Methyltransfer reactions

Svetlitchnaia T, Svetlitchnyi V, Meyer O, Dobbek H. Structural insights into methyltransfer reactions of a corrinoid iron-sulfur protein involved in acetyl-CoA synthesis. Proc. Natl. Acad. Sci. U.S.A. 2006 103 14331-14336. 

Rapsomanikis, S. (1986) Methyltransfer Reactions. In Organometallic Compounds in the Environment, P. J. Craig, Ed., Longmans, Harlow. 

Transfer of the adenosyl group of ATP onto one of the substrates, as shown in Figure 3.5. The activation of the methyl group of the amino acid methionine in methyltransfer reactions involves formation of S-adenosyl methionine (see also Figure 11.22). 

Analogs of metabolic intermediates have been widely used to investigate the mechanism of biochemical reactions. Along this line, a series of sulfonium compounds and thioethers, analogs of S-adeno-syl-L-methionine and S-adenosyl-L-homocysteine respectively have been assayed as substrate and/or inhibitors of methyltransfer reactions (33-36). However, these studies mainly concerned with methyltransferases acting on small molecules and tRNA (33-37). In this brief account, we have reviewed recent studies on the effect of afore-mentioned compounds on various protein-specific methyltransferases. 

As is well known, AdoMet is one of the most versatile compounds in biology it can function not only as a methyl donor in a very large number of methyltransfer reactions but also as a donor of a 3-amino-3-carboxypropyl group, of the amino group of homocysteinyl... 

Since preliminary studies showed that 6-hydroxymellein-O-methyl-transferase activity was appreciably inhibited in the presence of the reaction products, the mode of product inhibition of the enzyme was studied in detail in order to understand the regulatory mechanism of in vivo methyltransfer. It is well known that S-adenosyl-Z.-homocysteine (SAH), which is a common product of many O-methyltransferases that use SAM as methyl donor, is usually a potent inhibitor of such enzymes. In the 6-hydroxymellein-Omethyltransferase catalyzing reaction another product of this enzyme, 6-methoxymellein, has pronounced inhibitory activity, in addition to SAH. Since the specific product of the transferase reaction, 6-methoxymellein, is capable of inhibiting transferase activity [88], this observation suggests that activity of the transferase is specifically regulated in response to increases in cellular concentrations of its reaction products in carrot cells. It has been also found that 6-methoxymellein inhibits transferase activity with respect not only to 6-hydroxymellein but also to SAM, competitively. This competitive inhibition was also found in SAH as a function of the co-substrates of the enzyme [89]. It follows that the reaction catalyzed by 6-hydroxymellein-O-methyltransferase proceeds by a sequential bireactant mechanism in which the entry of the co-substrates to form the enzyme-substrate complexes and the release of the co-products to generate free enzyme take place in random order [Fig. (7)]. This result also implies that 6-methoxymellein and SAH have to associate with the free transferase protein to exhibit their inhibitory activities, and cannot work as the inhibitors after the enzyme forms complexes with the the substrate. If, therefore, 6-hydroxymellein-O-methyltransferase activity is controlled in vivo by its specific product 6-methoxymellein, this compound should... 

When C was introduced into the methyl group of S-adenosylmethionine and its rate of reaction with catechol 0-methyltransfer-ase was compared with that of the normal C-containing substrate, the expected effect on Tinax expressed as a first-order rate constant, was seen k- 2 / 13 = 1.09 + 0.05. This effect is small but it can be measured reliably and establishes that the methyl transfer step rather than substrate binding, product release, or a conformational change in the protein is rate limiting. ... 

The various active sites are ordered vertically in the core. The transcription complex is tethered inside the X,1 shell and below the X2 turret the guanylyltransferase active sites are at the base of the turret and one set of methyltransferase active sites is half way up, and another set is at the top of the turret. There is no biochemical evidence to establish which methyltransferase domain is the 7N and which is the 2 0 methylase. One possibility is that the vertical ordering of the active sites reflects the temporal ordering of the reactions, so that since 7N methyltransfer always precedes 2 0 methyltransfer, the methyltransferase near the middle of the turret methylates 7N and the methyltransferase near the top of the turret methylates the 2 0. Probably such a vertical ordering alone would not impose an order on the methylation reactions, and it seems likely that the reovirus 2 0 methyltransferase, like VP39 from vaccinia, only methylates a cap structure that has been methylated previously at the 5 guanosine moiety. 

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