Chapter 6 Biosynthesis of Insulin and Glucagon

Publisher Summary This chapter discusses the biosynthesis of the islet cell hormones insulin and glucagon. It was widely believed that insulin was formed by the combination of separately synthesized A and B chains. The discovery of pro-insulin disproved this hypothesis, and it is now known that a connecting peptide attaches the COOH terminus of the B chain to the NH 2 terminus of the A chain in the single-chain precursor. The C peptide connects the two insulin chains by pairs of dibasic amino acid residues (Lys–Arg and Arg–Arg at the A and B chains, respectively) and forms a bridge between the two portions of the insulin molecule. Studies on the translation of insulin messenger ribonucleic acid (mRNA) extracted from rat islets in cell-free systems have shown that the product is not pro-insulin but is a larger peptide that bears a 24-residue, NH 2 -terminal extension on the prohormone sequence. This molecule, called “preproinsulin,” has also been identified during the cell-free translation of insulin mRNA from cattle, anglerfish, sea raven, hagfish, and humans. An early indication of proglucagon structure arose from an examination of crystalline glucagon for higher molecular weight, hormone-related peptides. Because the COOH-terminal sequence is connected to the hormone structure by a pair of dibasic amino acid residues (Lys–Arg), both trypsin- and carboxypeptidase B-like enzymes would be necessary to convert this proglucagon fragment to glucagon. The use of trypsin and carboxypeptidase B digestions to probe the structures of glucagon-related peptides is discussed in the chapter.