Amide groups, peptide hormones

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... 

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. 

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... 

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. 

Quite a few peptide hormones have an amino acid amide rather than a free carboxyl group at their C-termini. Such peptide amides can be secured by ammonolysis of the... 

The serine proteases cleave amide (peptide) bonds in peptides and have a wide variety of functions, including food digestion, blood clotting, and hormone production. They feature as one of the best-understood groups of enzymes as far as mechanism of action is concerned. We are able to ascribe a function to many of the amino acid residues in the active site, and we also understand how they determine the specificity of the various enzymes in the group. 

Major hydrolysis reactions are ester and amide hydrolysis. These are catalyzed by a group of enzymes with overlapping substrate specificity and activity. Hydrazides can also undergo hydrolysis. Some of the newer drugs such as hormones, growth factors, and cytokines now being produced are peptides, and certain toxins are also peptides or proteins, so the role of peptidases may be important. 

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