Peptides, bonds hormones

Mammals, fungi, and higher plants produce a family of proteolytic enzymes known as aspartic proteases. These enzymes are active at acidic (or sometimes neutral) pH, and each possesses two aspartic acid residues at the active site. Aspartic proteases carry out a variety of functions (Table 16.3), including digestion pepsin and ehymosin), lysosomal protein degradation eathepsin D and E), and regulation of blood pressure renin is an aspartic protease involved in the production of an otensin, a hormone that stimulates smooth muscle contraction and reduces excretion of salts and fluid). The aspartic proteases display a variety of substrate specificities, but normally they are most active in the cleavage of peptide bonds between two hydrophobic amino acid residues. The preferred substrates of pepsin, for example, contain aromatic residues on both sides of the peptide bond to be cleaved. 

An exopeptidase that does not cleave standard peptide bonds. An example is pyroglutamyl-peptidase I (MEROPS C15.010), which releases an N-terminal pyroglutamyl from hormones such as thyrotropinreleasing hormone and luteinizing hormone. Omega peptidases are included in Enzyme Nomenclature subsubclass 3.4.19. 

In mammals, peptide hormones typically contain only the a-amino acids of proteins finked by standard peptide bonds. Other peptides may, however, contain nonprotein amino acids, derivatives of the protein amino acids, or amino acids finked by an atypical peptide bond. For example, the amino terminal glutamate of glutathione, which participates in protein folding and in the metabolism of xenobiotics (Chapter 53), is finked to cysteine by a non-a peptide bond (Figure 3—3). The amino terminal glutamate of thyrotropin-... 

Figure 10.10 Amino acid sequence of human adrenocorticotrophin. The amino acid residues in this polypeptide hormone are linked by peptide bonds and each residue is given a number starting with the N-terminal residue (number 1) to the C-terminal residue (number 39).

The amino group of the N-terminal amino acid residue of a peptide will react with the FDNB reagent to form the characteristic yellow DNP derivative, which may be released from the peptide by either acid or enzymic hydrolysis of the peptide bond and subsequently identified. This is of historic interest because Dr F. Sanger first used this reaction in his work on the determination of the primary structure of the polypeptide hormone insulin and the reagent is often referred to as Sanger s reagent. 

N-Terminal Glp Ring opening of Glp and cleavage of Glp peptide bonds Luteinizing hormone releasing hormone (Fig. 6.16) Glp-Phe-Leu-Phe-Arg-Pro-Arg, Glp-Leu-Gly-Pro, Glp-His-Pro, and Glp-His Thyrotropin-releasing hormone (Fig. 6.21)... 

Ser-Xaa or Thr-Xaa Hydrolysis of peptide bonds Luteinizing hormone releasing... 

K. Ohki, N. Sakura, T. Hashimoto, Hydrolytic Cleavage of Pyroglutamyl-Peptide Bond. IV. Highly Selective Cleavage of Thyrotropin-Releasing Hormone (TRH) in Aqueous Methanesulfonic Acid , Chem. Pharm. Bull. 1997, 45, 194-197. 

Y. Nabuchi, E. Fujiwara, H. Kuboniwa, Y. Asoh, H. Ushio, The Stability and Degradation Pathway of Recombinant Human Parathyroid Hormone Deamidation of Asparaginyl Residue and Peptide Bond Cleavage at Aspartyl and Asparaginyl Residues , Pharm. Res. 1997, 14, 1685-1690. 

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. 

An alternative to the synthesis of proteins by classical fragment synthesis in solution or by solid-phase synthesis on a support is the use of enzyme-catalyzed condensation of amino acids or peptides. This possibility was first demonstrated in 1938 91 with the synthesis of poorly soluble benzoyl-leucyl-leucine anilide by papain catalysis. After many years, this approach was extended to the preparation of peptide hormones such as Leu-enkephalin 92 and dynorphin(l -8).[93 This was made possible by the use of highly purified enzymes and by careful control of reaction conditions. The basic principles of protease-catalyzed peptide bond formation have been discussed.194 ... 

The retro-peptide bond is a true isosteric peptide bond surrogate and as such may offer an important tool to study topics such as the functional role of the peptide backbone in peptide hormone-receptor interactions, and modulation of metabolic stability and bioavailability. Partially modified retro-inverso-peptides (PMRI-peptides) (e.g., 2-4, 7 Scheme 1) result from a retro-inverso transformation of one or several peptide bonds in an amino- and carboxy-free peptide (e.g., 5 Scheme 1). Evidently, partial or exhaustive retro-inverso transformations result in the introduction of two non-amino acid residues into the... 

Table V summarizes experiments on the preferential cleavage of aspartyl peptide bonds by the action of 4.5% acetic acid. Such a method is desirable for the rapid assay of species differences in simple peptide hormones, such as the melanocyte-stimulating hormones (/3-MSH) of porcine, bovine, or human origin. There the species difference is located after the...

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