Klaus H. Hofmann: Difference between revisions

The first chemical synthesis of an active peptide hormone, the nine amino acid cyclic peptide, oxytocin, was achieved in 1954 by du Vigneaud<ref>du Vigneaud, V. Ressler, C. Swan, J. M. Roberts, C. W. and Katsoyannis, P. G. The Synthesis of Oxytocin. J. Am. Chem Soc. 76 3115-21 1954.</ref> for which he was awarded the Nobel Prize. At the same time, the isolation and structure determination of the anterior pituitary hormone, ACTH, was being pursued in three laboratories.<ref>Bell, P. H. Purification and Structure of β-corticotropin. J. Am. Chem. Soc. 76 5565-67 1954.</ref><ref>Li, C. H., Geschwind, I. I., Levy, A. L., Harris, J. I. Dixon, J. S., Pon, N. G., and Porath, J. O. Amino-Acid Sequence of Alpha-Corticotropin. Nature 173 251 1954.</ref><ref>White, W. F. and Landmann, W. A. Studies on Adrenocorticotropin XI. A Preliminary Comparison of Corticotropin-A with β-Corticotropin. J. Am. Chem. Soc. 77 1711 1955.</ref> The peptide was eventually determined to be 39 amino acids in length, however enzymatic and mild acid cleavage<ref>11. Brink, N. G., Kuehl, F. A. Richter, J. W. Bazemore, A. W., Meisinger, M. A. P. Ayer, D. E. and Folkers, K. Pituitary Hormones III. The isolation of Corticotropin-B. J. Am. Chem. Soc. 74 2120-21 1952.</ref> suggested that a structure comprising only the first 24 amino acids had full biological activity. It was apparent from the outset that ACTH contained the amino acid Arginine and thus methods had to be developed for the incorporation of this basic amino acid into peptides. Hofmann and his group set about this task.<ref>Hofmann, K, Rheiner, A. and Peckham, W. D. Studies on Polypeptides. V. The Synthesis of Arginine Peptides. J. Am. Chem. Soc. 75 6083 1953.</ref> Their efforts led to the synthesis of the melanocyte stimulating hormone, β-MSH, which corresponds to the first 13 amino acids of ACTH <ref>Hofmann, K and Yajima, H. Studies on Polypeptides. XX. Synthesis and Corticotropic Activity of a Peptide Amide Corresponding to the N-Terminal Tridecapeptide Sequence of the Corticotropins. J. Am. Chem. Soc. 83 2289-93 1961.</ref> and to the synthesis of a fully active ACTH peptide corresponding to the amino acid sequence of the first 23 amino acids.<ref>Hofmann, K., Yajima, H., Yanaihara, N., Liu, T-Y, and Lande, S. Studies on Polypeptides. XVIII. The Synthesis of a Tricosapeptide Possessing Essentially the Full Biological Activity of Natural ACTH J. Am. Chem. Soc. 83 487-89 1961.</ref>

 

===RNaseA===

In 1959, Fred Richards discovered that a proteolytic enzyme, Subtilisin, had the ability to cleave the enzyme Ribonuclease A into two components, a peptide corresponding to the first 20 amino acids of the enzyme (S-Peptide) and the remainder of the protein (S-Protein).<ref>Richards, F. M. and Vithayathil, P. J. The Preparation of Subtilisin-modified Ribonuclease and the Separation of the Peptide and Protein Components. J. Biol. Chem. 234 1459-65 1959.</ref> When separated from one another, each piece was inactive but when they were simply mixed together, full enzymatic activity was restored. Hofmann speculated that this system might be a model for the way peptide hormones interact with their receptors.<ref>Hofmann, K. Preliminary Observations Relating Structure and Function in Some Pituitary Hormones. Brookhaven Symposia in Biology 13 184-202 1960.</ref> Structure-function studies with ACTH were complicated by the necessity to assess activity in the whole animal. The S-Peptide:S-Protein system afforded a simple system with none of the biological complications inherent in testing ACTH analogs.