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Vincent du Vigneaud receives Nobel Prize in Chemistry from King of Sweden
Du Vigneaud and Oxytocin E. C. KENDALL, Princeton University, Princeton, N. J.
Results of synthesis of posterior pituitary hormone illustrate value of fundamental research A HE 1955 Nobel Prize in Chemistry was awarded to Vincent du Vigneaud for his work "on biochemically important sulfur compounds, especially for the first synthesis of a polypeptide hormone." The award marks the culmination of over 25 years of research concerning sulfur-containing compounds which are biochemically important. It is of interest to trace the sequence of the research problems and to note how the answers which were found to overcome obstacles in one project served as keys to unlock still greater barriers in subsequent research. The early demonstration that the sulfur in insulin was present in the form of one amino acid-cystine provided the theme for almost all of the work which followed. This amino acid can be incorporated in peptides through its amino group or through the carboxyl group. The method of Bergman and Zervas provided biochemists with a means to obtain peptides previously unknown or prepared only with great
difficulty. This procedure was based on protection of the amino group of one of the amino acids with the carbobenzoxy derivative which was subsequently reduced with hydrogen. But with peptides which contained cystine this did not work well. In the laboratory of d u Vigneaud four methods were devised which furnished elegant syntheses for sulfur-containing polypeptides. These methods were: the reduction of a disulfide to a sulfhydryl compound with sodium in liquid ammonia; the cleavage of a carbobenzoxy group with sodium in liquid ammonia; The Cover . . .
Shown are the five Nobel prize winners in Stockholm. They are, left to right: du Vigneaud; Polykarp Kusch of Columbia and Willis E. Lamb of Stanford University, Nobel Prize in Physics; Hugo Theorell of Nobel Institute, Sweden, Nobel Prize in Medicine, and Kiljan Laxness of Iceland, Nobel Prize in Literature.
the benzylation of a sulEhydryl group in liquid ammonia; the cleavage of a benzylthio ether with sodium in liquid ammonia. These contributions have made it possible for du. Vigneaud and his associates to prepare glutathione and all other desired peptides which contained cystine and finally to synthesize oxytocin, the first polypeptide hormone. The availability of rJhese new tools for the synthesis of polypeptides did not provide a straight and easy pathway for the preparation of the hormone, oxytocin. When the project concerning the hormones of the posterior pituitary gland was begun these substances had not been isolated. During the preceding 25 years many attempts had been made to separate the principle or principles i n pure form. In the late 1920's Kamrn and coworkers effected extensive purification and were able to obtain fractions highly potent in pressor activity with but little oxytocic activity and vice versa. t Preliminary Work on Hormones. The isolation of the hormones of the posterior pituitary was begun in du Vigneaud's laboratory in 1932 and after postponement during the war years the project was culminated i n 1952 by the separation of oxytocin in crystalline form as a flavianate. This was followed by the demonstration that eight amino acids and ammonia were released by hydrolysis. It was then shown that only one molecule of each amino acid was present. The ammonia was sufficient for three amide groups. The last details of structure were elucidated when the order o£ sequence for the eight amino acids, and t h e presence of an S-S bond, were established. By use of the classical methods for the synthesis of peptides including the four procedures devised b y d u Vigneaud the hypothetical structure of oxytocin was elaborated. Meticulous care was exercised when the physical and chemical properties of the synthetic material were compared with those of the natural hormone. In all respects they were found t o be identical. The final comparison was even more critical. Would the synthetic hormone produce all o£ the specific and unique physiologic effects of the natural principle and would the dose required be the same? T h e results of these tests were richly rewarding. In aD respects the synthetic and the natural hormones were skrwn to b e one and the same material. This achievement answers many questions which have accumulated during the past 50 years. Perhaps the most important concerned the chemical nature of oxytocin. "Was the hormone composed exclusively of well known amino acids arranged in simple DEC.
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PEOPLE peptide linkages or was the presence of a minute amount of some highly potent substance concealed within the peptide? The answer has been found. Another question which could be answered only by synthesis has to do with the "purity" of preparations of oxytocin and vasopressin. The most complete separation of one iium the oilier of the two hormones of the posterior pituitary gland affords oxytocin which still possesses some of the physiological properties of vasopressin and vice versa. Tlie work of du Vigneaud reveals the fact that synthetic oxytocin which cannot contain a trace of vasopressin possesses the characteristic effects of vasopressin but these are much reduced i n magnitude. This finding has a simple explanation. A 20-mernbered ring is present in both hormones. The only W N W c> Slondard* #»·* apKiihationt)
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