Chemical Messengers of the Adenohypophysis from Somatotropin to Lipotropin

CHEMICAL MESSENGERS OF THE ADENOHYPOPHYSIS FROM SOMATOTROPIN TO UPOTROPIN* CHOH HAO Uf I am greatly honored to be the first Herbert M. Evans Memorial Lecturer . When I completed my postgraduate studies of chemistry in the laboratories of Professor Gilbert N. Lewis, I was offered a position as a research associate in Dr. Evans's Institute of Experimental Biology. That began my association with Professor Evans from 1938 to 1949. During this period, I was introduced to the field of endocrinology and learned the importance of biology in chemical research. I am grateful to Dr. Evans for that opportunity. Since 1950, the structures of more than 25 hormonally active peptides and proteins have been determined in addition to a number of tissue hormones. Many of these have also been synthesized in the laboratory. These advances could not have been achieved without the isolation of these hormones in pure form. Methods of isolating these polypeptides depend greatly upon the development of techniques in protein chemistry . Thus, contributions made by A. Tiselius, L. C. Craig, and others have given tremendous impetus to the recent progress in this phase of hormone research. Bayliss and Starling [1] discovered secretin in 1902, and they defined the term "hormone" as a "chemical messenger." It took nearly 65 years to isolate secretin in pure form; its structure was finally determined by Mutt andJorpes [2]. In contrast, from the discovery ofcalcitonin in 1961 by Copp [3] to the determination of its structure and total synthesis in 1968 [4, 5] took only 7 years. A new era in the history ofprotein hormones began with the discovery ofinsulin by Banting, Best, and Macleod in 1922 [6], its crystallization by Abel in 1926 [7], and its structure determination by Sanger in 1954 [8]. *The first Herbert M. Evans Memorial Lecture, University of California, San Francisco, Ocober 20, 1976. The experimental work was supported in part over the years by grants from the National Institutes of Health, the American Cancer Society, and the Allen-Geffen Fund. tHormone Research Laboratory, University of California, San Francisco, California 94143.© 1978 by The University of Chicago. 0031-5982/78/2103-0065$01.00 Perspectives in Biology and Medicine ¦ Spring 1978 \ 447 Because of its immense importance in clinical medicine, insulin is probably the most unique hormone; it has been studied extensively as a protein as well as a biologically active molecule. InA Trail ofResearch, du Vigneaud [9] described how his interest in the hormones ofthe posterior lobe of the pituitary gland grew out of the work on the chemistry of insulin. Subsequently, du Vigneaud and his co-workers succeeded in obtaining oxytocin and vasopressin in pure form during 1950-1951, determining their structure in 1953, and preparing the synthetic products in 1954. Our work on anterior pituitary hormones follows the trail of Evans, Collip, van Dyke, and others. Ten hormones are now known to be secreted by the adenohypophysis [10]. All 10 hormones have been completely purified and characterized. Their primary structures (see [10]) are known (see figs. 1-3). Five of them have been either partially or totally synthesized in the laboratory. From the studies on their primary structures, it is possible to divide them into three groups having certain structural features in common (table 1). Because ofthese common structures , they exhibit overlapping biological activities. A high degree of structural resemblance has been found to exist among the glycoprotein hormones: thyrotropin, lutropin, and follitropin. Somatotropin and prolactin form the second groups, exhibiting considerable structural homology as well as common biological properties. Corticotropin, the melanotropins, and the lipotropins fall into the third group of structurally and biologically related molecules. Somatotropin.—The existence of a hormone from the pituitary gland that is responsible for growth has been recognized from experiments of Evans and Long [11] with normal plateau rats in 1921 and ofSmith [12] with hypophysectomized rats in 1926. It was not until 1944 that the isolation of pure growth hormone from bovine pituitaries [13, 14] securely established the existence of somatotropin. While the biological effects ofbovine growth hormone can readily be demonstrated in experimental animals, it was shown by Bennet et al. [15] in 1950 that the bovine hormone was not active in man. This led to...