Methyl group, donor

MAO converts dopamine to DOPAC (3,4-dihydrox-yphenylacetic acid), which can be further metabolized by COMT to form homovanillic acid (HVA). HVA is the main product of dopamine metabolism and the principal dopamine metabolite in urine. Increased neuronal dopaminergic activity is associated with increases in plasma concentrations of DOPAC and HVA. COMT preferentially methylates dopamine at the 3 -hydroxyl position and utilizes S-adenosyl-L-methio-nine as a methyl group donor. COMT is expressed widely in the periphery and in glial cells. In PD, COMT has been targeted since it can convert l-DOPA to inactive 3-OMD (3-O-methyl-dopa). In the presence of an AADC inhibitor such as carbidopa, 3-OMD is the major metabolite of l-DOPA treatment. 

Adenosylmethionine, the methyl group donor for many biosynthetic processes, also participates direcdy in spermine and spermidine biosynthesis. 

The first step is catalysed by the tetrahydrobiopterin-dependent enzyme tyrosine hydroxylase (tyrosine 3-monooxygenase), which is regulated by end-product feedback is the rate controlling step in this pathway. A second hydroxylation reaction, that of dopamine to noradrenaline (norepinephrine) (dopamine [3 oxygenase) requires ascorbate (vitamin C). The final reaction is the conversion of noradrenaline (norepinephrine) to adrenaline (epinephrine). This is a methylation step catalysed by phenylethanolamine-jV-methyl transferase (PNMT) in which S-adenosylmethionine (SAM) acts as the methyl group donor. Contrast this with catechol-O-methyl transferase (COMT) which takes part in catecholamine degradation (Section 4.6). 

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

Tetrahydrofolic acid (THF) Loose Folic acid Methyl group donor in one-carbon transfer reactions critical in biosynthesis of purines and pyrimidines... 

Fig. 1.43. The methylation of DNA 5-methyl-cytidine and maintenance methylation. a) The methylation of cytidine residues on DNA is catalyzed by a methyl transferase that employs S-ade-nosine methionine as a methyl group donor. The peferable substrate for the methyl transferase are hemi-methylated CpG sequences. 5-aza-cytidine is a specific inhibitor of methyl transferses. b) The methylation pattern of DNA remains intact upon DNA replication and is passed on to the daughter cells. The newly synthesized strands are unmethylated immediately after DNA rephca-tion. The methyltransferase uses the previously methylated parent strand as a matrix to methylate the CpG sequences of the newly synthesized strand.

FIGURE 22-12 Biosynthesis of serine from 3-phosphoglycerate and of glycine from serine in all organisms. Glycine is also made from C02 and NH( by the action of glycine synthase, with N5,N10-methy-lenetetrahydrofolate as methyl group donor (see text). 

Phosphocreatine, derived from creatine, is an important energy buffer in skeletal muscle (see Fig. 13-5). Creatine is synthesized from glycine and arginine (Fig. 22-26) methionine, in the form of S-adenosylmethionine, acts as methyl group donor. 

Methionine is one of four amino acids that form succinyl CoA. This sulfur-containing amino acid deserves special attention because it is converted to S-adenosylmethionine (SAM), the major methyl-group donor in one-carbon metabolism (Figure 20.8). Methionine is also the source of homocysteine—a metabolite associated with atherosclerotic vascular disease. 

S-adenosylmethionine is also a biological methyl group donor. The product of its methyl transferase reactions is S-adenosylhomocysteine. This product is further degraded by S-adenosylhomocysteine hydrolase, an enzyme that contains tightly bound NAD+, to form homocysteine and adenosine. 

A5, A1 °-Methylcnctctrahydrofolate is a hydroxymethyl-group donor substrate for several enzymes and a methyl-group donor substrate for thymidylate synthase (fig. 10.15). It arises in living cells from the reduction of A5,A10-methenyltetrahydrofolate by NADPH and also by the serine hydroxymethyltransferase-catalyzed reaction of serine with tetrahydrofolate. 

A5-Methyltetrahydrofolate is the methyl-group donor substrate for methionine synthase, which catalyzes the transfer of the five-methyl group to the sulfhydryl group of homocysteine. This and selected reactions of the other folate derivatives are outlined in figure 10.15, which emphasizes the important role tetrahydrofolate plays in nucleic acid biosynthesis by serving as the immediate source of one-carbon units in purine and pyrimidine biosynthesis. 

Thymidylate biosynthesis. (R = p-aminobenzoyl-L-glutamate.) Red symbols indicate precursors of the methyl group of thymidylate. The dTMP is formed from dUMP. 5,10-Methylenetetrahydrofolate donates the methyl group in this reaction. This methyl group donor is... 

Vitamin B12 activates methyl groups for methionine biosynthesis by binding them to the Co ion at the sixth position. The methyl group donor to Bi2 is 5-methyl tetrahydrofolate. The methyl-Bi2 donates its methyl group to homocysteine, forming methionine. 

Figure 28-5. The reaction catalyzed by methionine synthase, a vitamin B12-requiring enzyme. In this reaction, homocystine is converted to methionine, with the simultaneous production of tetrahydrofolate (THF) from 5-methyltetrahydrofolate.Methionine can then be converted to 5-adenosyhnethionine (SAM), the universal methyl-group donor.

Phosphatidylserine arises by an exchange of the ethanolamine residue of phosphatidylethanolamine for a seryl group. Decarboxylation of the serine of phosphatidylserine reforms phosphatidylethanolamine. Three successive methylation reactions convert phosphatidylethanolamine to phosphatidylcholine. 5-Adenosyl-methionine is the methyl-group donor (Chap. 15) (see Fig. 13-14). 

Why does feeding compounds that act as methyl-group donors to patients with fatty liver alleviate the condition ... 

Roje, S. (2006) S-Adenosyl-L-methionine beyond the universal methyl group donor. Phytochemistry, 67, 1686-98. 

Tannic acid causes centralobular liver necrosis following absorption from gastrointestinal tract, mucus membranes, or from denuded skin surfaces. Liver metabolism of tannic acid requires methyl-group donors. Therefore, methyl-group donors can be depleted following excessive tannic acid absorption. 

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