Homocysteine transmethylation

Mechanistic aspects of the action of folate-requiring enzymes involve one-carbon unit transfer at the oxidation level of formaldehyde, formate and methyl (78ACR314, 8OMI2I6OO) and are exemplified in pyrimidine and purine biosynthesis. A more complex mechanism has to be suggested for the methyl transfer from 5-methyl-THF (322) to homocysteine, since this transmethylation reaction is cobalamine-dependent to form methionine in E. coli. 

The final step in our understanding of transmethylation followed from the observation by Cantoni (1951) that betaine and dimethylthetin only acted as methyl donors in the presence of homocysteine, i.e. after the methyl group had been transferred to give methionine. Methionine would only transmethylate if ATP was available. S-adenosyl methionine was therefore proposed as the primary methyl donor, a suggestion confirmed after the compound had been synthesized by Baddiley and Jamieson in 1954. 

The product of transmethylation, S-adenosylhomocysteine, is converted (step g) into homocysteine in an unusual NAD-dependent hydrolytic reaction (Eq. 15-14) by which adenosine is removed (step g).302c Homocysteine can be reconverted to methionine, as indicated by the dashed line in Fig. 24-16. This can be accomplished by the vitamin B12-and tetrahydrofolate-dependent methionine synthase, (Eq. 16-43), which transfers a methyl group from methyl-tetrahydrofolate303 303b by transfer of a methyl group from betaine, a trimethylated glycine (Eq. 24-33)304, or by remethylation with AdoMet (Fig. 24-16).304a... 

When present in excess methionine is toxic and must be removed. Transamination to the corresponding 2-oxoacid (Fig. 24-16, step c) occurs in both animals and plants. Oxidative decarboxylation of this oxoacid initiates a major catabolic pathway,305 which probably involves (3 oxidation of the resulting acyl-CoA. In bacteria another catabolic reaction of methionine is y-elimination of methanethiol and deamination to 2-oxobutyrate (reaction d, Fig. 24-16 Fig. 14-7).306 Conversion to homocysteine, via the transmethylation pathway, is also a major catabolic route which is especially important because of the toxicity of excess homocysteine. A hereditary deficiency of cystathionine (3-synthase is associated with greatly elevated homocysteine concentrations in blood and urine and often disastrous early cardiovascular disease.299,307 309b About 5-7% of the general population has an increased level of homocysteine and is also at increased risk of artery disease. An adequate intake of vitamin B6 and especially of folic acid, which is needed for recycling of homocysteine to methionine, is helpful. However, if methionine is in excess it must be removed via the previously discussed transsulfuration pathway (Fig. 24-16, steps h and z ).310 The products are cysteine and 2-oxobutyrate. The latter can be oxidatively decarboxylated to propionyl-CoA and further metabolized, or it can be converted into leucine (Fig. 24-17) and cysteine may be converted to glutathione.2993... 

In addition, GSH dysregulation might play a role in the framework of the Single-Carbon Hypothesis of schizophrenia originally proposed by Smythies et al. (Smythies et al., 1997). In the transmethylation pathway, methionine is converted to homocysteine providing methyl groups to DNA, lipids and proteins. 

Methionine, homocysteine, and cysteine are linked by the methylation cycle and transsulfuratlon pathway (Figure 55-9). Conversion of methionine into homocysteine proceeds via the formation of S-adenosyl intermediates including S-adenosylmethionine, die methyl group donor in a wide range of transmethylation reactions. Homocysteine is further condensed with serine by cystathionine 3-synthase to form cystathionine. 

S-Adenosyl-L-methionine is the important methyl donor in biological transmethylation to form S-adenosyl-L-homocysteine, which is hydrolyzed to adenosine and homocysteine by S-adenosyl-L-homocysteine hydrolase (E.C. 3.3.1.1) in vivo. However, equilibrium of the S-adenosyl-L-homocysteine hydrolase reaction favors the direction toward synthesis of S-adenosyl-L-homocysteine. Shimizu et al. developed a simple and efficient method for the high yield preparation of S-adenosyl-L-homocysteine with S-adenosyl-L-homocysteine hydrolase of Alcaligenes faecalis, in which the cellular content of S-adenosyl-L-homocysteine hydrolase was about 2.5% of the total soluble protein. S-Adenosyl-r-homocysteine was produced at a concentration of about 80 g I. 1 with a yield of nearly 100% 661. However, when racemic... 

Through the oxidation of choline, to yield glycine betaine, followed by the transmethylation of homocysteine shown here. 

For human beings methionine is nutritionally essential and comes entirely from the diet. ITowever, the oxoacid analog of methionine can be used as a nutritional supplement. Dietary homocysteine can also be converted into methionine to a limited extent. Methionine is incorporated into proteins as such and as N-formylmethionine at the N-terminal ends of bacferial profeins (steps a and b, Fig. 24-16). In addition to its function in proteins methionine plays a major role in biological methylation reactions in all organisms. It is converted into S-adenosylmethionine (AdoMet or SAM Fig. 24-16, step e see also Eq. 17-37), ° ° which is the most widely used methyl group donor for numerous biological methylation reactions (Eq. 12-3). S-Adenosylmethionine is also the precursor of the special "wobble base" queuine (Fig. 5-33). The product of transmethylation, S-adenosylhomocysteine, is converted (step... 

Using differential screening, Tanaka et al. [34] found cDNAs representing cytokinin-induced mRNAs in the tobacco thin layer system. One cDNA encodes S-adenosyl-L-homocysteine hydrolase (SAH hydrolase), which is involved in regulating intracellular transmethylation reactions. The promoter sequence of the gene was fused to the 3-glucuronidase (GUS) reporter gene and introduced in suspension-cultured cells, which rendered expression of GUS inducible by kinetin. 

The more complex sulphur requirements of the marine animals are met largely by cysteine, cystine, methionine, biotin, and thiamine (Young and Maw, 1958) (Fig. 4). Cysteine is a component of the tripeptide glutathione and a precursor of taurine. Methionine is as an essential amino acid involved in biosynthesis of proteins, creatine and adrenaline. Adenosylmethionine is considered to be the active part in transmethylation, e.g. of choline. Methionine is part of the pathways to homocysteine, cystathionine and methylthioadenosine (Young and Maw, 1958). Various organisms convert cysteine and/or cystine into mercapturic acids, cysteine sulphinic acid, and thiazolidine derivatives (Zobell, 1963). 

Transmethylation yields 1 mole of adenosine for every mole of methylated product. Patients are known with inborn errors that lead to incomplete metabolism of the homocysteine released after transmethylation. Homocysteinurics release about 3 mg of homocysteine per kilogram on unsupplemented diets, more on supplemented (G3, LI). This is minimal, owing to other fates of homocysteine and possible incompleteness of the block (L2). Cystathioninurics have been reported to excrete over a gram of cystathionine per day and up to 0.6 g per gram of creatinine (F6, H3, K9). Since the latter probably have some cystadiioninase, and some remethylation of homocystine may occur, the reported values are also minimal. Nevertheless, the moles of homocysteine and its products are of the same order as the amount of hypoxanthine formed per day. 

Fig. 20.3 Pathway of methionine metabolism. The numbers represent the following enzymes or sequences (1) methionine adenosyltransferase (2) S-adenosylmethionine-dependent transmethylation reactions (3) glycine methyltransferase (4) S-adenosylhomocysteine hydrolase (5) betaine-homocysteine methyltransferase (6) 5-methyltetrahydrofolate homocysteine methyltransferase (7) serine hydroxymethyltransferase (8) 5,10-methylenetetrahydrofolate reductase (9) S-adenosylmethionine decarboxylase (10) spermidine and spermine synthases (11) methylthio-adenosine phosphorylase (12) conversion of methylthioribose to methionine (13) cystathionine P-synthase (14) cystathionine y-lyase (15) cysteine dioxygenase (16) cysteine suplhinate decarboxylase (17) hypotaurine NAD oxidoreductase (18) cysteine sulphintite a-oxoglutarate aminotransferase (19) sulfine oxidase. MeCbl = methylcobalamin PLP = pyridoxal phosphate...

Transmethylation Methionine adenosyl transferase Betaine-homocysteine methyltransferase iV -methyltetrahydrofolate-homocysteine 5-methyltransferase... 

This enzyme catalyses the reaction that generates methionine from homocysteine, a metabolic step associated with transmethylation by iS-adenosylmethionine. 

This enzyme contains tightly bound cyanocobalamin which imparts a salmon pink colour. It catalyses one of the reactions which generate methionine from homocystein, and is thus involved indirectly in transmethylation. It may be assayed radiochemically. 

The S-adenosyl homocysteine produced in the transmethylation reactions is generally cleaved to adenosine and homocysteine. The latter can be degraded as previously discussed or be remethylated to methionine and eventually regenerate S-adenosyl methionine. Thus the operation of a methionine cycle provides a route whereby one-carbon metabolites reduced through the tetrahydrofolic acid sequence provide methyl groups for biosynthetic pathways. Certain other sulphonium compounds such as... 

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. 

Homocysteine is produced during methionine metabolism via the adenosylated compounds 5-adenosylmethionine (SAM) and 5-adenosylhomocysteine (SAH). Accumulation of homocysteine causes slowing in the hydrolysis of SAH, resulting in an accumulation of SAM and a decrease in the ratio of SAM to SAH (an indicator of transmethylation activities) (McKeever el at. 1995). This transmethylation produces various metabolites. The possible influences of the reduced production of these metabolites are as follows (Perna et at. 1996) ... 

Since homocysteine-lowering therapy, which activates the remethylation pathway, accelerates the transmethylation reaction (Koyama et at. 2010) (Figure 47.6, Table 47.1, the clinical assessment of homocysteine-lowering therapy may have to include examinations of wide-ranging factors (dementia, prevalence of cancer, etc.) as listed above (i-viii). 

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. 

Transmethylation. Methionine is formed from homocysteine by the addition of a one-carbon moiety that becomes the methyl group of the thioether (VI). The methyl group of methionine may be derived from certain preformed methyl groups or from various one-carbon donors, such as serine and formate. In the latter case the one-carbon unit must... 

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