Amide bond hydrolysis

A major advance was devised by Pehr Edman (University of Lund Sweden) that has become the standard method for N terminal residue analysis The Edman degrada tion IS based on the chemistry shown m Figure 27 12 A peptide reacts with phenyl iso thiocyanate to give a phenylthwcarbamoyl (PTC) denvative as shown m the first step This PTC derivative is then treated with an acid m an anhydrous medium (Edman used mtromethane saturated with hydrogen chloride) to cleave the amide bond between the N terminal ammo acid and the remainder of the peptide No other peptide bonds are cleaved m this step as amide bond hydrolysis requires water When the PTC derivative IS treated with acid m an anhydrous medium the sulfur atom of the C=S unit acts as... 

Fig. 3.2. Common catalytic groups of hydrolases involved in ester and amide bond hydrolysis (Z+ = electrophilic component polarizing the carbonyl group Y = nucleophilic group attacking the carbonyl C-atom H-B = proton donor transforming the -OR or -NR R" moiety into...

Affinity labeling ATP sites, 194-96 creatine kinase, 200-205 Amastatin, 94-96 Amide bond hydrolysis, 227 Amino acid sequences, renin inhibitors, 139,141f D-Amlno acids and activity,... 

In succinyl derivatives, the freely rotating single bond between carbon 2 and 3 allows the terminal carboxyl group to assume many more orientations and as a result this drastically reduces the probability that it will stay in the proper conformation long enough for deacylation to occur. Kirby et al. (46) proposed an intramolecular catalysis of amide bond hydrolysis by a proton transfer from external general acids and also showed that in dilute acid the O-protonated amide is the reactive species that initiates the deacylation process (see Reaction 3). 

Cyclization is one of the earliest techniques applied to design peptidomimetics. Cyclic peptides are more stable to amide bond hydrolysis and allow less conformational flexibility consequently, the resulting analogs are anticipated to be more selective and less toxic. Methods for restricting conformations include peptide backbone cyclization, disulfide bond formation, side-chain cyclization, and metal ion chelation. 

Sulfonamidopeptides can be considered as interesting candidates to find new protease inhibitors and new drugs, since the structure of the sulfonamide bond is similar to the tetrahedral transition state involved in the amide bond hydrolysis by proteolytic enzymes [33]. In the field of sulfonamide-containing peptidomimetics, several scaffolds have been proposed (Fig. 7.5). While the preparation of a-sulfonopeptides 5 has remained elusive [34,35], probably due to synthetic problems, such as p-elimination of S02, the other two types of oligomers turned out to be easily obtained. 

Another example where aggregation of a library member drives its synthesis was recently reported by Ulijn ct al. [24, 25]. They used reversible amide bond formation, mediated by thermolysin, which is an enzyme that can catalyze both amide bond hydrolysis and formation, and is only moderately peptide-sequence-dependent. The authors reported that starting from dipeptides and fluorenyl-protected amino acids, the action of thermolysin gives rise to a dynamic mixture of peptides of different lengths (containing typically one to five amino acid residues). When using phenylalanine or leucine as the starting amino acids the... 

This model is applicable to amide bond hydrolysis by proteases and it would be surprising if enzyme hydrolyses do not obey this principle. 

The human genome contains 18 HDACs that are classified according to their catalytic mechanism. The focus of this chapter is the eleven zinc-dependent HDACs 1-11, which contain a zinc cation as the active site catalyst. In addition, there are seven sirtuins, SIRTs 1-7, which instead employ the cofactor NAD for amide bond hydrolysis. The zinc-dependent HDACs are further subdivided into elass I (HDACs 1, 2, 3 and 8), class Ila (HDACs 4, 5, 7 and 9), class Ilb (HDACs 6 and 10) and class IV (HDAC 11) based on sequence homology and cellular loealization. The class I HDACs are ubiquitously expressed and primarily located in the cell nucleus, where... 

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