Glutamine side-chain methylation

Lysine is the most common site for N-methylation, but methylation can also occur on arginine, histidine, glutamine, and asparagine. The enzymes responsible for N-methylation are known as N-methyltransferases aided with SAM as a cosubstrate. All forms of methylation share the same mechanism the nucleophilic amino acid side chain attacks the electrophilic methyl group of SAM and releases S-adenosylhomocysteine (SAH) (Scheme 7). 

Amino acid methyl esters are fairly simple to prepare. The classical method uses a suspension of amino acid hydrochloride in MeOH and gaseous HCl as catalyst b° l di-carboxylic acids yield the dimethyl esters.Hydrolytic and alcoholytic cleavage of side-chain amide groups of glutamine and asparagine as well as peptide bond cleavage prevents the use of this method for the esterification of peptide fragments. 

Side-chain NH2 of glutamine may be methylated, giving 7V5-methylglutamine, and the side-chain NH2 of asparagine may be glycosylated. 

The general approach for carboxyl protection is esterification. The simplest solution, the use of methyl or ethyl esters, is suitable for semipermanent blocking, although the commonly applied process of unmasking, alkaline hydrolysis, is far from unequivocal. It is accompanied by racemization, partial hydrolysis of carboxamide groups in the side chain of asparagine and glutamine residues and by several other side reactions which are initiated by proton abstraction (Cf. Chapter VII). Nevertheless, perhaps because of the attractively simple esterification of amino acids... 

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