Protein imide formation

Deamidation and imide formation can also negatively influence a protein s biological activity. Deamidation refers to the hydrolysis of the side-chain amide group of asparagine and/or... 

Asparagine residues in peptides and proteins undergo deamidation via cyclic imide formation followed by subsequent hydrolysis to form the corresponding aspartic and Ao-aspartic acid peptides. This mechanism occurs primarily under neutral-to-basic pH conditions. Deamidation of an asparagine residue to the corresponding aspartic acid residue may also occur via a mechanism that does not involve cyclic imide formation, as shown in Scheme 80. Glutamine residues also undergo deamidation, but at much slower rates. 

Peptides and proteins having an aspartic acid residue undergo hydrolysis, isomerization, and racemization via cyclic imide formation. As shown in Scheme 80, L-aspartic acid peptide can isomerize to L-iso -aspartic acid peptide via its L-cyclic imide. The L-cyclic imide intermediate is capable of undergoing racemization to the D-cyclic imide and thus forms the D-aspartic acid peptide and the D-Ao-aspartic acid peptide on hydrolysis. 

Isoaspartyl peptide bond, a peptide bond formed via an intramolecular rearrangement of the peptide backbone of peptides and proteins at amide bonds of asparagine (—> aspartimide, /i-aspartylpeptides). Sensitive peptide bonds such as Asp-Gly sequences are often prone to succin-imide formation and concomitant isoaspartyl peptide shift) formation, especially when treated with strong acids such as HF or TFMSA during peptide synthesis operations. 

The influence of secondary structure on reactions of deamidation has been confirmed in a number of studies. Thus, deamidation was inversely proportional to the extent of a-helicity in model peptides [120], Similarly, a-hel-ices and /3-turns were found to stabilize asparagine residues against deamidation, whereas the effect of /3-sheets was unclear [114], The tertiary structure of proteins is also a major determinant of chemical stability, in particular against deamidation [121], on the basis of several factors such as the stabilization of elements of secondary structure and restrictions to local flexibility, as also discussed for the reactivity of aspartic acid residues (Sect. 6.3.3). Furthermore, deamidation is markedly decreased in regions of low polarity in the interior of proteins because the formation of cyclic imides (Fig. 6.29, Pathway e) is favored by deprotonation of the nucleophilic backbone N-atom, which is markedly reduced in solvents of low polarity [100][112],... 

Imide Bond Formation with Terminal Hydrazide Group (a hydrazide-activated protein)... 

Very recently, a new class of water-soluble imide-based polymers known as polymeric betaines has been discovered with a view for application in medicine. Polymers possessing positive and negative charges on the same repeat unit are insoluble in pure water because of the formation of intra- and inter-chain associations. However, they become soluble in water after adding small amounts of salt (e.g., NaCl). Some of these polymeric betaines have attracted much interest for their biocompatible properties due to strong resistance toward protein absorption [64, 65]. 

---