Human insulin structure

Fig.l. Insulin. Primary structure of sheep insulin. Human (H) and bovine (B) insulin differ from sheep insulin in the sequence region A8 to 10 in addition, in human insulin, the C-terminal alanine of the B-chain is replaced by threonine. 

The treatment of type 1 diabetes is the subcutaneous injection of insulin, as insulin cannot be administered orally because it would be broken down in the stomach due to the low pH. Initially, animal insulin was used in the treatment of diabetes, since bovine and porcine insulin are structurally similar to human insulin. Nowadays, most of the insulin used in the treatment of diabetes is human insulin produced via recombinant DNA (see Ch. 27). There are a number of insulin formulations available, e.g. short-, intermediate- or long-acting and biphasic (a mixture short- and intermediate-acting insulin), and these are described in more detail in Chapter 27. There is a range of therapy protocols indicated, based on the individual condition of the patient. 

Sanger also determined the sequence of the A chain and identified the cysteine residues involved in disulfide bonds between the A and B chains as well as in the disulfide linkage within the A chain. The complete insulin structure is shown in Figure 27.11. The structure shown is that of bovine insulin (from cattle). The A chains of human insulin and bovine insulin differ in only two amino acid residues then B chains are identical except for the amino acid at the C terminus. 

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. 

Look up the structure of human insulin (Section 26.7), and indicate w here in each chain the molecule is cleaved by trypsin and chymotrypsin. 

Human and horse insulin both have two polypeptide chains, with one chain containing 21 amino acids and the other containing30 amino acids. They differ in primary structure at two places. At position 9 in one chain, human insulin has Ser and horse insulin has Gly at position 30 in the other chain, human insulin has Thr and horse insulin has Ala. How must the DNA for the two insulins differ ... 

Antidiabetic Drugs other than Insulin. Figure 8 Structure of human amylin and its soluble analogue pramlintide. 

Human insulin is derived from a biosynthetic process using strains of Escherichia coli (recombinant DNA, rDNA). Human insulin appears to cause fewer allergic reactions than does insulin obtained from animal sources. Insulin analogy, insulin lispro, and insulin aspart are newer forms of human insulin made by using recombinant DNA technology and are structurally similar to human insulin. 

Figure 42-12. Structure of human proinsulin. Insulin and C-peptide molecules are connected at two sites by dipeptide links. An initial cleavage by a trypsin-like enzyme (open arrows) followed by several cleavages by a car-boxypeptidase-like enzyme (solid arrows) results in the production of the heterodimeric (AB) insulin molecule (light blue) and the C-peptide.

Many of the initial biopharmaceuticals approved were simple replacement proteins (e.g. blood factors and human insulin). The ability to alter the amino acid sequence of a protein logically coupled to an increased understanding of the relationship between protein structure and function (Chapters 2 and 3) has facilitated the more recent introduction of several engineered therapeutic proteins (Table 1.3). Thus far, the vast majority of approved recombinant proteins have been produced in the bacterium E. coli, the yeast S. cerevisiae or in animal cell lines (most notably Chinese hamster ovary (CHO) cells or baby hamster kidney (BHK) cells. These production systems are discussed in Chapter 5. 

Mature insulin consists of two polypeptide chains connected by two interchain disulfide linkages. The A-chain contains 21 amino acids, whereas the larger B-chain is composed of 30 residues. Insulins from various species conform to this basic structure, while varying slightly in their amino acid sequence. Porcine insulin (5777 Da) varies from the human form (5807 Da) by a single amino acid, whereas bovine insulin (5733 Da) differs by three residues. 

A vast number of hormones and neurotransmitters are synthesized from simple structural units including chains of amino acids. Among the amino acid based hormones are comparatively large protein molecules such as prolactin, growth hormone and insulin, and shorter chains of amino acids which may form peptide hormones, such as oxytocin and vasopressin. Protein based hormones are essential for metabolism, growth and some components of reproduction. However, evidence for specific influences of these compounds on human behavior is limited. 

Before we take leave of primary structures for proteins, there is one last, important realization. Proteins serving the same function in different species may have different primary structures. For example, the primary structures of bovine, ovine, and human insulins are not quite the same. They are closely related but not identical. Different species have discovered different protein solutions for the same biological problem. 

Generai This human insulin product differs from animal-source insulins because it is structurally identical to the insulin produced by the body s pancreas and because of its unique manufacturing process. 

Many of the initial biopharmaceuticals approved were simple replacement proteins (e.g. blood factors and human insulin). The ability to logically alter the amino acid sequence of a protein, coupled to an increased understanding of the relationship between protein structure and function has facilitated the more recent introduction of several engineered therapeutic... 

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