DNA methyltransferase

In biochemistry, the DNA methyltransferase (DNA MTase, DNMT) family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl methionine (SAM) as the methyl donor.

MTases can be divided into three different groups on the basis of the chemical reactions they catalyze:

m6A and m4C methyltransferases are found primarily in prokaryotes (although recent evidence has suggested that m6A is abundant in eukaryotes). m5C methyltransferases are found in some lower eukaryotes, in most higher plants, and in animals beginning with the echinoderms.

The m6A methyltransferases (N-6 adenine-specific DNA methylase) (A-Mtase) are enzymes that specifically methylate the amino group at the C-6 position of adenines in DNA. They are found in the three existing types of bacterial restriction-modification systems (in type I system the A-Mtase is the product of the hsdM gene, and in type III it is the product of the mod gene). These enzymes are responsible for the methylation of specific DNA sequences in order to prevent the host from digesting its own genome via its restriction enzymes. These methylases have the same sequence specificity as their corresponding restriction enzymes. These enzymes contain a conserved motif Asp/Asn-Pro-Pro-Tyr/Phe in their N-terminal section, this conserved region could be involved in substrate binding or in the catalytic activity. The structure of N6-MTase TaqI (M.TaqI) has been resolved to 2.4 A. The molecule folds into 2 domains, an N-terminal catalytic domain, which contains the catalytic and cofactor binding sites, and comprises a central 9-stranded beta-sheet, surrounded by 5 helices; and a C-terminal DNA recognition domain, which is formed by 4 small beta-sheets and 8 alpha-helices. The N- and C-terminal domains form a cleft that accommodates the DNA substrate. A classification of N-MTases has been proposed, based on conserved motif (CM) arrangements. According to this classification, N6-MTases that have a DPPY motif (CM II) occurring after the FxGxG motif (CM I) are designated D12 class N6-adenine MTases. The type I restriction and modification system is composed of three polypeptides R, M and S. The M (hsdM) and S subunits together form a methyltransferase that methylates two adenine residues in complementary strands of a bipartite DNA recognition sequence. In the presence of the R subunit, the complex can also act as an endonuclease, binding to the same target sequence but cutting the DNA some distance from this site. Whether the DNA is cut or modified depends on the methylation state of the target sequence. When the target site is unmodified, the DNA is cut. When the target site is hemimethylated, the complex acts as a maintenance methyltransferase, modifying the DNA so that both strands become methylated. hsdM contains an alpha-helical domain at the N-terminus, the HsdM N-terminal domain.

Among the m6A methyltransferases (N-6 adenine-specific DNA methylase) there is a group of orphan MTases that do not participate in the bacterial restriction/methylation system. These enzymes have a regulatory role in gene expression and cell cycle regulation. EcoDam from E. coli and CcrM from Caulobacter crescentus are well characterized members of these family. More recently, CamA from Clostridioides difficile, was shown to play key functional roles in sporulation, biofilm formations and host-adaptation.

m4C methyltransferases (N-4 cytosine-specific DNA methylases) are enzymes that specifically methylate the amino group at the C-4 position of cytosines in DNA. Such enzymes are found as components of type II restriction-modification systems in prokaryotes. Such enzymes recognise a specific sequence in DNA and methylate a cytosine in that sequence. By this action they protect DNA from cleavage by type II restriction enzymes that recognise the same sequence^{[citation needed]}

m5C methyltransferases (C-5 cytosine-specific DNA methylase) (C5 Mtase) are enzymes that specifically methylate the C-5 carbon of cytosines in DNA to produce C5-methylcytosine. In mammalian cells, cytosine-specific methyltransferases methylate certain CpG sequences, which are believed to modulate gene expression and cell differentiation. In bacteria, these enzymes are a component of restriction-modification systems and serve as valuable tools for the manipulation of DNA. The structure of HhaI methyltransferase (M.HhaI) has been resolved to 2.5 A: the molecule folds into 2 domains - a larger catalytic domain containing catalytic and cofactor binding sites, and a smaller DNA recognition domain.

Highly conserved DNA methyltransferases of the m4C, m5C, and m6A types have been reported, which appear as promising targets for the development of novel epigenetic inhibitors to fight bacterial virulence, antibiotic resistance, among other biomedical applications.