In Memoriam: Osamu Hayaishi (1920–2015)

Dr. Osamu Hayaishi, a world-renowned biochemist and oxygenase scientist, passed away on December 17, 2015, at the age of 95. He was the teacher of the authors of this tribute. In 1932, a short paper reported “the presence of an oxydase of lipid or lipoxydase of soy seed” (1Andre E. Hou R. Sur la présence d'une oxydase des lipides ou lipoxydase dans la graine de soja.Computus Rendus. 1932; 194: 645-647Google Scholar). Later the “lipoxidase” was crystallized and its properties were described by Theorell et al. (2Theorell H. Holman R.T. Åkeson Å. Crystalline lipoxidase.Acta Chem. Scand. 1947; 1: 571-576Crossref PubMed Google Scholar). Although lipoxidase was the first example of “oxygenase”, its characterization as an oxygenase awaited the epoch-making work in 1955 by the groups of Mason and Hayaishi as will be described below. Osamu Hayaishi was born in Stockton, CA, in 1920 when his father studied and practiced medicine in the United States. In 1923, his family returned to Japan after visiting Germany for some time. He graduated from Osaka Imperial University School of Medicine in 1942, and then served in the navy as a medical officer until the end of the World War II. When he decided to become a basic researcher, the laboratory conditions were miserable. There were no chemicals or experimental animals, and the research facilities were almost useless. In several works (3Hayaishi O. Tryptophan, oxygen and sleep.Annu. Rev. Biochem. 1994; 63: 1-24Crossref PubMed Google Scholar, 4Hayaishi O. An odyssey with oxygen.Biochem. Biophys. Res. Commun. 2005; 338: 2-6Crossref PubMed Scopus (9) Google Scholar, 5Hayaishi O. From oxygen to sleep.J. Biol. Chem. 2008; 283: 19165-19175Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 6Hayaishi O. Memoirs of a biochemist.IUBMB Life. 2006; 58: 242-245Crossref PubMed Scopus (2) Google Scholar, 7Hayaishi O. Odyssey of a biochemist.Comprehensive Biochemistry. 2007; 45: 1-36Crossref Scopus (0) Google Scholar) written by Hayaishi himself, he vividly and concretely described his life in Japan immediately after World War II. A famous biochemist at Osaka University, Yashiro Kotake, extensively studied tryptophan metabolism in mammals. His group's approach was to feed animals with tryptophan and to extract and analyze the urinary metabolites. Their famous contribution was the discovery of kynurenine as a central metabolite, which was further transformed to kynurenic, xanthurenic, and anthranilic acids. Fortunately, Kotake donated several grams of tryptophan to Hayaishi, and this “tryst with tryptophan” (4Hayaishi O. An odyssey with oxygen.Biochem. Biophys. Res. Commun. 2005; 338: 2-6Crossref PubMed Scopus (9) Google Scholar) was the starting point of Hayaishi's lifelong research and led him to the discovery of oxygenase. Inspired by a paper by Mirick (8Mirick G.S. The oxidation of p-aminobenzoic acid and anthranilic acid by specifically adapted enzymes of a soil bacillus.J. Exp. Med. 1943; 78: 255-272Crossref PubMed Scopus (5) Google Scholar), Hayaishi attempted to isolate a soil bacterium that grew on nitrogen with tryptophan as its sole source of carbon, and he obtained a bacterial strain identified later as a pseudomonad. In contrast to mammals, this microorganism metabolized anthranilic acid further to cis, cis-muconic acid, which was decomposed to carbon dioxide, ammonia, and water. Although he tried to extract the enzymes responsible for such a metabolic pathway, the only isolable enzyme was the one catalyzing the cleavage of the benzene ring of catechol to produce cis, cis-muconic acid (Fig. 2A). The enzyme consumed a stoichiometric amount of O2, but the oxygen molecule could not be replaced by any other hydrogen acceptor molecules known at that time. Thus, the enzyme seemed to be different from classical oxidases and dehydrogenases, and he referred to the enzyme as pyrocatechase (9Hayaishi O. Hashimoto K. Pyrocatechase a new enzyme catalyzing oxidative breakdown of pyrocatechin.J. Biochem. 1950; 37: 371-374Crossref Scopus (65) Google Scholar). It took him five more years before he ultimately characterized this enzyme as an oxygenase. Upon receiving an invitation letter from D. E. Green in 1949, Hayaishi traveled to Madison, WI, where he worked at the Enzyme Research Institute for several months. At the meeting of the Federation of the American Society of Experimental Biology, he attended a lecture by Arthur Kornberg, whose presentation so impressed and inspired Hayaishi that he applied for a job in Kornberg's laboratory. Waiting for the available fellowship, he spent three productive months with Roger Stanier in California working on the bacterial metabolism of tryptophan, and then moved to the National Institutes of Health to work with Kornberg. Hayaishi subsequently accompanied Kornberg to Washington University in St. Louis and stayed there as an assistant professor with Paul Berg. What Hayaishi experienced and learned in the Kornberg laboratory established his style as a researcher and a teacher and was very influential later to a number of his students. In 1954, Hayaishi was appointed chief of the Toxicology Section of the National Institute of Arthritis and Metabolic Diseases at the NIH, and he established his independent laboratory. To start his research program, he decided to characterize pyrocatechase enzyme, “his first love” (4Hayaishi O. An odyssey with oxygen.Biochem. Biophys. Res. Commun. 2005; 338: 2-6Crossref PubMed Scopus (9) Google Scholar). The enzyme utilized one mole of oxygen per mole of catechol. Using a heavy isotope of oxygen (18O2) generated by electrolysis of H218O, donated by D. Samuel of the Weizmann Institute in Israel, Hayaishi performed isotope labeling experiments and mass spectrometry in collaboration with M. Katagiri and S. Rothberg. Their experimental results established that two 18O atoms were incorporated into cis,cis-muconic acid from 18O2 but not from H218O (10Hayaishi O. Katagiri M. Rothberg S. Mechanism of the pyrocatechase reaction.J. Am. Chem. Soc. 1955; 77: 5450-5451Crossref Scopus (227) Google Scholar) (Fig. 2A). In the same year H. S. Mason and his coworkers used mushroom phenolase enzyme, and demonstrated the incorporation of one 18O atom into 3,4-dimethyl phenol from 18O2 to produce 4,5-dimethyl catechol (11Mason H.S. Fowlks W.L. Peterson E. Oxygen transfer and electron transport by the phenolase complex.J. Am. Chem. Soc. 1955; 77: 2914-2915Crossref Scopus (168) Google Scholar) (Fig. 2B). The other atom of 18O2 was presumed to be reduced to H218O (12Mason H.S. Mechanism of oxygen metabolism.Science. 1957; 125: 1185-1188Crossref PubMed Scopus (61) Google Scholar). Thus, two types of enzymatic oxygenations of organic substrates were demonstrated for the first time, and these findings suggested a hitherto-unknown role of molecular oxygen. Such a role for an oxygen molecule was in sharp contrast to Wieland's dehydrogenation theory. Previously, the oxygen molecule had only been considered as a terminal hydrogen acceptor producing H2O or H2O2. Although the first discoveries of oxygenases were with mushroom and bacterial enzymes, a number of papers soon appeared reporting a wide distribution of oxygenases in the animal and plant kingdoms. Oxygenases were now known to be involved in the biosynthesis and degradation of amino acids, fatty acids, steroids, prostanoids, and a variety of aromatic compounds (13., Hayaishi, O., (ed.). 1962. Oxygenases. Academic Press, New York and London.Google Scholar, 14Hayaishi O. Molecular Mechanisms of Oxygen Activation. Academic Press, New York and London1974Google Scholar). Soybean “lipoxidase” discovered much earlier (1Andre E. Hou R. Sur la présence d'une oxydase des lipides ou lipoxydase dans la graine de soja.Computus Rendus. 1932; 194: 645-647Google Scholar, 2Theorell H. Holman R.T. Åkeson Å. Crystalline lipoxidase.Acta Chem. Scand. 1947; 1: 571-576Crossref PubMed Google Scholar) was characterized as a dioxygenase and renamed “lipoxygenase”, based on isotope labeling experiments with 18O2; moreover, the initiation of the lipoxygenase reaction by a regio- and stereo-specific hydrogen abstraction was demonstrated (15Hamberg M. Samuelsson B. On the specificity of the oxygenation of unsaturated fatty acids catalyzed by soybean lipoxidase.J. Biol. Chem. 1967; 242: 5329-5335Abstract Full Text PDF PubMed Google Scholar). Various prosthetic groups and coenzymes were found in oxygenases: heme, nonheme-iron, copper, flavin, pterin, and so on (14Hayaishi O. Molecular Mechanisms of Oxygen Activation. Academic Press, New York and London1974Google Scholar). An important development was the discovery of a new hemoprotein named P450 (16Omura T. Sato R. A new cytochrome in liver microsomes.J. Biol. Chem. 1962; 237: PC1375-PC1376Abstract Full Text PDF Google Scholar), and its functions in steroidogenesis were elucidated by action spectra (17Estabrook R.W. Cooper D.Y. Rosental O. The light reversible carbon monoxide inhibition of the steroid C-21 hydroxylase system of the adrenal cortex.Biochem. Z. 1963; 338: 741-755PubMed Google Scholar). The cytochrome P450s (CYP) are now known to be a large family of hemoproteins that function as monooxygenases in the biosynthesis and degradation of a variety of compounds including steroids, fatty acids, and xenobiotics. After these prominent achievements during his eight-year stay in the United States, Hayaishi returned to Japan as a professor of medical chemistry at Kyoto University, Faculty of Medicine in 1957. He established his new laboratory not only with startup grants from the Japanese government but also with support from various American foundations including the NIH. Hayaishi was subsequently appointed a professor of biochemistry at Osaka University School of Medicine (1961–1963) and a professor of nutrition at the University of Tokyo, Faculty of Medicine (1970–1974). He began performing two lines of research, one on tryptophan metabolism and the other focuse

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