Van Deenen Lecture

KEIZO INOUE

Dr. Inoue started his scientific research with the chemical synthesis of cardiolipin and characterizing its immunogenic properties with Dr. S. Nojima as a graduate student at Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, the University of Tokyo. He was awarded his Ph.D. degree from the University of Tokyo in 1967. After that, he worked as a postdoctoral fellow under the instruction by Prof. S.C. Kinsky at Washington University in St. Louis, where he conducted several studies on the damaging effects of complement on liposomes as a model membrane. In 1970, he returned to Japan and joined the research group directed by Dr. Nojima at Department of Chemistry, N.I.H., Japan, and undertook studies on liposomes by focusing on the dynamic biophysical properties of phospholipids. In 1975, he moved to the University of Tokyo as an Associate Professor of Faculty of Pharmaceutical Sciences. After he became a Professor in 1985, he initiated studies on anti-phospholipid antibodies, phospholipases and lipid transfer proteins.


Dr. Inoue’s first scientific publication in 1963 was related to the chemical synthesis of cardiolipin, in which he cited a paper by Prof. van Deenen’s group describing the procedure of an early step of the chemical synthesis of cardiolipin. After being awarded his Ph.D. degree, he had the opportunity to work in the laboratory of Prof Kinsky, who had just come back from a sabbatical stay in van Deenen’s laboratory for a year. Dr. Inoue learned there how to prepare and handle liposomes ‘indirectly’ from van Deenen. In 1976, Prof. van Deenen visited and stayed in Prof. Nojima laboratory for a month. During those days, he again learned a lot directly from Prof. van Deenen. In 1988, Prof. van Deenen gave a plenary lecture at 29th ICBL in Tokyo chaired by Prof. Nojima, and Dr. Inoue enjoyed renewing old and long-lasting friendship with Prof. van Deenen.


Dr. Inoue demonstrated how lipid-binding proteins recognize specific lipid structures by taking advantage of anti-phospholipid monoclonal antibodies and their anti-idiotypic antibodies, which was a unique approach and spotlighted in this field. He investigated how membrane-interacting substances interfere with membranous functions by using liposomes as a model membrane and found that the phase transition of phospholipids was a critical determinant for membrane permeability. This finding led to the development of temperature-sensitive liposomes used as a drug delivery system. By focusing on lipid transport between separate membranes, he identified and cloned alpha-tocopherol (vitamin E) transfer protein termed alpha-TTP, which was subsequently found to be a causative gene for a human disease, namely ataxia with isolated vitamin E deficiency (AVED). He also extensively worked on the biochemistry and molecular biology of bacterial and mammalian phospholipase A2s (PLA2s). In fact, he was the first researcher who identified and purified non-pancreatic PLA2 group IIA (PLA2G2A) secreted from activated platelets. He found that phospholipase A1 (PLA1) was released from platelets together with group IIA PLA2; his structural study has promoted further identifications of phosphatidylserine- and phosphatidic acid-specific PLA1s and the functions of their products. He also identified and cloned distinct types [types I (alpha1 and alpha2 subunits) and II, also known as PLA2G8A, PLA2G8B and PLA2G7B, respectively) of platelet-activating factor acetylhydrolase (PAF-AH), a distinct class of PLA2 that shows unique substrate specificity for PAF and oxidized phospholipids, from mammals and C. elegans. He also found that the beta subunit of type I PAF-AH was a causative gene for Miller-Dieker lissencephaly syndrome, a human disorder with brain malformation. Overall, Dr. Inoue’s pioneering studies on the biochemistry of enzymes and transfer proteins recognizing specific lipids continuously led him to open up new fields of research. He was the first Japanese scientist working as a member of Editorial Board of the J. Biol. Chem. He has published more than 300 original papers and 25 review articles. Moreover, Dr. Inoue has mentored more than 100 graduate students during his 25-year research life at the University of Tokyo, and many of them became leading scientists in the field of lipid bioscience in Japan.


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