The methylation reaction is catalyzed by DNA methyltransferases (DNMTs), enzymes transferring a methyl group from the S-adenosyl-l-methionine (SAM) to the C5 of a cytosine. Such reaction includes SAM as a electrophile methyl donor and C5 as a weak nucleophile incapable to interact with SAM by itself. However, a nucleophile from a DNMT can bind covalently to the carbon-6 of cytosine, which activates the nucleophilic nature of C5, enabling the transfer of a methyl group from SAM. The enzyme nucleophile is consequently removed and deprotonation at C5 breaks up the nucleotide-DNMT complex. DNA methylation typically leads to gene silencing. There are various routes to gene silencing through methylation. Since the greater part of mammalian transcription factors exhibit DNA recognition elements containing motifs rich in CpG, as well as GC-rich binding sites, DNA methylation can block or abolish their capability to act on many significant regulatory sites. 342