Peptides cleaving

Whereas acid catalyzed hydrolysis of peptides cleaves amide bonds indiscriminately and eventually breaks all of them enzymatic hydrolysis is much more selective and is the method used to convert a peptide into smaller fragments... 

To this list of protein misfolding diseases can be added rare familial amyloidoses in which the mutated proteins have the classic amyloid fibril congophilic birefringence and cross-(3-sheet structure (Table 3). Many of these deposits have an impact on the central nervous system (TTR, cystatin, lysozyme) as well as on other organ systems. A newly described disease, familial British dementia, is associated with the deposition of Abri, a 34 amino acid, 4 kDa peptide cleaved from a 277 amino acid precursor sequence, the last 10 amino acids of which are not normally translated [52]. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is... 

The identification of the morphine receptor spurred an effort in many laboratories to find an endogenous agonist for which that receptor was normally intended. Ultimately, a pair of pentapeptides that bound quite tightly to opiate receptors were isolated from mammalian brains. These peptides, called enkephalins (2, 3), show many of the activities of synthetic opiates in isolated organ systems. They do in fact show analgesic activity when injected directly into the brain. It is thought that lack of activity by other routes of administration is due to their rapid inactivation by peptide cleaving enzymes. 

The enzymatic methods are most promising, but on the other hand chemical methods are relatively independent of tertiary stmcture of the cleavage site and have technical scale-up advantages. Chemical methods are therefore very well suited for production of bioactive peptides cleaved off from a fusion protein. 

Atrial natriuretic peptide (ANP) Several active peptides cleaved from precursor polypeptide of 126 residues Smooth muscle relaxation diuretic activity... 

Major classes of peptide-cleaving enzymes Section 9.1.6... 

Cysteine, Aspartyl, and Meta Hop ro teases Are Other Major Classes of Peptide-Cleaving Enzymes... 

The metalloproteases constitute the final major class of peptide-cleaving enzymes. The active site of such a protein contains a bound metal ion, almost always zinc, that activates a water molecule to act as a nucleophile to attack the peptide carbonyl group. The bacterial enzyme thermolysin and the digestive enzyme carboxypeptidase A are classic examples of the zinc proteases. Thermolysin, but not carboxypeptidase A, is a member of a large and diverse family of homologous zinc proteases that includes the matrix metalloproteases, enzymes that catalyze the reactions in tissue remodeling and degradation. 

A peptide (73 residues) which has chymotrypsin-like esterase activity has been designed and synthesized by Hahn et al. (1990). The peptide consists of a bundle of four short helical sequences, and the catalytic residues were synthesized at the amino end of the bundle in spatial relationships similar to chymotrypsin. Also, the oxyanion hole and substrate binding pocket for acetyltyrosine ethyl ester, a chymotrypsin substrate, have been included in the design, the peptide cleaves this ester at a rate that is 1/100 of the chymotrypsin rate. It is also inhibited by chymotrypsin inhibitors. 

This study reported the first peptide-cleaving catalyst selective for a protein related to a disease. Moreover, mechanistic analysis of the protein cleavage was performed for the first time owing to the moderate size (MW of ligand of CF = 644 where MW = molecular weight) of the catalyst. 

Results of this study indicate that the concept of the peptide-cleaving catalysts can be expanded to include oligopeptides as the targets and nonhy-drolytic reactions as the means for cleavage. 

PAC/HMPP supports (see Section V) with disuccinimidyl carbonate (DSC) and used to anchor amino acids as carbamates [106]. After further chain elongations using the Fmoc strategy, lactamization reactions were conducted on resin and the resulting cyclic peptides cleaved by treatment with TFA in the presence of cation scavengers. 

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