Alkyltransferases

A number of enzymes catalyze alkylation reactions, most of which are reactions of S-adenosyl-L-methionine (SAM) as a methylating agent in the biosynthesis of hormones, modification of DNA, and methyl esterification of proteins involved in signal transduction. Other examples of enzymatic alkylation include prenyl transfer reactions, adenosyltransfer from ATP to methionine in the biosynthesis of SAM, and adenosyltransfer from ATP to cob(I)alamin in the biosynthesis of adenosylcobalamin. Methyl group transfer is also the essential step in the reaction of methionine synthase, which uses 5-methyltetrahydrofolate as an alkylating agent. In an analogous reaction, an analog of 5-methyltetrahydrofolate is the methyl group donor in the methylation of coenzyme M to form methyl coenzyme M, the proximate precursor of methane in methanogenesis (see chap. 4). Glysosyl transfer is an alkylation reaction catalyzed by a large class of enzymes, the glycosyltransferases and glycosidases. The special nature of the glycosyl compounds and their potential for undergoing glycosyltransfer places them in their own class in biochemistry (see chap. 12). The reactivity of glycosyl compounds can be attributed to the contribution of the oxygen atom directly bonded to the glycosyl carbon, the locus of alkylation. In this chapter, we consider other enzymatic alkylations. Alkylation consists of the transfer of a carbon from a leaving group to a nucleophilic acceptor, as in eq.15-1, where R is H or an organic group. The rate is controlled by the reactivity of the nucleophile X:, the stability of the leaving group Y:, and the electrophilic reactivity of the central carbon atom. Alkylation may be regarded as one of the simplest organic chemical reactions because there are few complications in the mechanism. It is the reaction of a nucleophilic molecule with an electrophilic molecule to displace a leaving group. Enzymatic alkylations proceed by polar and not radical mechanisms. In organic chemistry, polar alkylation can occur either by an associative or one-step mechanism, as in fig. 15-1A, or by a dissociative or two-step mechanism through a carbocationic intermediate, as in fig. 15-1B. The chemical nature of the alkylating agent, the propensity of the leaving group to leave, and the polarity of the solvent determine the mechanism.