S-Adenosyl-L-methionine-Dependent Methyltransferases

an S 2 transition state including donor and receptor is likely. 

Cantoni, G. L. Biological methylation selected aspects. Annu. Rev. Biochem. 44, 435-451 (1975) 

Poulton, J. E. Transmethylation and demethylation reactions in the metabolism of secondary plant products. In The Biochemistry of Plants, Vol. 7, Secondary Plant Products (E. E. Conn, ed.), pp. 667-723. Academic Press, New York 1981 Udsin, E., R. T. Borchardt, C. R. Creveling (eds.) Transmethylation. Elsevier/North Holland, Amsterdam 1978 

Wimmer, M. J., Rose, I. A. Mechanisms of enzyme-catalyzed group transfer reactions. Annu. Rev. Biochem. 46, 1331-1378 (1978) 

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JOSHI, C. P., CHIANG, V. L., Conserved sequence motifs in plant S-adenosyl-L-methionine- dependent methyltransferases., Plant Mol.Biol., 1998,37,663-674. 

LEUSTEK, T SMITH, M MURILLO, M., SINGH, D. P., SMITH, A. G., WOODCOCK, S. C AW AN, S. J., WARREN, M. J., Siroheme biosynthesis in higher plants - Analysis of an S- adenosyl-L-methionine-dependent uroporphyrinogen III methyltransferase from Arabidopsis thaliana., J. Biol. Chem., 1997,272,2744-2752. 

Vevodova J, Graham RM, Raux E, Schubert HL, Roper Dl, Brindley AA, et al. Structure/function studies on a S-adenosyl-L-methionine-dependent uroporphyrinogen 111 C methyltransferase (SUMT), a key regulatory enzyme of tetrapyrrole biosynthesis. J. Mol. Biol. 2004 344 419-433. 

Methyl transfer reactions play a significant part in the modifications of aromatic polyketides, both of the polyketide core [61,62] as well as of several of the sugar moieties [44,53]. In Streptomyces, more than 20 amino acid sequences have been found that may represent enzymes involved in methyl transfer reactions in the biosynthesis of aromatic polyketides [149]. One of these enzymes, the S-adenosyl-L-methionine-dependent DnrK, is involved in the methylation of the C-4 hydroxyl group in daunorubicin/doxorubicin biosynthesis (Scheme 10, step 12). The subunit of the homo-dimeric enzyme displays a fold typical for small-molecule methyltransferases. The structure of the ternary complex with bound products S-adenosyl-L-homocysteine and 4-methoxy-8-rhodomycin provided insights into the structural basis of substrate recognition and catalysis [149]. The position and orientation of the substrates suggest an Sn2 mechanism for methyl transfer, and mutagenesis experiments show that there is no catalytic base in the vicinity of the substrate. Rate enhancement is thus most likely due to orientational and proximity effects [149]. 

According to the above-mentioned hypothesis, the caffeic acid moiety is retransferred to coenzyme A for further modification reactions. Methylation of the caffeoyl moiety in position 3 is achieved by S-adenosyl-L-methionine (SAM)-dependent 0-methyltransferases (OMTs) either acting on the level of the free acid or the coenzyme A thioester. Hydroxylation in position 5 is catalysed by a cytochrome P450 of the CYP84 family which will be described in more detail. Establishment of the sinapoyl substitution pattern by adding another methyl group will be depicted below. 

The crystal structure of 5-8-azaadenosyl-L-homocysteine has been examined because this substance inhibits a methyltransferase that depends on S -adenosyl-L-methionine as a cofactor. ... 

S-adenosyl-L-methionine (SAM)-dependent methyl-ation was briefly discussed under Thiomethylation (see Figure 14). Other functional groups that are methylated by this mechanism include aliphatic and aromatic amines, N-heterocyclics, monophenols, and polyphenols. The most important enzymes involved in these methylation reactions with xenobiotics are catechol O-methyltransferase, histamine N-methylt-ransferase, and indolethylamine N-methyltransferase - each catalyzes the transfer of a methyl group from SAM to phenolic or amine substrates (O- and N-methyltransferases, respectively). Methylation is not a quantitatively important metabolic pathway for xenobiotics, but it is an important pathway in the intermediary metabolism of both N- and O-contain-ing catechol and amine endobiotics. 

Borchardt, R.T., Wu, Y.S., and Wu, B.S. (1978) Potential inhibitors of S-adenosyl-methionine-dependent methyltransferases. 7. Role of the ribosyl moiety in enzymatic binding of S-adenosyl-L-homocysteine and S-adenosyl-L-methionine. J. Med. Chem. 21, 1307-1310. 

Struck, A.-W., Thompson, M.L., Wong, L.S., and Micklefield, J. (2012) S-adenosyl-methionine-dependent methyltransferases highly versatile enzymes in biocatalysis, biosynthesis and other biotechnological applications. ChemBioChem, 13, 2642-2655. 

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