Dipeptide cleavage

It can be seen that the ease with which a peptide bond can be cleaved depends greatly on the character of the partners concerned (i.e., on the amino acid residues R). If dipeptide cleavage occurs at different rates, it can be assumed that the formation of the peptide bonds also occurs at different rates. 

Dipeptide cleavage. The C-N bond scission is selective to glycine moieties. ... 

The principal pathway for the decomposition of aspartame begins with the cleavage of the ester bond, which may or may not be accompanied by cyclization (Eig. 2). The resultant diketopipera2ine and/or dipeptide can be further hydroly2ed into individual amino acids (qv). 

Figure 42-12. Structure of human proinsulin. Insulin and C-peptide molecules are connected at two sites by dipeptide links. An initial cleavage by a trypsin-like enzyme (open arrows) followed by several cleavages by a car-boxypeptidase-like enzyme (solid arrows) results in the production of the heterodimeric (AB) insulin molecule (light blue) and the C-peptide.

Dipeptides and longer peptides are typically synthesized by solid-phase chemistry at polymer beads, a route discovered by and named after Merrifield [5, 88]. Disadvantages of this approach are that the polymer support is expensive and additional steps for linkage to and cleavage from the polymer are required. Hence solution chemistries are an alternative to the Merrifield approach. 

OS 24] [R 5] [P 16/Dmab-y0-alanineand Emoc-yS-alanine were reacted to give a dipeptide [5], After cleavage of the Emoc function, Emoc-yS-alanine was added to such a dipeptide resulting in tripeptide formation with 30% yield [5]. 

If prebiotic peptides and/or proteins were in fact initially formed in aqueous solution (the hypothesis of biogenesis in the primeval ocean ), the energy problems referred to above would have needed to be solved in order for peptide synthesis to occur. As discussed in Sect. 5.3, there is some initial experimental evidence indicating that the formation of peptide bonds in aqueous media is possible. An important criterion for the evolutionary development of biomolecules is their stability in the aqueous phase. The half-life of a peptide bond in pure water at room temperature is about seven years. The stability of the peptide bond towards cleavage by aggressive compounds was studied by Synge (1945). The following relative hydrolysis rates were determined experimentally, with the relative rate of hydrolysis for the dipeptide Gly-Gly set equal to unity ... 

Fig. 5.2 Peptide synthesis using Leuchs anhydrides amino acid 1 (with residue Ri) is reacted with phosgene to give the Leuchs anhydride. This reacts with amino acid 2 (residue R2) to give the peptide carbamate. The dipeptide is obtained after cleavage of C02...

To decide whether to use Ddz or Trt protection, the following considerations apply In general, Ddz-protected derivatives couple more efficiently that the corresponding Trt derivatives. Thus, Trt-Gly-OH and Trt-Ala-OH couple very well, but more sterically crowded amino acids with Trt protection couple slowly and Ddz is preferred. However, because Ddz removal conditions require a somewhat higher acid concentration, low-level premature cleavage (1-3%) of dipeptide from the resin can occur as a side reaction. 

FIGURE 6.15 Imide formation from a dipeptide sequence containing an aspartyl residue with side-chain functional group in various states followed by generation of two peptide chains resulting from cleavage at the bonds indicated by the dashed arrows. The reaction is catalyzed by base52 or acid. [Merrifield, 1967]. The table shows the effect of the nature of the substituent on the extent of this side reaction. Dmpn = 2,4-dimethylpent-3-yl. 

Bradykinin (Fig. 6.34) is a vasoactive nonapeptide that is hydrolyzed by a variety of peptidases. Its N-terminus is susceptible to cleavage, but only by aminopeptidase P (X-Pro aminopeptidase, EC 3.4.11.9). Dipeptidyl-pepti-dase IV can then cleave the N-terminus dipeptide of bradykinin-(2-9). However, most cleavage reactions have been found to occur at or close to the C-terminus, with angiotensin-converting enzyme (ACE, peptidyl-dipeptidase A, EC 3.4.15.1) playing an important role. In fact, aminopeptidase P and ACE accounted for ca. 30 and 70%, respectively, of total bradykininase activity in the isolated perfused rat heart [164], As shown in Fig. 6.34, ACE... 

Aziridine cleavage based on an Sn2 reaction was used for the synthesis of peptides bearing E alkene dipeptide isosteres, a novel class of potent bombesin receptor antagonists [62]. Treatment of the vinylaziridine 86 (Scheme 9.19) with isobutyl and isopentyl magnesiocyanocuprates in THF at —78 °C for 30 min. stereospecifi-cally gave the desired E alkene isosteres 87 in high isolated yields [63]. 

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