Transmethylation inhibition

We have found that the adenosine analogues, 3-deazaadenosine and 5 -deoxy-5 -S-isobutyladenosine, which are potent inhibitors of transmethylation, inhibit IgE-mediated histamine release when incubated with L-homocysteine thiolactone (16). In addition, we have found that exogenous adenosine, in the presence of an ADA inhibitor and L-homocysteine thiolactone, markedly inhibits IgE-mediated secretion from human basophils (16). Thus, histamine secretion can be inhibited by two separate effects of adenosine interaction with an A2 receptor linked to adenylate cyclase and inhibition of intracellular transmethylation. 

Miscellaneous Synthetic compounds - Procarbazine, (N-isopropyl-Of-(2 methylhydrazino)-g -toluamide hydrochloride), one of several derivatives of methylhydrazine which have antineoplastic activity against transplanted tumors, has proven clinically useful in the management of Hodgkin s disease. A second derivative, N-allophanoyl-a-(2 methylhydrazine)- -toluam-ide, appeared to have activity comparable to that of procarbazine in a preliminary clinical trial. 47 The mechanism by which procarbazine and related compounds produce cytotoxicity is not established. Procarbazine produced a short-lived inhibition of synthesis of DNA, RNA and protein when studied in a mouse lymphoma 48 the methyl group enters the 1-carbon pool and participates in transmethylation reactions. 49 Pertinence of these observations, as well as those previously described of molecular autoxidation to the drug s antitumor effects, awaits demonstration. 

Kakiki et ai. (1969) reported that EBP inhibited the incorporation of glucosamine-into the cell wall of Piricularia orysae. This suggested that a mode of action of this compound might be the inhibition of chitin biosynthesis. According to the experiments of Akatsuka et al. (1977) and of Kodama et al. (1979) the specific inhibition of conversion from phosphatidylethanolamine to phos-phatidylcholin by the transmethylation of S-adenosylmethionine might be one of the modes of action of IBP. 

Procarbazine may inhibit transmethylation of methyl groups of methionine into tRNA. The absence of functional tRNA could cause the cessation of protein synthesis and consequently DNA and RNA synthesis. In addition, procarbazine may directly damage DNA. Hydrogen peroxide, formed during the autooxidation of the drug, may attack protein sulfhydryl groups contained in residual protein that is tightly bound to DNA. 

Vidarabine is an inhibitor of viral DNA synthesis. Cellular enzymes phosphorylate vidarabine to the triphosphate, which inhibits viral DNA polymerase activity in a manner that is competitive with deoxyadenosine triphosphate. Vidarabine triphosphate is incorporated into both cellular and viral DNA, where it may act as a chain terminator. Vidarabine triphosphate also inhibits ribonucleoside reductase, RNA polyadenylation, and 5 -adenosylhomocysteine hydrolase, an enzyme involved in transmethylation reactions. Resistant variants due to mutations in viral DNA polymerase can be selected in vitro. 

This nucleoside appears to control the immune system in vitro both by interacting extracellularly with A1 and A2 membrane receptors and also intracellularly by inhibiting transmethylation and by acting on a P-site. Although adenosine is not the only endogenous modulator of the immune function, the above cited effects and the observation of patients with ADA deficiency suggest that this nucleoside may well have a significant role in the control of human inflammatory and immune reactions. 

Since an accumulation of homocysteine decreases transmethylation activities and DDAH is inhibited by homocysteine, homocysteine metabolism is involved both in the synthesis and degradation of ADMA. 

There is little evidence for the participation of cofactors or other activators in transmethylation reactions. An occasional methyltransferase has been found to be stabilized by mercaptoethanol or other sulfhydryl compounds and to be inhibited by p-chloromercuribenzoate (Mann and Mudd, 1963). A purified yeast sterol methyltransferase requires gluta-... 

Transmethylation reactions are widely used in modification of a variety of biomolecules such as nucleic acids, proteins, phospholipids, and bioamines. In these reactions, SAM serves as the universal methyl donor (Mato et al. 1997). Methylation reactions yield the common product 5-adenosyl-L-homocysteine (SAH), and most SAM-dependent methylations are strongly inhibited by accumulation of SAH (Mato... 

Kirsch and co-workers (unpublished data) attempted to obtain more information on the nature of ethionine inhibition by studying the reversal of this effect by L-methionine. Graphs showing a pattern of reversal are offered in Fig. 5. At least two significant facts emerge from these data the first is the L-methionine which is known to be an effective competitor of ethionine inhibition of transmethylation reactions does indeed reverse the ethionine effect on mitomycin synthesis. The second fact is that there appears to be a lag period of about 24 hours... 

It is of interest to point out the difference in behavior of the stereoisomers of methionine. The work of Handler and Bernheim (58) shows in effect that d(-f-)-methionine has only 50% of the activity of the natural isomer in the synthesis of creatine by rat liver slices. Besides, the transmethylation with d(-b)-methionine is inhibited by benzoic acid, while the latter has no action on the transjnethylation with i (—)-methionine. Furthermore, benzoic acid inhil)its the action of d-amino acid oxidase, it appears that the transmethylation observed in the presence of d(-t-)-methionine does not proceed directly from that compound, but, only after its deamination, from the corresponding keto acid. 

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