Amino acid disulfide bonds joining

Since its discovery, isolation, and purification in the early twentieth century, insulin has been administered to diabetic patients exclusively by injection until the recent introduction of inhaled insulin. Insulin possesses certain physiochemical properties that contribute to its limited absorption from the gastrointestinal tract, and requires subcutaneous injection to achieve clinically relevant bioavailability. With a molecular size of 5.7 kDa, insulin is a moderately sized polypeptide composed of two distinct peptide chains designated the A chain (21 amino acid residues) and the B chain (30 amino acid residues) and joined by two disulfide bonds. Like all polypeptides, insulin is a charged molecule that cannot easily penetrate the phospholipid membrane of the epithelial cells that line the nasal cavity. Furthermore, insulin monomers self-associate into hexameric units with a molecular mass greater than 30 kDa, which can further limit its passive absorption. Despite these constraints, successful delivery of insulin via the nasal route has been reported in humans and animals when an absorption enhancer was added to the formulation. 

Insulin is produced in the pancreas by (3 cells in the region called the islets of Langerhans. It is a polypeptide hormone consisting of two chains an A chain with 21 amino acids with an internal disulfide bond, and a B chain with 30 amino acids. There are two disulfide bonds joining these two chains together... 

The primary structure of enzymes is determined by peptide covalent bonds joining each amino acid to the neighboring one, as well as by disulfide bonds joining sulfur atoms in two cysteine radicals. 

Insulin has 51 anino acids, divided between two chains. One of these, the A chain, has 21 amino acids the other, the B chain, has 30. The A and B chains are joined by disulfide bonds between cysteine residues (Cys-Cys). Figure 27.10 shows some of the information that defines the amino acid sequence of the B chain. 

The essential distinction between the approaches used to formulate and evaluate proteins, compared with conventional low molecular weight drugs, lies in the need to maintain several levels of protein structure and the unique chemical and physical properties that these higher-order structures convey. Proteins are condensation polymers of amino acids, joined by peptide bonds. The levels of protein architecture are typically described in terms of the four orders of structure [23,24] depicted in Fig. 2. The primary structure refers to the sequence of amino acids and the location of any disulfide bonds. Secondary structure is derived from the steric relations of amino acid residues that are close to one another. The alpha-helix and beta-pleated sheet are examples of periodic secondary structure. Tertiary... 

Insulin consists of two chains, designated as the A-chain and the B-chain, as shown in the diagram on page 67. The two chains are joined by two disulfide (-S-S-) bonds. The A-chain contains 21 amino acid residues, and the B-chain has 30 amino acid residues. 

Asparagine and glutamine are the amides of two other amino acids also found in proteins, aspartate and glutamate, respectively, to which asparagine and glutamine are easily hydrolyzed by acid or base. Cysteine is readily oxidized to form a covalently linked dimeric amino acid called cystine, in which two cysteine molecules or residues are joined by a disulfide bond (Fig. 3-7). The disulfide-linked residues are strongly hydrophobic (nonpolar). Disulfide bonds play a special role in the structures of many proteins by forming covalent links between parts of a protein molecule or between two different polypeptide chains. 

ANTIBIOTICS PEPTIDES. Peptide antibiotics are classified according to their overall shape, which can be linear or cyclic, and by the nature of the bonds joining the constituent amino acids and other carboxylic acids, which can be all amide bonds or amide plus ester bonds. Most peptide antibiotics are cyclic peptides that do not contain disulfide linkages. 

The linear sequence of amino acids joined together by peptide bonds is termed the primary structure of the protein. The position of covalent disulfide bonds between cysteine residues is also included in the primary structure. 

The primary level of structure in a protein is the linear sequence of amino acids as joined together by peptide bonds. This sequence is determined by the sequence of nucleotide bases in the gene encoding the protein (see Topic HI). Also included under primary structure is the location of any other covalent bonds. These are primarily disulfide bonds between cysteine residues that are adjacent in space but not in the linear amino acid sequence. These covalent cross-links between separate polypeptide chains or between different parts of the same chain are formed by the oxidation of the SH groups on cysteine residues that are juxtaposed in space (Fig. 4). The resulting disulfide is called a cystine residue. Disulfide bonds are often present in extracellular proteins, but are rarely found in intracellular proteins. Some proteins, such as collagen, have covalent cross-links formed between the side-chains of Lys residues (see Topic B5). 

Amide linkages (peptide bonds) form the backbone of the amino acid chains we call peptides and proteins. A second kind of covalent bond is possible between any cysteine residues present. Cysteine residues can form disulfide bridges (also called disulfide linkages) that can join two chains or link a single chain into a ring. 

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. 

Human insulin, a hormone that controls blood sugar levels, is made up of two protein chains. Each of the circles represents an amino acid in the protein chains. Disulfide bonds hold the A and B chains of insulin together. Disulfide bonds also join sections of the A chain together. 

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