Methionine methyl group synthesis

Triglyceride and phospholipid formation. This figure depicts the formation of triacylglycerol from a-glycerolphosphate and fatty-acyl CoA. The formation of phosphatidylethanolamine and phosphatidylcholine from scratch (i.e., from serine and methionine methyl groups) is also shown. The formation of phosphatidylcholine, starting with choline, is also depicted and is the major pathway for phosphatidylcholine synthesis. 

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. 

Folic acid is a vitamin, as we developed in chapter 15. It is a complex molecule that serves as an essential precursor for coenzymes involved in the metabolism of one-carbon units. For example, folic acid-derived coenzymes are critically involved in the biosynthesis of thymidine for nucleic acid synthesis and methionine for protein biosynthesis. The synthesis of both demands donation of a methyl group and they come from folic acid-derived coenzymes. 

The anaemia in B deficiency is caused by an inability to produce sufficient of the methylating agent S-adenosyhnethionine. This is required by proliferating cells for methyl group transfer, needed for synthesis of the deoxythymidine nucleotide for DNA synthesis (see below and Chapter 20). This leads to failure of the development of the nucleus in the precursor cells for erythrocytes. The neuropathy, which affects peripheral nerves as well as those in the brain, is probably due to lack of methionine for methyl transfer to form choline from ethanolamine, which is required for synthesis of phosphoglycerides and sphingomyelin which are required for formation of myelin and cell membranes. Hence, the neuropathy results from a... 

Small methyl groups are important in the stractnre of some small compounds, nucleotides, some bases in DNA mole-cnles and in postranslational modification of amino acids in proteins. The transfer of a single carbon atom is important in the synthesis of purine nncleotides. The componnds involved in the whole process of methyl gronp transfer, and are carbon metolism, are methionine, homocysteine, serine and the vitamins, folic acid and B12. 

Methionine, which is involved in methyl group donation for nucleotide synthesis, methylation of bases in DNA (Chapter 20) and conversion of choline to ethanolamine for membrane synthesis (Chapter 11). 

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. 

Cobalamin compounds Tight Cobalamin (B12) Transfer of methyl group to homocysteine during synthesis of methionine metabolism of methylmalonyl coenzyme A... 

Homocysteine (Hey) metabolism is closely linked to that of the essential amino acid methionine and thus plays a central role in several vital biological processes. Methionine itself is needed for protein synthesis and donates methyl groups for the synthesis of a broad range of vital methylated compounds. It is also a main source of sulphur and acts as the precursor for several other sulphur-containing amino acids such as cystathionine, cysteine and taurine. In addition, it donates the carbon skeleton for polyamine synthesis [1,2]. Hey is also important in the metabolism of folate and in the breakdown of choline. Hey levels are determined by its synthesis from methionine, which involves several enzymes, its remethylation to methionine and its breakdown by trans-sulphuration. 

Plants and bacteria produce the reduced sulfur required for the synthesis of cysteine (and methionine, described later) from environmental sulfates the pathway is shown on the right side of Figure 22-13. Sulfate is activated in two steps to produce 3-phosphoadeno-sine 5 -phosphosulfate (PAPS), which undergoes an eight-electron reduction to sulfide. The sulfide is then used in formation of cysteine from serine in a two-step pathway. Mammals synthesize cysteine from two amino acids methionine furnishes the sulfur atom and serine furnishes the carbon skeleton. Methionine is first converted to 5-adenosylmethionine (see Fig. 18-18), which can lose its methyl group to any of a number of acceptors to form A-adenosylhomocysteine (adoHcy). This demethylated product is hydrolyzed to free homocys-... 

Homocysteine is formed as an intermediary amino acid in the methionine cycle (Fig. I). Methionine is metabolized to s-adenosylmethionine (SAM), the methyl donor in most methylation reactions and essential for the synthesis of creatinine, DNA, RNA, proteins, and phospholipids. SAM is converted by methyl donation to s-adenosylhomocysteine (SAH), which is then hydrolyzed to homocysteine. SAH is an inhibitor of methyl group donation from SAM. 

Aminopterin and amethopterin are 4-amino analogues of folic acid (Fig. 11.5) and as such are potent inhibitors of the enzyme dihydrofolate reductase (EC 1.5.1.3) (Blakley, 1969). This enzyme catalyses the reduction of folic acid and dihydrofolic acid to tetrahy-drofolic acid which is the level of reduction of the active coenzyme involved in many different aspects of single carbon transfer. As is clear from Fig. 11.6, tetrahydrofolate is involved in the metabolism of (a) the amino acids glycine and methionine (b) the carbon atoms at positions 2 and 8 of the purine ring (c) the methyl group of thymidine and (d) indirectly in the synthesis of choline and histidine. 

If a stationary culture of mouse L929 cells is subcultured in the absence of methionine the cells fail to enter S-phase and even the presence of 10% the normal amount of methionine may have serious effects (Turnbull and Adams, 1975). However, once the cells have entered S-phase DNA synthesis will continue in the virtual absence of methionine, but the DNA and probably other polymers made are deficient in methyl groups. 

Cobalamin is a complex molecule containing a Co atom. In the mamalian synthesis of methionine, cobalamin acts as a coenzyme by accepting the methyl group from N5-methyltetrahydrofolate and transferring it to homocysteine. The reaction is catalyzed by cobalamin-N%-methyl-THF homocysteine methyltransferase. The overall reaction is... 

The methyl group on methionine is activated when methionine is converted to S-adenosyl-methionine. It is the methyl group of 5-adenosylmethionine that is the immediate donor in biological methylations. Important reactions in which 5-adenosylmethionine acts as the methyl donor are the synthesis of creatine, epinephrine, and phosphatidylcholine. 

Fig. 6 Methyl trap hypothesis 5,10-Methylenetetrahydrofolate is reduced to 5-methyltetiahy-drofolate in an irreversible reaction. When vitamin Bn is deficient, methyl groups are trapped as 5-methyltetrahydrofolate, resulting in decreased substrates for DNA synthesis and neural lipid methylation. MTHFR, methylenetetrahydrofolate reductase DHFR, dihydrofolate reductase MS, Methionine synthase TS, thymidylate synthase SAM, S-adenosyl-methionine dUMP, deoxyuridine 5 -monophosphate dTTP, deoxythymidine 5 -monophosphate...

Methylcobalamin is completely different from adenosylcobalamin because it is essentially a conduit for synthetic reactions catalyzed by methyltransferases, illustrated in Scheme 2 for the case of methionine. These reactions depend on the supemucle-ophilicity of cob(I)alamin. In one case, this species removes a methyl group from A -methyltetrahydrofolate with the formation of methylcobalamin, and then transfers this group to the acceptor homocysteine, which results in the synthesis of methionine (see Scheme 2). 

These tetrahydrofolate derivatives serve as donors of one-carbon units in a variety of biosyntheses. Methionine is regenerated from homocysteine by transfer of the methyl group ofF -methyltetrahydrofolate, as will be discussed shortly. We shall see in Chapter 25 that some of the carhon atoms of purines are acquired from derivatives of N lO-formyltetrahydrofolate. The methyl group of thymine, a pyrimidine, comes from N, N lO-methylenetetrahydrofolate. This tetrahydrofolate derivative can also donate a one-carhon unit in an alternative synthesis of glycine that starts with CO2 and NH4 +, a reaction catalyzed by glycine synthase (called the glycine cleavage enzyme when it operates in the reverse direction). 

The methyl group of the methionine unit is activated hy the positive charge on the adjacent sulfur atom, which makes the molecule much more reactive than N -methyltetrahydrofolate. The synthesis of -adenosylmethionine is unusual in that the triphosphate group of ATP is split into pyrophosphate and orthophosphate the pyrophosphate is subsequently hydrolyzed to two molecules of Pj. S-Adenosylhomocysteine is formed when the methyl group of -adenosylmethionine is transferred to an acceptor. -S-Adenosylhomocysteine is then hydrolyzed to homocysteine and adenosine. 

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