The Nobel Prize in Chemistry 1955

Presentation Speech by Professor A. Fredga, member of the Nobel Committee for Chemistry of the Royal Swedish Academy of Sciences

Your Majesties, Your Royal Highnesses, Ladies and Gentlemen.

The word sulphur may give rise to rather disparate sensations; to most people it has not a very pleasing ring. Also many chemists are inclined to keep their distance; they know that organic sulphur compounds may infect the atmosphere around wood pulp mills and that they form part of the chemical weapon of the common skunk. In spite of that, the element sulphur is of vital importance, and it has many functions in the living organism.

Professor du Vigneaud once defined true exploratory research as "the working out of a winding trail into the unknown". He himself has followed the trail of sulphur in metabolism.

The story starts in the nineteen-twenties with insulin, a substance whose importance is now well-known. As to its chemical nature, it is a protein with a remarkably high percentage of sulphur. The proteins are built up from so-called amino acids, and their sulphur is due to the presence of one or two sulphur-containing amino acids: cystine and methionine. Considering the special properties of insulin, one could perhaps expect to find its sulphur in quite a new combination, but it turned out that it was present in cystine. The result may seem to be of little significance, but the trail pointed in a definite direction; the sulphur-containing amino acids must be more closely investigated.

It would lead too far to give an account of Professor du Vigneaud's numerous works on cystine, methionine, and related compounds. They led, inter alia, to the discovery of the biological importance of the methyl group and of its migrations in the organism. I must also leave aside the distinguished works on biotin, also known as vitamin H, and coenzyme R, and the important contributions to the chemistry of penicillin.

Underneath the brain, there is a small, well-protected gland, the pituitary gland. In man it is about as big as a bean. There are secreted several hormones, that is, substances which regulate important physiological functions. spite of its small size, the pituitary gland is made up of several distinct parts with different functions. We are interested here in the posterior lobe, which contains two substances called oxytocin and vasopressin. The former stimulates the contractions of the uterus and also the lactation, the latter raises the blood pressure and regulates the function of the kidneys. As early as in 1933, when rather impure preparations from the posterior lobe were used in experiments, du Vigneaud found a high percentage of sulphur, which seemed to be correlated to the physiological activity.

Using the experimental methods, which the development of science has put at his disposal and making the best of his own intimate knowledge of the organic chemistry of sulphur, du Vigneaud has step by step forced his way. Both hormones were isolated in a state of purity, and it was found that they are built up from amino acids in the same way as proteins, but with a far lower molecular weight. Such compounds are, as distinguished from real proteins, called polypeptides. The nature of the amino acids and their positions in the molecule could be determined. The sulphur is present in cystine. The two hormones have a very similar structure; both contain eight amino acids, connected to a chain, which at one point is closed to a ring. The molecule has some resemblance to a figure six or nine, where the loop contains five amino acids and the "tail" three. Two sulphur atoms, linked to each other, form a part of the ring.

The design of the molecule was thus known. It remained to build it up by synthesis and check the correctness of the design. That was perhaps the most difficult part of the work. The interest was first concentrated on the synthesis of oxytocin. Step by step the amino-acid chain was built up with the two sulphur atoms in the proper positions, one at the end of the chain and the other near the middle. At last the ring was closed by formation of a bond between the sulphur atoms. Now followed the most thrilling moment, the testing of the chemical properties and the physiological activity; perhaps there had been some mistake after all. It turned out, however, that the synthetic polypeptide was identical with the natural product.

A biologically important substance of complicated structure had been investigated and synthesized with eminent skill. However, more important still are the far-reaching consequences of this achievement. It is the first synthesis of a polypeptide hormone. It also shows, that such substances with very important physiological properties may be built up from well-known amino acids according to well-known principles. The eight amino acids must, however, be combined in a special sequence; it may not be out of place to draw attention to the principle of the combination lock. The result may also be of importance for revealing the secrets of the real proteins.

Professor du Vigneaud. Some years ago you gave a survey of your most important works and you called it: "A trail of research in sulphur chemistry and metabolism". At an early stage you found that the element sulphur has a special fascination, and you started out to follow its winding trail into the unknown. It has led you to many important discoveries and recently to the first synthesis of a polypeptide hormone. We are sure it will lead you further still.

In the structure of these hormones there is nothing mysterious, nothing thrilling. They are built up like proteins, and the building-stones, the eight amino acids, are those found in common proteins. The conspicuous properties must be due to the sequence, the arrangement. This is a very important step on the way, leading to the understanding of the mode of action of such hormones.

In our days, there is often a tendency to draw a borderline between organic and biological chemistry. If you have heard about this borderline, you have never cared for it. Your work is a triumph for organic chemistry, but the most important consequences fall within the regions of biochemistry and physiology. In recognition of your services to Natural Science, the Royal Academy has decided to bestow upon you the Nobel Prize for Chemistry for your work on sulphur compounds of biochemical importance, and especially for the first synthesis of a polypeptide hormone. To me has been granted the privilege of conveying to you the warmest congratulations of the Academy and of inviting you to receive your prize from the hands of His Majesty the King.

From Nobel Lectures, Chemistry 1942-1962, Elsevier Publishing Company, Amsterdam, 1964