| Co-Investigator(Kenkyū-buntansha) |
ITO Seiji Kansai Medical University, Dept.of Medical Chemistry, Professor, 医化学, 教授 (80201325)
OISHI Kenji University of East Asia, Faculty of Medical Technology, Professor, 医療工学部, 教授 (10152042)
WATANABE Kikuko University of East Asia, Faculty of Medical Technology, Professor (90211672)
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| Research Abstract |
Prostaglandin (PG)s regulate diverse biological functions during both homeostasis and inflammation, and are synthesized through the enzymatic conversion of arachidonic acid to PGH_2 by cyclooxygenase (COX). PGF_2 and E_2, which are primary PGs, are widely distributed in various organs, and exhibits various biological actions such as smooth muscle contraction, pain transmission, and so forth. Watanabe, K., who is a head investigator of this project, discovered PGF synthase and mPGE synthase-2. PGF synthase is a dual function enzyme, which catalyzes the reduction of not only PGD_2 but also that of PGH_2 in the presence of NADPH. It forms 9α, 11β-PGF_2, a stereoisomer of PGF_<2α>, from PGD_2 and PGF_<2α> from PGH_2 on the same molecule. Watanabe, K.has characterized the enzymatic and molecular properties of PGF synthase for a long time. On the other hand, many PGE synthases including the membrane-associated PGE synthase (mPGE synthase)-1 and cytosolic PGE synthase (cPGE synthase) require glutathione (GSH) for their synthase activity, and they thus belong to the GSH S-transferase family. In contrast, mPGE synthase-2 has a broad specificity in its thiol requirement for catalytic activity, and its amino acid sequence places it in the redoxin family. We have crystallized mPGE synthase-2 as well as PGF synthase, and determined the active site for each substrate for both enzymes. Moreover, we studied the localization of both enzymes and COX-1 and -2 in kidney and renal cell carcinoma, and suggest that these enzymes contribute to the syntheses of PGF and E in renal cell carcinoma.
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