Project: Membrane protein enzymology
Cells are surrounded by membranes that separates the cell from the outside world and allows a specific internal chemical environment. Membranes are also found in the cell interior. These membranes form a barrier in which many biochemical processes occur, such as energy conversion , transport, and signalling. These processes are relatively well studied. The membranes are also a compartment in the cell where lipophilic substances dissolve. Membrane processes where enzymes synthesize products by conjugating water soluble and membrane- dissolved components is less well investigated. Generally speaking, the detailed knowledge of membrane-bound enzymes mechanism is rare because these proteins represent a methodological challenge. In this project we will investigate two membrane-bound enzymes for which the crystal structure was determined and where tools have been developed for detailed mechanistic studies. We can thus contribute to new knowledge about a class of enzymes that have been very difficult to study in detail. Since the enzymes under study are involved in protection against toxic substances or participate in the synthesis of endogenous substances (such as fever, pain and inflammation signals) results will provide a better understanding of these processes. This can lead to better prevention strategies and the development of new and safer drugs.
- The Swedish Research Council (NT)
Structural basis for induced formation of the inflammatory mediator prostaglandin E2.
Jegerschöld C, Pawelzik S, Purhonen P, Bhakat P, Gheorghe K, Gyobu N, et al
Proc. Natl. Acad. Sci. U.S.A. 2008 Aug;105(32):11110-5
Synthesis and characterization of a series of highly fluorogenic substrates for glutathione transferases, a general strategy.
Zhang J, Shibata A, Ito M, Shuto S, Ito Y, Mannervik B, et al
J. Am. Chem. Soc. 2011 Sep;133(35):14109-19
A dynamic Asp-Arg interaction is essential for catalysis in microsomal prostaglandin E2 synthase.
Brock J, Hamberg M, Balagunaseelan N, Goodman M, Morgenstern R, Strandback E, et al
Proc. Natl. Acad. Sci. U.S.A. 2016 Jan;113(4):972-7
Catalytic Conversion of Lipophilic Substrates by Phase constrained Enzymes in the Aqueous or in the Membrane Phase.
Cebula M, Turan I, Sjödin B, Thulasingam M, Brock J, Chmyrov V, et al
Sci Rep 2016 12;6():38316
Global Kinetic Mechanism of Microsomal Glutathione Transferase 1 and Insights into Dynamic Enzyme Activation.
Spahiu L, Ålander J, Ottosson-Wadlund A, Svensson R, Lehmer C, Armstrong R, et al
Biochemistry 2017 06;56(24):3089-3098
Dead-end complex, lipid interactions and catalytic mechanism of microsomal glutathione transferase 1, an electron crystallography and mutagenesis investigation.
Kuang Q, Purhonen P, Ålander J, Svensson R, Hoogland V, Winerdal J, et al
Sci Rep 2017 08;7(1):7897
MGST1, a GSH transferase/peroxidase essential for development and hematopoietic stem cell differentiation.
Bräutigam L, Zhang J, Dreij K, Spahiu L, Holmgren A, Abe H, et al
Redox Biol 2018 07;17():171-179