Methyltransferases

Methyltransferases are an eclectic mix of enzymes of which the majority, over 95%, use S-adenosyl-1-methionine (Ado-Met) as a methyl donor. The basic methyl transfer reaction is the catalytic attack of a nucleophile (carbon, oxygen, nitrogen, or sulfur) on a methyl group to form methylated derivatives of proteins, lipids, polysaccharides, nucleic acids, and various small molecules. Such methyl conjugation is an important pathway in the metabolism of many drugs and xenobiotic compounds, in addition to endogenous neurotransmitters and hormones; Methylation is essential for the control of gene transcription.

The Ado-Met methylation enzymes are an example of convergent evolution, a series of enzymes with very different general structures but with similar properties at the local active site, which allow the catalysis of the methyl transfer reaction (Schluckebier et al. 1995 ; Schubert et al. 2003). There are five structurally distinct families of Ado-Met-dependent methyltransferases, each family representing a series of enzymes with structurally similar active sites and, among the classes of methyltransferases, different structures with similar functions (Schubert et al. 2003). The Enzyme Commission (EC) has assigned numbers to more than 150 methyltransferases: pyridine N-methylation, documented in the late 19th century, was the first methyl conjugation reaction described (His 1887; Weinshilboum et al. 1999), and glycine N-methyltransferase (EC 2.1.1.162) will not be the last.

Methylation is integral to the maintenance of life. DNA methylation is a prerequisite for gene expression and mutation repair; Subsequent post-translational methylation of expressed proteins modifies subsequent functional activity. Mammals have long been known to mark their DNA by adding methyl groups to cytosine residues. DNA methylation is essential for development and is involved in programmed and ectopic gene inactivation (Bestor and Verdine 1994), and DNA methyltransferase (cytosine-5′-methyltransferase, EC 2.1.1.37) plays an important role in the gene profiling control. expression in mammalian cells. Inhibition of this enzyme, for example, by the deoxycytidine analog 5-aza-2'-deoxycytidine, induces gene expression and cell differentiation (Christman 2002; Juttermann et al. 1994; Szyf 1994).

DNA methyltransferase binds directly to the DNA helix by base change (Cheng and Roberts 2001) and catalyzes the transfer of the methyl group from Ado-Met to carbon 5 of the deoxycytidine residues.