Methionine 5-methyltransferase

AdoMet methionine 5-methyltransferase partially purified from cabbage leaves displays a marked specificity for (5)-5-adenosyl-L-methionine as methyl donor (Table III). To investigate the reversibility of the reaction, enzyme was incubated with 5-[ C]methylmethionine and AdoHcy in the presence of a small amount (3 nmoles) of methionine. After incubation, the methionine was examined for the presence of C. No radioactivity was detected, indicating that if the back reaction was occurring at all, it must have been doing so at a rate less than 0.3% of the rate of the forward reaction (S. H. Mudd, unpublished). 

Fig. 6.3 Generalized overview of Se metabolism in plants. Numbers denote known enzymes. (1) ATP sulfurylase, (2) adenosine-5-phosphosulfate reductase, (3) glutathione or sulfite reductase, (4) glutathione reductase or O-acetylserine thiol lyase, (5) Selenocysteine methyltransferase, (6) Selenocysteine lyase, (7) cystathionine-g-synthase, (8) cystathionine-b-lyase, (9) methionine synthase, (10) methionine methyltransferase, (11) DMSP lyase, (12) g-gjutamylcysteine synthetase (Source Parker et al. (2003), Sors et al. (2005b), Pilon-Smits and Quinn (2010), Lindblom et al. (2012), Yu and Gu (2013), PUon-Smits et al. (2014), Winkel et al. (2015) and PUon-Smits (2015))...

Modulation of second-messenger pathways is also an attractive target upon which to base novel antidepressants. Rolipram [61413-54-5] an antidepressant in the preregistration phase, enhances the effects of noradrenaline though selective inhibition of central phosphodiesterase, an enzyme which degrades cycHc adenosiae monophosphate (cAMP). Modulation of the phosphatidyl iaositol second-messenger system coupled to, for example, 5-HT,, 5-HT,3, or 5-HT2( receptors might also lead to novel antidepressants, as well as to alternatives to lithium for treatment of mania. Novel compounds such as inhibitors of A-adenosyl-methionine or central catechol-0-methyltransferase also warrant attention. 

Methylcobalamin is involved in a critically important physiological transformation, namely the methylation of homocysteine (8) to methionine (9) (eq. 2) catalyzed by A/ -methyltetrahydrofolate homocysteine methyltransferase. The reaction sequence involves transfer of a methyl group first from... 

Catechol O-methyltransferase (COMT) is a widespread enzyme that catalyzes the transfer of the methyl group of S-adenosyl-l-methionine (AdoMet) to one of the phenolic group of the catechol substrate (Fig. 1). High COMT activity is found in the liver, kidney and gut wall... 

Catechol-O-Methyltransferase. Figure. 1 The basic function of COMT. Enzymatic O-methylation of the catechol substrate to 3-methoxy (major route) or 4-methoxy (minor route) products in the presence of Mg2+ and S-adenosyl-methionine (AdoMet). 

S-adenosyl-L-methionine (AdoMet, SAM) is a cofactor and the most important donor of the methyl (CH3-) group for methyltransferases, including COMT. When the methyl-group has been transferred, the remaining demethylated compound is called S-adenosyl-L-homo-cysteine. 

De Luca, V. and Ibrahim, R. K. 1985a. Enzymatic synthesis of polymethylated flavonols of Chrys-osplenium americarmm. I. Partial purification and some properties of S-adenosyl-L-methionine flavonol 3-, 6-, 7-, and 4 -0-methyltransferases. Arch. Biochem. Biophys. 238 596-605. 

Although the pathway has not been established, relatively high yields of trimethyltin from inorganic tin have been observed in yeast concomitant with the degradation of butyltin compounds (Errecalde et al. 1995). Exceptionally, methionine transferase may carry out the methylation of Hg in Neurospora crassa (Landner 1971) and thiopurine methyltransferase the methylation of inorganic Se in Escherichia coli (Ranjard et al. 2003). 

Mazzafera, P., Wingsle, G., Olsson, O., Sandberg, G., S-Adenosyl-L-methionine theobromine 1-N-methyltransferase, an enzyme catalyzing the synthesis of caffeine in coffee, Phytochemistry, 37(6), 1577, 1994. (CA122 259411n)... 

The introduction of redox activity through a Co11 center in place of redox-inactive Zn11 can be revealing. Carboxypeptidase B (another Zn enzyme) and its Co-substituted derivative were oxidized by the active-site-selective m-chloroperbenzoic acid.1209 In the Co-substituted oxidized (Co111) enzyme there was a decrease in both the peptidase and the esterase activities, whereas in the zinc enzyme only the peptidase activity decreased. Oxidation of the native enzyme resulted in modification of a methionine residue instead. These studies indicate that the two metal ions impose different structural and functional properties on the active site, leading to differing reactivities of specific amino acid residues. Replacement of zinc(II) in the methyltransferase enzyme MT2-A by cobalt(II) yields an enzyme with enhanced activity, where spectroscopy also indicates coordination by two thiolates and two histidines, supported by EXAFS analysis of the zinc coordination sphere.1210... 

The mechanism of tellurium resistance has been investigated using genetic manipulation similar to that of Se (see above) and cellular oxidant capacity apparently plays an important role.144,206 A few tellurite determinants - both chromosomal and plasmid encoded - have been identified in bacte-ria.113,147 192 207 208 Recent studies have focused on the role of methyltransf-erases in Te resistance. Liu et a/.111 determined that the E. coli gene tehB uses S-adenosyl methionine and a methyltransferase in tellurite detoxification, but while no methylated tellurium compounds (see below) were observed, a loss of tellurite was observed in tellurite-amended cultures and Te complexation was inferred.191... 

A high intracerebral level of S-adenosylhomocysteine may inhibit methylation reactions involving S-adenosyl-methionine. The metabolic repercussions would be extensive, including deficient methylation of proteins and of phos-phatidylethanolamine as well as an inhibition of catechol-O-methyltransferase and histamine-N-methyltransferase. 

A relatively large number of agents have been utilized to treat this intractable disorder folinic acid (5-formyl-tetrahydrofolic acid), folic acid, methyltetrahydrofolic acid, betaine, methionine, pyridoxine, cobalamin and carnitine. Betaine, which provides methyl groups to the beta i ne ho mocystei ne methyltransferase reaction, is a safe treatment that lowers blood homocysteine and increases methionine. 

SMM synthesis is mediated by the enzyme methionine S-methyltransferase (MMT) through the essentially irreversible, AdoMet-mediated methylation of methionine.48"5 Both MMT and SMM are unique to plants 48,50 The opposite reaction, in which SMM is used to methylate homocysteine to yield two molecules of methionine, is catalyzed by the enzyme homocysteine S-methyltransferase (HMT).48 Unlike MMT, HMTs also occur in bacteria, yeast, and mammals, enabling them to catabolize SMM of plant origin, and providing an alternative to the methionine synthase reaction as a means to methylate homocysteine. Plant MMT and HMT reactions, together with those catalyzed by AdoMet synthetase and AdoHcy hydrolase, constitute the SMM cycle (Fig. 2.4).4... 

JAMES, F., NOLTE, K.D., HANSON A.D., Purification and properties of S-adenosyl-L-methionine L-methionine S-methyltransferase from Wollastonia biflora leaves, J. Biol. Chem., 1995, 270,22343-22350. 

RANOCHA, P, BOURGIS, F., ZEEMAK, M.J., RHODES, D., GAGE, D.A., HANSON, A.D., Characterization and functional expression of cDNAs encoding methionine-sensitive and -insensitive homocysteine. S -methyltransferases from Arabidopsis, J. Biol. Chem., 2000, 275, 15962-15968. 

MORISHIGE, T TSUJITA, T YAMADA, Y SATO, F., Molecular characterization of the S-adenosyl-L-methionine 3 -hydroxy-A-methylcoclaurine 4 -0-methyltransferase involved in isoquinoline alkaloid biosynthesis in Coptis japonica, J. Biol. Chem., 2000, 275, 23398-23405. 

The methyltransferases represent a relatively large number of enzymes that utilize the cofactor, S-adenosyl-L-methionine, in which the methyl group is bound to a positively charged sulfur, to transfer a methyl group to an oxygen, sulfur, or nitrogen atom in an appropriate substrate as shown in Figure 7.9 (8). 

The best characterized B 12-dependent methyltransferases is methionine synthase (Figure 15.11) from E. coli, which catalyses the transfer of a methyl group from methyltetrahydrofolate to homocysteine to form methionine and tetrahydrofolate. During the catalytic cycle, B12 cycles between CH3-Co(in) and Co(I). However, from time to time, Co(I) undergoes oxidative inactivation to Co(II), which requires reductive activation. During this process, the methyl donor is S-adenosylmethionine (AdoMet) and the electron donor is flavodoxin (Fid) in E. coli, or methionine synthase reductase (MSR) in humans. Methionine synthase... 

Cya n ocobalamin (Bir) Homocysteine methyltransferase Methylmalonyi CoA mutase Methionine, SAM Odd-carbon fatty acids, Val, Met, He, Thr MCC pernicious anemia. Also in aging, especially with poor nutrition, bacterial overgrowth of terminal ileum, resection of the terminal ileum secondary to Crohn disease, chronic pancreatitis, and, rarely, vegans, or infection with D. latum Megaloblastic (macrocytic) anemia Progressive peripheral neuropathy. ... 

Important pathways requiring SAM include synthesis of epinephrine and of the 7-methylgua-nine cap on eukaryotic mRNA, Synthesis of SAM from methionine is shown in Figure T17-3. After donating the methyl group, SAM is converted to homocysteine and remethylated in a reaction catalyzed by N-methyl THF-homocysteine methyltransferase requirii both vitamin Bj2 and N-meth d-THF. The methionine produced is once again used to make SAM. 

Researchers studying the metalloenzyme hydrogenase would like to design small compounds that mimic this enzyme s ability to reversibly reduce protons to H2 and H2 to 2H+, using an active center that contains iron and nickel. Cobalamins (vitamin and its derivatives) contain an easily activated Co-C bond that has a number of biological functions, one of which is as a methyl transferase, 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). This enzyme converts homocysteine (an amino acid that has one more CH2 group in its alkyl side chain than cysteine see Figure 2.2) to methionine as methylcobalamin is converted to cobalamin. 

Figure 22.7 Homocysteine formation from methionine and formation of thiolactone from homocysteine. The homocysteine concentration depends upon a balance between the activities of homocysteine methyltransferase (methionine synthase) and cystathionine p-synthase. Both these enzymes require vitamin B12, so a deficiency can lead to an increase in the plasma level of homocysteine. (For details of these reactions, see Chapter 15.) Homocysteine oxidises spontaneously to form thiolactone, which can damage cell membrane.

Histone-lysine methyltransferases are chromatin-bound enzymes that catalyses the addition of methyl groups onto lysine or arginine residues of chromatin-bound H3 and H4 [151]. The methyl group is transferred enzymatically to the histone with S-adenosyl methionine as the methyl donor. Histone methylases have been isolated from HeLa S-3 cells [182], chick embryo nuclei [183], and rat brain chromatin [184]. The histone methyltransferases methylated H3 and H4 in nucleosomes [184]. Histone-lysine methyltransferase is a chromatin-bound enzyme [129,151]. Initial characterization of the Tetrahymena macronuclear H3 methyltransferase suggests that the enzyme has a molecular mass of 400 kDa. The enzyme preferred free histones rather than nucleosomes as substrate [138]. More recent studies have now... 

PRMTl, a nuclear receptor coactivator, exists as in a 330 kDa complex and is a H4 Arg-3 methyltransferase [133,215]. The enzyme appears to be a chromatin bound, and evidence from immunodepletion and knockout studies suggest that it is the principle, if not sole, H4 Arg-3 methyltransferase [133,215]. Mutation of the S-adenosyl methionine binding site in PRMTl annihilated its nuclear receptor coactivator activity with the androgen receptor, providing evidence for the importance of the methylation event in gene expression [215]. Yeast Rmtl, which is homologous to human PRMTl, methylates Arg-3 only in free H4 [208]. 

In methylcobalamin, X is a methyl group. This compound functions as a coenzyme for several methyltransferases, and among other things is involved in the synthesis of methionine from homocysteine (see p. 418). However, in human metabolism, in which methionine is an essential amino acid, this reaction does not occur. 

In multicellular eukaryotes, DNA methylation is associated with transcriptional silencing [3]. In these organisms, DNA methylation has been observed exclusively on the C5 position of the cytosine ring and is frequently found in CpG-rich regions. This process is attributed to the action of DNA methyltransferases (DNMTs), which utilize the cofactor, S-adenosyl-L-methionine. Approximately half of all human genes have CpG islands in their promoter regions but these stretches of DNA are typically... 

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