SAM-dependent methylases

Among the acceptors modified by 5 -adenosylmethionine are specific bases in DNA. The methylation of DNA protects bacterial DNA from cleavage by restriction enzymes (Section 9.3). The base to be methylated is flipped out of the DNA double helix into the active site where it can accept a methyl group from 5 -adenosylmethionine (Figure 24.15). A recurring 5 -adenosylmethionine-binding domain is present in many SAM-dependent methylases. 

Figure 24.15. DNA Methylation. The structure of a DNA methylase bound to an oligonucleotide target shows that the base to be methylated is flipped out of the DNA helix into the active site of a SAM-dependent methylase.

A second group of SAM-dependent methylases acts on much larger substrates, such as proteins and nucleic acids (9). Only recently has progress been made on isolating purified proteins which methylate macromolecules such as tRNA (10), mRNA (11), and proteins (12). In the case of tRNA (adenine-1)-methyltransferase (E.C. 2.1.1.36) (10a) and protein carboxyl-0-methyltransferase (E.C. 2.1.1.24) (13), kinetic studies are consistent with the random sequential reaction proposed for COMT, and thus suggest a direct methyl transfer in the ternary complex. One enzyme which does not show kinetics consistent with a direct methyl transfer is histamine-N-rnethyltransferase (E. C. 2.1.1.8) (14). The data reported are consistent with a double—displacement mechanism of... 

The modular function of MetH is an elegant example of signaling in a closed system. It rationalizes all of the formerly confusing information about MetH. Other SAM and cobalamin-dependent methylases, such as the radical SAM methylases, might function in analogous ways. 

As observed in the section discussing BtrN and DesII, radical SAM enzymes have already been shown to play a critical role in the synthesis of certain elements of antibiotic compounds. Moreover, we observed in the MiaB section that a radical SAM enzyme is responsible for catalyzing a methylation reaction in the synthesis of ms i A. Methyl transfer reactions in biology commonly utilize DNA methylase enzymes or SAM-dependent methyltransferases the latter system has been touched upon in the multiple SAM-dependent methyl transfer reactions involved in yW synthesis. However, a unique methylation reaction has recently been proposed that invokes the use of both SAM and methylcobalamin. 

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