The Bakerian Lecture - Towards synthesis of proteins

Proteins, as their name indicates, occupy the prime place in Nature’s architecture. It is worth remarking that Nature uses the structural type for diverse purposes, in addition to those familiar in enzymology, immunology, etc. A striking example is provided by the recent publication (Bradbury et al. 1976), showing that the C fragment of lipotropin (residues 61‒91) is firmly bound by opiate receptors and is an analgesic 200 times as potent as morphine in molar terms. The pentapeptide comprising residues 61‒65 of this sequence is already well known as enkephalin (Hughes et al. 1975). Reference should also be made to the host of hormones from the pituitary gland, hypothalamus, and intestinal tract. An example of the last is gastrin which has been studied at Liverpool, principally by R. A. Gregory in the Department of Physiology. Recently the structure of the big gastrins, isolated by Gregory & Tracy (1972), has been elucidated by Harris & Runswick (1974) following preliminary work in the Robert Robinson Laboratories (Barton, Choudhury, Dancsi & Kenner 1973) (figure 1). This structure typifies the way in which small fragments are carved from a protein chain in order to provide an active hormone (Smyth 1975). Thus the gastrins originally described (Gregory & Tracy 1964; Kenner & Sheppard 1968) correspond to the sequence 18‒34 of the big gastrins. The lysyl glutaminyl bond is enzymically cleaved, as can be achieved in the laboratory by trypsin, and then the N-terminal glutaminyl residue cyclizes to the pyroglutamyl structure (pyrrolidone carbonyl). The pyroglutamyl structure at the N-terminus of the big gastrins must have arisen in the same way. It should also be noted that the C-terminal amide, which is essential for biological activity (Tracy & Gregory 1964), very likely arises from enzymatic aminolysis of a protein chain extending further to the right; the extensive studies by Morley (1968) of structure‒activity relations in the gastrin tetrapeptide indicate that the gastrin tetrapeptide embedded in a protein chain would not have hormonal activity until aminolysis had occurred, and therefore the gastrin sequence can be stored in a prohormone. The sequence of human big gastrin 1 (figure 1) has been synthesized by a collaborative effort between our laboratory at Liverpool and that of Professor E. Wünsch in the Max Planck Institute at Munich (Choudhury et al. 1976). Two points concerning our experience of synthesis in the gastrin series are relevant to the main theme of this lecture. Firstly, although the synthesis was accomplished by the combination of section 1‒19 synthesized in Liverpool with section 20‒34 made in Munich according to the original design, additional superior routes have been devised in both laboratories. In other words, even those skilled Glp1-Leu-Gly-Pro-Gln-Gly-His-Pro-Ser-Leu-Val-Ala-Asp-Pro-Ser-Lys-Lys17-Gln18- Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH234