Insulin

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One of the major triumphs of the 20th century occurred in 1922, when Banting and Best34 extracted insulin from dog pancreas. Advances in the biochemistry of insulin have been reviewed with emphasis on proinsulin biosynthesis, conversion of proinsulin to insulin, insulin secretion, insulin receptors, metabolism, effects by sulfonylureas, and so on.35-38

Insulin is synthesized by the islet jS-cells from a single-chain, 86-amino-acid polypeptide precursor, proinsulin.39 Proinsulin itself is synthesized in the polyribosomes of the rough endoplasmic reticulum of the jS-cells from an even larger polypeptide precursor, preproinsulin. The B chain of preproinsulin is extended at the NH2-terminus by at least 23 amino acids. Proinsulin then traverses the Golgi appara tus and enters the storage granules, where the conversion to insulin occurs.

The subsequent proteolytic conversion of proinsulin to insulin is accomplished by the removal of the Arg-Arg residue at positions 31 and 32 and the Arg-Lys residue at positions 64 and 65 by an endopeptidase that resembles trypsin in its specificity and a thiol-activated carboxypeptidase B-like enzyme.40

The actions of these proteolytic enzymes on proinsulin result in the formation of equimolar quantities of insulin and the connecting C-peptide. The resulting insulin molecule consists of chains A and B, with 21 and 31 amino acid residues, respectively. The chains are connected by two disulfide linkages, with an additional disulfide linkage within chain A (Fig. 27.6).

The three-dimensional structure of insulin was determined by x-ray analysis of single crystals. These studies demonstrated that the high bioactivity of insulin depends on the integrity of the overall conformation. The biologically active form of the hormone is thought to be the monomer. The receptor-binding region consists of A-1 Gly, A-4 Glu, A-5 Gln, A-19 Tyr, A-21 Asn, B-12 Val, B-16 Tyr, B-24 Phe, and B-26 Tyr. The three-dimensional crystal structure appears to be conserved in solution and during its receptor interaction.

The amino acid sequence of insulins from various animal species has been examined.35 Details of these are shown in

Figure 27.6 • Conversion of proinsulin to insulin.

Figure 27.6 • Conversion of proinsulin to insulin.

TABLE 27.6 Some Sequence Differences in Insulins of Various Species

Species

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