Cyclization of -glutamic acid

Correspondingly, the use of other anhydrides of aliphatic acids provides the appropriate 2-acyl derivatives. Cyclization of glutamic acid dipeptides... 

Cyclization reactions of glutamic acid analogous to those of aspartic acid have not been found in sequence studies with peptides, but an a — 7 interconversion in model peptides of glutamic acid has been observed (Kornguth el al., 1963). 

Cyclization of aspartic acid and asparagine to form aspartimides, and to a lesser extent of glutamic acid and glutamine to form glutarimide is an acid- and base-catalyzed common side reaction in peptide synthesis (see also Section 2.2.2). In SPPS it is particularly troublesome when Asp-Gly, Asp-Ala, and Asp-Ser sequences are present,but also with Asp-Asn.P P Piperidine-catalyzed aspartimide formation can be very rapid,and in this context DBU is even worse than piperidine.P The formation of aspartimide is reduced by the addition of HOBt or 2,4-dinitrophenol, but more efficiently it is reduced by protecting the aspartyl amide bond with the 2-hydroxy-4-methoxybenzyl (Hmb) group (see Section 2.3.2).P 1... 

The biosynthesis of proline has been elucidated with the aid of strains of E. coU which are specifically auxotrophic for proline. These strains fall into two groups those which accumulate glutamic y-semialdehyde and those in which this substance can replace glutamic acid as a growth factor. The reduction of glutamic acid to the semialdehyde is no doubt not so simple as is indicated by the arrow in the scheme set out below. The cyclization of proline would not require enzymic aid since y and S-amino-aldehydes cyclize rapidly in neutral aqueous solution. 

Since the proline residue in peptides facilitates the cyclization, 3 sublibraries each containing 324 compounds were prepared with proline in each randomized position. Resolutions of 1.05 and 2.06 were observed for the CE separation of racemic DNP-glutamic acid using peptides with proline located on the first and second random position, while the peptide mixture with proline preceding the (i-alamine residue did not exhibit any enantioselectivity. Since the c(Arg-Lys-0-Pro-0-(i-Ala) library afforded the best separation, the next deconvolution was aimed at defining the best amino acid at position 3. A rigorous deconvolution process would have required the preparation of 18 libraries with each amino acid residue at this position. 

In subsequent experiments (66), this locked substrate was used to obtain evidence for the hypothesis (67) that enzyme-bound y-glutamyl phosphate 14 is an intermediate in the enzyme-catalyzed reaction. All attempts to isolate this acyl phosphate 14 have failed (66), presumably because of the marked tendency of this intermediate to cyclize to pyrrolidonecarboxyUc acid, 15, and to hydrolyze to glutamic acid. 

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