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Your search keyword '"Damian Niegowski"' showing total 2 results
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2 results on '"Damian Niegowski"'

1. Structure and inhibition of mouse leukotriene C4 synthase.

Author

Damian Niegowski, Thea Kleinschmidt, Shabbir Ahmad, Abdul Aziz Qureshi, Michaela Mårback, Agnes Rinaldo-Matthis, and Jesper Z Haeggström

Subjects
Medicine, Science
Abstract

Leukotriene (LT) C4 synthase (LTC4S) is an integral membrane protein that catalyzes the conjugation reaction between the fatty acid LTA4 and GSH to form the pro-inflammatory LTC4, an important mediator of asthma. Mouse models of inflammatory disorders such as asthma are key to improve our understanding of pathogenesis and potential therapeutic targets. Here, we solved the crystal structure of mouse LTC4S in complex with GSH and a product analog, S-hexyl-GSH. Furthermore, we synthesized a nM inhibitor and compared its efficiency and binding mode against the purified mouse and human isoenzymes, along with the enzymes' steady-state kinetics. Although structural differences near the active site and along the C-terminal α-helix V suggest that the mouse and human LTC4S may function differently in vivo, our data indicate that mouse LTC4S will be a useful tool in future pharmacological research and drug development.

Published
2014
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2. Structure and inhibition of mouse leukotriene C4 synthase

Author

Jesper Z. Haeggström, Thea Kleinschmidt, Damian Niegowski, Abdul Aziz Qureshi, Agnes Rinaldo-Matthis, Michaela Mårback, and Shabbir Ahmad

Subjects
Models, Molecular, Protein Conformation, Competitive Inhibitors, lcsh:Medicine, Biochemistry, chemistry.chemical_compound, Mice, 0302 clinical medicine, Medicine and Health Sciences, Cloning, Molecular, Enzyme Inhibitors, lcsh:Science, Integral membrane protein, Glutathione Transferase, chemistry.chemical_classification, 0303 health sciences, Leukotriene, Multidisciplinary, ATP synthase, Fatty Acids, Lipids, Enzyme structure, 3. Good health, Enzymes, Isoenzymes, 030220 oncology & carcinogenesis, Research Article, Protein Structure, Inflammatory Diseases, Molecular Sequence Data, Biology, 03 medical and health sciences, Lipid Mediators, In vivo, Transferases, Chemical Biology, Animals, Humans, Enzyme kinetics, Amino Acid Sequence, 030304 developmental biology, Enzyme Kinetics, Leukotriene C4, lcsh:R, Biology and Life Sciences, Proteins, Biochemical Activity, Enzyme, chemistry, Enzyme Structure, biology.protein, Biocatalysis, Enzymology, lcsh:Q
Abstract

Leukotriene (LT) C4 synthase (LTC4S) is an integral membrane protein that catalyzes the conjugation reaction between the fatty acid LTA4 and GSH to form the pro-inflammatory LTC4, an important mediator of asthma. Mouse models of inflammatory disorders such as asthma are key to improve our understanding of pathogenesis and potential therapeutic targets. Here, we solved the crystal structure of mouse LTC4S in complex with GSH and a product analog, S-hexyl-GSH. Furthermore, we synthesized a nM inhibitor and compared its efficiency and binding mode against the purified mouse and human isoenzymes, along with the enzymes’ steady-state kinetics. Although structural differences near the active site and along the C-terminal α-helix V suggest that the mouse and human LTC4S may function differently in vivo, our data indicate that mouse LTC4S will be a useful tool in future pharmacological research and drug development.

Published
2014

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