Methionine S-adenosyl

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). 

Histone methylation is a common posttranslational modification fond in histones. Histone methylations have been identified on lysine and arginine residues. In case of lysines S-adenosyl-methionine (SAM) dependent methyl transferases catalyze the transfer of one, two or three methyl groups. Lysine methylation is reversible and lysine specific demethylases have been... 

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. 

Kluijtmans, L. A., Boers, G. H., Stevens, E. M. et al. Defective cystathionine beta-synthase regulation by S-adenosyl-methionine in a partially pyridoxine responsive homocys-tinuria patient./. Clin. Invest. 98 285-289,1996. 

Studies on three different iron-sulfur enzyme systems, which all require S-adenosyl methionine—lysine 2,3-aminomutase, pyruvate formate lyase and anaerobic ribonucleotide reductase—have led to the identification of SAM as a major source of free radicals in living cells. As in the dehydratases, these systems have a [4Fe-4S] centre chelated by only three cysteines with one accessible coordination site. The cluster is active only in the reduced... 

Figure 13.18 S-adenosyl methionine (SAM), a source of 5 -deoxyadenosyl radicals. SAM binds to the subsite iron (in blue) of the reduced [4Fe-4S] cluster via its a-aminocarboxylate group. The 5 -deoxyadenosine radical is formed by electron transfer which occurs either (a) by outer-sphere mechanism or (b) by p-sulfide alkylation followed by homolytic cleavage of the 5 -S-CH2Ado bond. In both cases, methionine is released. (From Fontecave et al., 2004. Copyright 2004, with permission from Elsevier.)...

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. 

Some of the catecholamine will enter the target cell rather than be recaptured by the neurone. Inactivation is brought about by the second enzyme, COMT which uses S-adenosyl methionine as a methyl donor as does PNMT (involved with catecholamine... 

It is the role of jV5-methyl THF which is key to understanding the involvement of cobalamin in megaloblastic anaemia. The metabolic requirement for N-methyl THF is to maintain a supply of the amino acid methionine, the precursor of S-adenosyl methionine (SAM), which is required for a number of methylation reactions. The transfer of the methyl group from jV5-methyl THF to homocysteine is cobalamin-dependent, so in B12 deficiency states, the production of SAM is reduced. Furthermore, the reaction which brings about the formation of Ns-methyl THF from N5,N10-methylene THF is irreversible and controlled by feedback inhibition by SAM. Thus, if B12 is unavailable, SAM concentration falls and Ah -methyl THF accumulates and THF cannot be re-formed. The accumulation of AT-methyl THF is sometimes referred to as the methyl trap because a functional deficiency of folate is created. 

MTHFR = methylene tetrahydrofolate reductase DHFR = dihydrofolate reductase SAM = S-adenosyl methionine... 

Creatine is synthesized from glycine and arginine (Figure 7.13) and requires S-adenosyl methionine (SAM) as a methyl group donor. 

Histone methylation is another posttranslational modification which involves a transfer of a methyl group from the methyl donor S-adenosyl methionine (SAM) to lysine or arginine residues (Fig. 1). In sharp contrast with histone acetylation, this modification occurs particularly in histones H3 and H4 with a remarkable specificity (Kouzarides, 2002 Shilatifard, 2006) (Fig. 1, Table 2). Another feature of histone methylation is that a large fraction of histones in mature chromatin is... 

The compounds that are the immediate methyl gronp donors are methyltetra hydrofate (CH3-FH4) and S-adenosyl methionine (SAM) (see Figure 15.2). These are involved in, at least, five key reactions or processes which are summarised in Figure 15.4. Complexity arises in the topic of methyl group transfer in formation and reformation of the methylating compounds 5-adenosylmethione and methyl tetrahydrofolate. There are four important reactions in the formation utilisation and then the reformation of 5-adenosylmethionine as follows ... 

A high level of homocysteine is an indication of a low rate of conversion of homocysteine to methionine and hence a low level of the methylating agent S-adenosyl methionine. The latter, plus the toxic effects of homocysteine, provides a link between the reactions listed above and three diseases cardiovascular disease (Chapter 22), senile dementia (Chapter 14) and cancer (Chapter 21). 

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]. 

The coenzyme tetrahydrofolate (THF) is the main agent by which Ci fragments are transferred in the metabolism. THF can bind this type of group in various oxidation states and pass it on (see p. 108). In addition, there is activated methyl, in the form of S-adenosyl methionine (SAM). SAM is involved in many methylation reactions—e. g., in creatine synthesis (see p. 336), the conversion of norepinephrine into epinephrine (see p. 352), the inactivation of norepinephrine by methylation of a phenolic OH group (see p. 316), and in the formation of the active form of the cytostatic drug 6-mercaptopurine (see p. 402). 

Transfer of a phosphocholine residue to the free OH group gives rise to phosphatidylcholine (lecithin enzyme l-alkyl-2-acetyl-glycerolcholine phosphotransferase 2.7.8.16). The phosphocholine residue is derived from the precursor CDP-choline (see p. 110). Phos-phatidylethanolamine is similarly formed from CDP-ethanolamine and DAG. By contrast, phosphatidylserine is derived from phosphatidylethanolamine by an exchange of the amino alcohol. Further reactions serve to interconvert the phospholipids—e.g., phosphatidylserine can be converted into phosphatidylethanolamine by decarboxylation, and the latter can then be converted into phosphatidylcholine by methylation with S-adenosyl methionine (not shown see also p. 409). The biosynthesis of phosphatidylino-sitol starts from phosphatidate rather than DAG. 

Creatine does not derive from the muscles themselves, but is synthesized in two steps in the kidneys and liver (left part of the illustration). Initially, the guanidino group of arginine is transferred to glycine in the kidneys, yielding guanidino acetate [3]. In the liver, N-methylation of guanidino acetate leads to the formation of creatine from this [4]. The coenzyme in this reaction is S-adenosyl methionine (SAM see p. 110). 

DNMTs catalyze the methylation of cytosines located 5 to a guanosine as part of a CpG dinucleotide (CpG) in DNA to 5-methylcytosines using S-adenosyl methionine... 

Once the azacytosine analogs are incorporated into the DNA, they are also subjed to a covalent addition of the thiol group of the DNMT and an adduct (la) similar to (I) in Figure 8.5 is formed. This addud (la) in most cases also reacts with S-adenosyl methionine (II) to a methylated addud (Ilia). But due to the absence of an a-proton the enzyme carmot be liberated by elimination and remains trapped to DNA (Figure 8.8). 

---