Abstract
Studies of the biosynthesis of insulin in a human insulinoma beginning in 1965 provided the first evidence for a precursor of insulin, the first such prohormone to be identified. Further studies with isolated rat islets then confirmed that the precursor became labeled more rapidly than insulin and later was converted to insulin by a proteolytic processing system located mainly within the secretory granules of the beta cell and was then stored or secreted. The precursor was designated “proinsulin” in 1967 and was isolated and sequenced from beef and pork sources. These structural studies confirmed that the precursor was a single polypeptide chain which began with the B chain of insulin, continued through a connecting segment of 30–35 amino acids and terminated with the A chain. Paired basic residues were identified at the sites of excision of the C-peptide. Human proinsulin and C-peptide were then similarly obtained and sequenced. The human C-peptide assay was developed and provided a useful tool for measuring insulinlevels indirectly in diabetics treated with insulin. The discovery of other precursor proteins for a variety of peptide hormones, neuropeptides, or plasma proteins then followed, with all having mainly dibasic cleavage sites for processing. The subsequent discovery of a similar biosynthetic pathway in yeast led to the identification of eukaryotic families of specialized processing subtilisin-like endopeptidases coupled with carboxypeptidase B-like exopeptidases. Most neuroendocrine peptides are processed by two specialized members of this family – PC2 and/or PC1/3 – followed by carboxypeptidase E (CPE). This brief report concentrates mainly on the role of insulin biosynthesis in providing a useful early paradigm of precursor processing in the secretory pathway.
Member of the National Academy of Science (USA) and Laureate of the Wolf Prize in Medicine, 1985.
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Acknowledgments
I am indebted to many students, postdocs, and colleagues who have contributed to the work from my laboratory discussed in this review. In particular, I would like to mention Philip Oyer, Jeffrey Clark, Wolfgang Kemmler, Dennis Cunningham, Hiroyuki Sando, Franco Melani, Arthur Rubenstein, Simon Pilkis, Howard Tager, James Peterson, Shu ** Chan, Susan Terris, Sooja Cho Nehrlich, Ray Carroll, Ole Madsen, Sture Falkmer, Stefan Emdin, Christoph Patzelt, Åke Lernmark, Cecelia Hoffman, Jon Marsh, Masakazu Haneda, Simon Kwok, Kevin Docherty, John Hutton, David Nielsen, Michael Welsh, Susumu Seino, Kishio Nanjo, Steve Smeekens, Graeme Bell, Kenneth Polonsky, Steve Duguay, Motoshige Miyano, Masahiro Nishi, Shinya Ohagi, Machi Furuta, Shinya Nagamatsu, Yasunao Yoshimasa, Jonathan Whittaker, Tadashi Hanabusa, Hisako Ohgawara, Yves Rouille, Jeremy Paul, Mohammad Pashmforoush, Louis Philipson, Grigory Lipkind, Sean Martin, Tony Oliva, An Zhou, Gene Webb, Joe Bass, **aorong Zhu, Takeshi Kurose, Arunangsu Dey, Jie Wang, Iris Lindberg, Per Westermark, Soo Young Park, and Gunilla Westermark. Work from my laboratory has been supported by NIH grants DK13914 and DK20595 and by the Howard Hughes Medical Institute.
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Steiner, D.F. (2011). On the Discovery of Precursor Processing. In: Mbikay, M., Seidah, N. (eds) Proprotein Convertases. Methods in Molecular Biology, vol 768. Humana Press. https://doi.org/10.1007/978-1-61779-204-5_1
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