5-adenosylmethionine metabolism

Lawrence, F. and Robert-Gero, M. (1991) S-Adenosylmethionine metabolism in parasitic protozoa. In Biochemical Protozoology (eds Coombs, G. H. and North, M. J.), Taylor and Francis, London, pp. 436-449. 

Metabolic interrelations between 5-adenosylmethionine, folates, and vitamin Bl2 96CLY165. 

Divalent sulfur compounds are achiral, but trivalent sulfur compounds called sulfonium stilts (R3S+) can be chiral. Like phosphines, sulfonium salts undergo relatively slow inversion, so chiral sulfonium salts are configurationally stable and can be isolated. The best known example is the coenzyme 5-adenosylmethionine, the so-called biological methyl donor, which is involved in many metabolic pathways as a source of CH3 groups. (The S" in the name S-adenosylmethionine stands for sulfur and means that the adeno-syl group is attached to the sulfur atom of methionine.) The molecule has S stereochemistry at sulfur ana is configurationally stable for several days at room temperature. Jts R enantiomer is also known but has no biological activity. 

Figure 2.16. Pathways for the synthesis and metabolism of the catecholamines. A=phenylalanine hydroxylase+pteridine cofactor+Oj B tyrosine hydroxylase+ tetrahydropteridme+Fe+ +Oj C=dopa decarboxylase+pyridoxal phosphate D= dopamine beta-oxidase+ascorbate phosphate+Cu+ +Oj E=phenylethanolamine N-methyltransferase+S-adenosylmethionine l=monoamine oxidase and aldehyde dehydrogenase 2=catechol-0-methyltransferase+S-adenosylmethionine.

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. 

Several pharmacological studies were earned out to substantiate the proposed prodrug concept for (/< )-a-methylhistamine (12). The parent compound of this series of azomethines is the 2-hydroxybenzophenone derivative of (ft)-a-methylhistamine which is designated BP 2.94 (36). To evaluate the desired protection against HMT metabolization, BP 2.94 (36) was tested as a possible substrate in the presence of S-adenosylmethionine in comparison to histamine and ( )-a-methylhistamine (12). As a result no methylation of the prodrug 36 was observed, whereas both primary amines displayed similar Km- and Fmax-values [6],... 

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. 

The principal anabolic pathways for secondary metabolites originate from just a few intermediates of primary metabolic pathways, such as acetyl CoA, shikimic acid, and melvonic acid.86 Among the important cofactors are ATP, NADPH, and S-adenosylmethionine, which need to be continuously regenerated via primary metabolic pathways of respiration or photosynthesis. The fact that secondary metabolism shares chemical precursors with primary metabolism means that secondary and primary metabolic pathways may compete for substrates and cofactors, strongly suggesting that trade-offs occur at the biochemical level. 

Highly populated protein domain families of H. pylori include (1) the cellular component Helicobacter outer membrane protein family (2) the sell family, which is associated with P-lactamase activity (3) members of the CagA and VacA protein families, which are secreted into host cells and are involved in pathogenesis (4) the ABC transporter family, which is associated with ATP-dependent transport of molecules across the membrane (5) the DNA methyltransferase protein domain family (6) the radical SAM (S-adenosylmethionine) family associated with various metabolic functions of pathogens and (7) the response regulator receiver domain family, which is involved in receiving the signal from the sensor domain in bacterial two-component systems. 

Figure 16.10 Catecholamine biosynthesis and metabolism. MAO, monoamine oxidase COMT, catecholamine-O-methyltransferase SAM, 5-adenosylmethionine.

Biotransformations Epinephrine, like the other catecholamines, is metabolized by two enzymatic pathways COMT, which has S-adenosylmethionine as a cofactor, and MAO (see Figure 6.3). The final metabolites found in the urine are metanephrine and vanillylmandelic acid. [Note Urine also contains normeta-nephrine, a product of norepinephrine metabolism.]... 

Homocysteine is formed in the cytoplasm during the intracellular metabolism of methionine. Within the methionine cycle (Fig. 21-2), methionine is converted to 5-adenosylmethionine... 

Figure 21-2. Metabolism of homocysteine. BHMT, betaineihomocysteine methyl-transferase CBS, cystathionine P-synthase Cob, cobalamin CTH, cystathionine y-lyase DHF, dihydrofolate DMG, dimethylglycine FAD, flavin adenine dinucleotide MAT, methionine adenosyltransferase 5-MTHF, 5-methyltetrahydrofolate 5,10-MTHF, 5,10-methylenetetrahydrofolate MTHFR, methylenetetrahydrofolate reductase MS, methionine synthase MTRR, methionine synthase reductase MTs, methyl transferases PLE pyridoxal phosphate SAH, S-adenosylhomocysteine SAHH, SAH hydrolase SAM, 5-adenosylmethionine SHMT, serine hydroxymethyltransferase THF, tetrahydrofolate Zn, zinc.

All the cosubstrates that occur in drug conjugation (Figure 2.28) have other roles in metabolism e.g., UDP-glucuron-ic acid and PAPS provide acidic groups for the S5mthesis of mucopolysaccharides, whereas S-adenosylmethionine provides methyl groups for the synthesis of phosphatidylcholine from phosphatidylethanolamine. 

Figure 2.28. Coenzymes that are important in dmg metabolism. The groups transferred to the drags are shown in red. a UDP-glucuronide (transfers glucmonate), b PAPS (transfers sulfate), c S-adenosylmethionine (transfers methyl group).

In experimental animals and with isolated tissue preparations and organ cultures, the test can be refined by measuring the production of G02 from [ C]histidine in the presence and absence of added methionine. If the impairment of histidine metabolism is the result of primary folate deficiency, the addition of methionine wUl have no effect. By contrast, if the problem is trapping of folate as methyl-tetrahydrofolate, the addition of methionine will restore normal histidine oxidation as a result of restoring the inhibition of methylene-tetrahydrofolate reductase by S-adenosylmethionine and restoring the activity of 10-formyl-tetrahydrofolate dehydrogenase, thus permitting more normal folate metabolism (Section 10.3.4.1). 

The second nitrogen of biotin is incorporated by transamination of keto-aminopelargonic acid, with S-adenosyfinethionine - an apparently unique metabolic role for thus amino acid derivative that is normally a methyl donor. The immediate product of the deamination of S-adenosylmethionine, S-adenosyl-2-oxo-4-methylthiobutyric acid, is unstable and decomposes non-enzymicaUy to 2-oxo-3-butenoic acid and 5 -methyl tbioadenosine. 

Methylation is a common feature of the metabolism of phenols and A-heterocyclic compounds. Thus, phenolic steroids, adrenaline, and some other catecholamines undergo O-methylation, while pyridine, nicotinic acid, and normorphine undergo N-methylation. The reaction occurs under the influence of 5-adenosylmethionine and a non-specific methyl transf erase. 

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