Int. J. Peptide Rotein Res. 23, zyxwvutsr 1984, 335-341 zyxwvut INVITED REVIEW Precursor polyproteins in endocrine a n a n d o c r i n e systems M. CHRGllEN and N.G. SEIDAH Protein and Pituitary Hormone Laboratory, Clinical Research Institute of Montreal, Montreal, Canada Received 19 July, accepted for publication zyxw 25 August 1983 The biosynthesis of neuro and hormonal peptides is in a state of rapid progress. The development of protein microsequencing is making it possible to charac- terize more and more new important molecules with nanomolar quantities, while the DNA structural studies favor the sequencing of the precursors of all these new peptides. These precursors are often polyproteins containing more than one active end-product. Their maturation processes are following a highly similar pattern with cleavage of the precursors at sites characterized by the presence of pairs of basic amino acid as noted in 1967-68 for the LPH and the pro-insulin models. This now constitutes a general concept which has good chances to be applicable to all the exciting neuro and hormonal peptides recently identified or yet to be discovered. Key words zyxwvutsr : biosynthesis; neuropeptides; polyproteins; pro-hormones The concept of pro-hormones, although sus- pected in the early ~O’S, really started in July 1967 when two articles were simultaneously published by two different groups working with two different approaches in the field of peptide hormones. Based on pulse-chase experiments, Steiner er zyxwvutsrq al. (1) arrived at the conclusion that insulin was biosynthesized in the pancreatic &cells as a larger molecule. Based on amino acid sequence homologies between P-LPH (2), 7-LPH and 0-MSH, Chretien & Li (3) proposed a similar biosynthetic scheme for this group of pituitary polypeptides. At the same time, it became obvious that the sites of cleavage in 0-LPH, the precursor molecule, were pairs of basic amino acid residues. One year later, when Chance er al. zyxwvutsr (4) published the complete sequence of pro-insulin, the same type of cleavage was noticed for the release of the connecting peptide from the pro-insulin (Fig. 1). More than 15 years later, the characteristics of these cleaving sites have become almost universal in most published models of peptide hormones and of neuropeptides, including the recently described pre-pro-enkephalin (5), pre- pro-dynorphin (6) and pre-procorticotropin- releasing factor (CRF) (7). Initially, the LPH model (3) was received with some skepticism but it received greater attention in 1975-76 when it was discovered that the endorphins (8, 9) were located at the C-terminal portion of 0-LPH and more so when it was suggested and confirmed by cDNA sequence studies (10) that both 0-LPH and ACTH were part of the same precursor, called pro-opiomelanocortin The pioneering concept of pro-hormone will 335 (1 1).