Peptide hormone amidation

A number of peptide hormones have a carboxyl terminal amide which is derived from a glycine terminal residue. This glycine is hydroxylated on the a-carbon by a copper-containing enzyme, peptidylglycine hydroxylase, which, again, requires ascorbate for reduction of Cu ". ... 

Peptides make up the largest group among the neurosecretions. Many peptide hormones—e.g., thyroliberin (TRH) and angiotensin 11—simultaneously act as transmitters. Most neuropeptides are small (3-15 AA). At their N-terminus, many of them have a glutamate residue that has been cyclized to form pyroglutamate (5-oxoproline, [Pg.352]

A pyroglutamyl N terminus is found in the thyrotropin-releasing hormone (Fig. 2-4) and in many other peptide hormones and proteins. It presumably arises by attack of the a-NH2 group of an N-terminal glutamine on the side chain amide group with release of NH3 (Eq. 10-10).111 112... 

Another frequent modification at the C terminus of peptide hormones and of other proteins is amidation. In this reaction a C-terminal glycine is oxidatively removed as glyoxylate in an 02-, copper- and ascorbate... 

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. 

More than half of the peptide hormones undergo postsynthetic modification to form a carboxy terminal amide, which is essential for biological activity. One function of this amidation is to render the peptides more hydrophobic and enhance receptor binding. The amide group is derived from a glycine residue that is to the carboxyl side of the amino acid which will become the amidated terminal of the mature peptide. 

Many neuropeptides and peptide hormones are posttrans-lationally modified by C-terminal amidation, in which a... 

The replacement of amide bonds by retro-in-verso amide replacements (71, 72) and other amide bond isosteres generates pseudopeptides (11). This process was first used to stabilize peptide hormones in vivo and later to prepare transition state analog (TSA) inhibitors. Systematic efforts to convert good in vitro inhibitors into good in vivo inhibitors became the driving force for further development of peptidomimetics. Figure 15.17 illustrates some of the peptide backbone modifications that have been made in an effort to increase bioavailability. Replacement of scissile amide (CONH) bonds with groups insensitive to hydrolysis (e.g., CHaNH) has been extensively practiced. Reviews of this work have appeared (11,73). Removal of the proton donors and... 

The pituitary gland is involved in feedback regulation of thyroid activity High levels of T4 in the bloodstream result in inhibition of TSH secretion. Low levels of T4 result in an increase in TSH secretion. These effects are dependent on the conversion of T4 to T3 within the pituitary, fhe activity of the pituitary is controlled by thyrotropin-releasing hormone (TRH), a hormone synthesized in the hypothalamus. TRH is a tripeptide with the structure pyroglutamate-histidine-proline-NH . Note the C-terminal amide group, which is required for the activity of many peptide hormones. TRH stimulates the synthesis and secretion of TSH. Apparently TRH is involved in regulating the sensitivity of the pituitary to the inhibitory feedback control mechanism mentioned earlier. 

When faced with a set of flexible molecules with too large a number of variables, one must turn to chemical modification to reduce the number of variables to a managable set. In the case of peptide hormones, introduction of proline eliminates the torsional degree of freedom < > by introducing a cyclic constraint, but adds the necessity of considering both cis and trans isomers of the amide bond. Replacement of the a-proton of an amino acid by a methyl group has been shown to reduce the number of possible combinations of values for the <(> and i > torsional rotation to essentially two (25). Introduction of a cyclic constraint in a linear flexible molecule reduces the... 

Bradykinin This peptide hormone has a relative molecular mass of 1059.578 0.021 Da for [M + H]+. After 3min of hydrolysis, the same [M + H]+ ion was present, indicating that Asn, Gin and terminal amide are all absent from the peptide, since ammonia would have been released and that, since a peak 18 atomic mass units higher was not created by hydrolysis (M plus H20), it is not a cyclic peptide. 

Peptidylglycine mono-oxygenase Required for removal for carboxy terminal residue and a-amidation Processing and maturation of neuroendocrine and gastro-intestinal peptide hormones. 

The C terminus is often an amide of the carboxyl group with ammonia, which usually arises from a peptide chain containing one additional glycine residue at the C terminus (Eq. 10-11). The processing of peptide hormones doesn t end with their S5mthesis. They are usually degraded quickly or are converted into derivatives with weaker hormonal activity. 

Bradykinin, vasopressin, and oxytocin are peptide hormones. They are all nonapeptides. Bradykinin inhibits the inflammation of tissues. Vasopressin controls blood pressure by regulating the contraction of smooth muscle. It is also an antidiuretic. Oxytocin induces labor in pregnant women and stimulates milk production in nursing mothers. Vasopressin and oxytocin both have an intrachain disulfide bond, and their C-terminal amino acids contain amide rather than carboxyl groups. Notice that the C-terminal amide group is indicated by writing NH2 after the name of the C-terminal amino acid. In spite of their very different physiological effects, vasopressin and oxytocin differ only by two amino acids. 

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