The ABC of Insulin: The Organic Chemistry of a Small Protein
Mads Østergaard, Narendra Kumar Mishra, Knud J. Jensen
Abstract
Abstract Insulin is a small protein crucial for regulating the blood glucose level in all animals. Since 1922 it has been used for the treatment of patients with diabetes. Despite consisting of just 51 amino acids, insulin contains 17 of the proteinogenic amino acids, A‐ and B‐chains, three disulfide bridges, and it folds with 3 α‐helices and a short β‐sheet segment. Insulin associates into dimers and further into hexamers with stabilization by Zn 2+ and phenolic ligands. Selective chemical modification of proteins is at the forefront of developments in chemical biology and biopharmaceuticals. Insulin's structure has made it amenable to organic and inorganic chemical reactions. This Review provides a synthetic organic chemistry perspective on this small protein. It gives an overview of key chemical and physico‐chemical aspects of the insulin molecule, with a focus on chemoselective reactions. This includes N‐acylations at the N‐termini or at Lys B29 by pH control, introduction of protecting groups on insulin, binding of metal ions, ligands to control the nano‐scale assembly of insulin, and more.