Insulin, disulfide bridges structure

These steps can be repeated to add one amino acid at a time to the growing chain or to link two peptide chains together. Many remarkable achievements in peptide synthesis have been reported, including a complete synthesis of human insulin. Insulin is composed of two chains totaling 51 amino acids linked by two disulfide bridges. Its structure was determined by Frederick Sanger, who received the 1958 Nobel Prize in chemistry for his work. 

F ig U re 10.2 The primary structure of bovine insulin. This molecule possesses two polypeptide chains, labeled A and B. These are joined by two disulfide bridges between Cys amino acid residues. There is a third disulfide bridge linking two Cys residues in the A chain. 

Figure 7-17 The structure of insulin. (A) The amino acid sequence of the A and B chains linked by disulfide bridges. (B) Sketch showing the backbone structure of the insulin molecule as revealed by X-ray analysis. The A and B chains have been labeled. Positions and orientations of aromatic side chains are also shown. (C) View of the paired N-terminal ends of the B chains in the insulin dimer. View is approximately down the pseudo-twofold axis toward the center of the hexamer. (D) Schematic drawing showing packing of six insulin molecules in the zinc-stabilized hexamer.

Figure 24-10 shows the structure of insulin, a more complex peptide hormone that regulates glucose metabolism. Insulin is composed of two separate peptide chains, the A chain, containing 21 amino acid residues, and the B chain, containing 30. The A and B chains are joined at two positions by disulfide bridges, and the A chain has an additional disulfide bond that holds six amino acid residues in a ring. The C-terminal amino acids of both chains occur as primary amides. 

Structure of insulin. Two chains are joined at two positions by disulfide bridges, and a third disulfide bond holds the A chain in a ring. 

The structure of the hormone insulin (many diabetics lack this hormone and must inject themselves with it daily) was deduced in the 1950s by Sanger. It has two peptide chains, one of 21 amino acids and one of 30, linked by three disulfide bridges—just like the links in oxidized glutathione. This is a very small protein. 

Figure 6.1-1. The x-ray crystal structure of a human insulin homodimer (A/B/C/D) at 1.5-A resolution (PDB ID IZEH). Each component of the dimer is composed of a smaller chain (A/C of 21 residues) linked by disulfide bridges to a larger chain (B/D of 30 residues).

The sulfur atom binds readily to heavy meted ions. Under oxidizing conditions, two cysteines can join together in a disulfide bond to form the amino acid cystine. When cystines are part of a protein, insulin for example, this stabiUzes tertiary structure and makes the protein more resistant to denaturation disulfide bridges are therefore common in proteins that have to function in harsh environments including digestive enzymes (e.g., pepsin and chymotrypsin) and structural proteins (e.g., keratin). Disulfides are also found in peptides too small to hold a stable shape on their own (e.g., insulin). 

The primary structures of IGF-I and IGF-II were determined by Rinderknecht and Humbel (1978) and were shown to have 49 and 47% homology, respectively, with human insulin A and B chains (Table I). Both molecules are single-chain polypeptides with three disulfide bridges corresponding to the B chain and an extended A chain of insulin plus a C peptide of 12 or 8 residues. From the known crystal structure of insulin it has been possible to postulate three-dimensional structures for both IGF-I and IGF-II (Blundell et al, 1978). The proposed conformation of IGF-I (Fig. 5) allows an arrange-... 

Disulfide bridges As in the structure of insulin (Figure 9.5), a disulfide linkage can form between two cysteine residues that are close to each other in the same chain or between cysteine residues in different chains. The existence and location of these... 

Probably the most important achievement in insulin research was the determination of its primary structure by Frederick Sanger and his associates in Cambridge, England. In order to elucidate the amino acid sequence of the hormone it was necessary to separate the two chains constituting the molecule. This was accomplished by oxidation with performic acid. This operation cleaved the three disulfide bridges by converting each cystine to two cysteic acid residues ... 

Figure 3.9. A Steps in the conversion of the gene product for insulin from preproinsulin to active (mature) insulin. B Space-filling representation of the active insulin molecule, as obtained from the crystal structure. C The ribbon model of active insulin showing the helical and extended regions of the A and B chains and the disulfide bridges that hold the A and B chains together after removal of the C peptide. (Reproduced with permission from Lehninger, Nelson, and Cox, Principles of Biochemistry, Second Edition, Worth Publishers.)...

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