008)
Structure of Human Microsomal Prostaglandin E Synthase 1 in Complex with Glutathione
Proc. Natl. Acad. Sci. 105, 11110-11115.
Ålander, J., Lengqvist, J., Holm, P.J., Svensson,R., Gerbaux, P., van den Heuvel, R.H.H., Hebert, H., Griffiths, W.J., Armstrong, R.N.and Morgenstern R. (2009)
Microsomal glutathione transferase 1 exhibits one-third-of-the-sites-reactivity towards glutathione.
Arch. Biochem. Biophys. 487, 42-48.