Adenosyl-L-methionine

The nonprotein amino acid, 1-aminocyclopropane-l-carboxylic acid, is an intermediate of ethylene biosynthesis in plants. This amino acid is synthesized from the L-a-amino acid methionine through the intermediate 5 -adenosyl-L-methionine (SAM) (Scheme 8). ... 

The possibility that many organic compounds could potentially be precursors of ethylene was raised, but direct evidence that in apple fruit tissue ethylene derives only from carbons of methionine was provided by Lieberman and was confirmed for other plant species. The pathway of ethylene biosynthesis has been well characterized during the last three decades. The major breakthrough came from the work of Yang and Hoffman, who established 5-adenosyl-L-methionine (SAM) as the precursor of ethylene in higher plants. The key enzyme in ethylene biosynthesis 1-aminocyclopropane-l-carboxylate synthase (S-adenosyl-L-methionine methylthioadenosine lyase, EC 4.4.1.14 ACS) catalyzes the conversion of SAM to 1-aminocyclopropane-l-carboxylic acid (ACC) and then ACC is converted to ethylene by 1-aminocyclopropane-l-carboxylate oxidase (ACO) (Scheme 1). 

DNA (cytosine-5-)-methyltransferase [EC 2.1.1.37] catalyzes the reaction of 5-adenosyl-L-methionine with DNA to produce 5-adenosyl-L-homocysteine and DNA containing a 5-methylcytosine residue. Site-specific DNA methyltransferase (cytosine-specific) [EC 2.1.1.73] catalyzes the reaction of 5-adenosyl-L-methionine with DNA containing a cytosine to produce 5-adenosyl-L-homocys-teine and DNA containing a 5-methylcytosine. 

This enzyme [EC 2.1.1.8] catalyzes the reaction of 5-adenosyl-L-methionine with histamine to produce 5-adenosyl-L-homocysteine and A -methylhistamine. 

This cobalamin-dependent enzyme [EC 2.1.1.13], also known as methionine synthase and tetrahydropteroyl-glutamate methyltransferase, catalyzes the reaction of 5-methyltetrahydrofolate with L-homocysteine to produce tetrahydrofolate and L-methionine. Interestingly, the bacterial enzyme is reported to require 5-adenosyl-L-methionine and FADH2. See also Tetrahydropteroyl-triglutamate Methyltransferase... 

Kinetics of O-Methylaiion. The steady state kinetic analysis of these enzymes (41,42) was consistent with a sequential ordered reaction mechanism, in which 5-adenosyl-L-methionine and 5-adenosyl-L-homocysteine were leading reaction partners and included an abortive EQB complex. Furthermore, all the methyltransferases studied exhibited competitive patterns between 5-adenosyl-L-methionine and its product, whereas the other patterns were either noncompetitive or uncompetitive. Whereas the 6-methylating enzyme was severely inhibited by its respective flavonoid substrate at concentrations close to Km, the other enzymes were less affected. The low inhibition constants of 5-adenosyl-L-homocysteine (Table I) suggests that earlier enzymes of the pathway may regulate the rate of synthesis of the final products. 

Thiopurine methyltransferase S-methylates 6-mercaptopurine and 6-thiogua-nine, both of which are used as antileukemic drugs. The source of the methyl group is 5-adenosyl-L-methionine. 

The 0-methylation of TIQ 77a with 5-adenosyl-L-methionine (SAM) in the presence of mammalian catechol O-methyltransferase (COMT) gave... 

With the assumption that reticulines are also precursors in mammalian synthesis of morphine, it was challenging to investigate whether they could be produced by enzymatic reactions similar to those utilized in benzylisoquinoline-producing plants (274). This plan focused attention on reactions controlled by the enzyme catechol 0-methyltransferase (COMT), using 5-adenosyl-L-methionine (SAM) for the methylation reaction. Mammalian COMT is present in mammalian tissues, particularly the liver, and an enzyme preparation from rat liver was used for the experiments. It was found that (S)-norcoclaurine, which is the first isoquinoline produced in benzylisoquinoline-producing plants, was similarly O-methylated in vitro by SAM in the presence of COMT, and a reverse proportion of methylated products was obtained with the (/ )-enantiomer (277). Similar 0-methylation of (5)-4 -demethylreticuline (3 -hydroxy-N-methylcoclaurine), prepared by total synthesis (162), however, afforded almost exclusively (5)-orientaline, with a methoxy group at C-3 and not at C-4 as in (5)-reticuline (Fig. 37) (762). 

Figure 2.12 A hypothetical view of compartmentation of indole alkaloid biosynthesis in Catharanthus roseus. Enzymes located with dashed arrows are hypothetical and circles indicate membrane associated enzymes (after Meijer et at, 1 993b). Cl OH, geraniol-1 0-hydroxylase NMT, 5-adenosyl-L-methionine 11 -methoxy 2,16-dihydro-16-hydroxytabersonine N-methyltransferase DAT, acetylcoenzyme A deacetylvindoline 1 7-0-acetyltransferase OHT, 2-oxyglutarate-dependent dioxygenase SSpC, strictosidine-((3)-glucosidase SSS, strictosidine synthase.

Figure 2.17 Biosynthesis of theobromine and caffeine in Coffea arabica. SAM, 5-adenosyl-L-methionine SAH, 5-adenosyl-L-homocysteine.

Figure 2 Structural analogs of 5,5-AdoMet with replacements in the sulfonium center and the transferable methyl group. Formulas are aligned to show the methyl group (or its equivalent) above, and the C-y and C-5 atoms below to the left and right side from the onium center, respectively, (a) 5-adenosyl-L-methionine (AdoMet) (b) Se-adenosyl-L-selenomethionine (Se-AdoMet) (c) Fe-adenosyl-t-telluromethionine CFe-AdoMet) ...

Stramentinoli, G. 5-Adenosyl-L-methionine the healthy joint product. Oxid. Stress Dis. 2001, 6, 63-73(Special Issue Nutraceuticals in Health and Disease Prevention). 

Bottiglieri, T. 5-Adenosyl-L-methionine (SAMe) from the bench to the bedside—molecular basis of a pleiotrophic molecule. Am. J. Clin. Nutr. 2002, 76 (5), 1151S-1157S. 

Bressa, G.M. 5-Adenosyl-L-methionine (SAMe) as antidepressant meta-analysis of chnical studies. Acta Neurol. Scand. Suppl. 1994,154, 7-14. 

Fetrow, C.W. Avila, J.R. Efficacy of the dietary supplement 5-adenosyl-L-methionine. Ann. Pharmacother. 2001, 35, 1414-1425. 

In E. coli, ThiH catalyzes the formation of the glycine imine 23 from tyrosine (26). ThiH is an oxygen-sensitive radical 5-adenosyl-L-methionine (SAM) enzyme. Its activity has been reconstituted and the mechanism outlined in Figure 8 has been proposed. It is unclear why E. coli adopts such a complex route to the glycine imine when oxidation of glycine using nicotinamide adenine dinucleotide (NAD) would accomplish the same transformation. 

Fig. 7. Biosynthesis of choline plasmalogens (plasmenylcholines) via modification of the sn-3 polar head group of ethanolamine plasmalogens (plasmenylethanolamines). These reactions are proposed to be catalyzed directly by (1) a base exchange enzyme or (II) At-methyltransferase. A combination of other enzymatic reactions could also result in replacement of the ethanolamine moiety of plasmenylethanolamine to produce plasmenylcholines the enzymes responsible include (IB) phospholipase C, (IV) the reverse reaction of ethanolamine phosphotransferase, (V) phospholipase D, (VI) phosphohydtolase, and (VII) cholinephosphotransferase. AdoMet, 5-adenosyl-L-methionine AdoHcy, 5-adenosyl-L-homocysteine Etn, ethanolamine GPE, sn-glycero-...

Two differences exist between fatty acid and complex polyketide syntheses (Fig. 2). First, in fatty acid synthesis, synthase uses only malonyl moieties as extender units to build an acyl chain. In general, acetate is used as the starter unit in vertebrate fatty acid synthase, but bacterial fatty acid synthase may use a branched-chain carboxylic acid as the starter unit because bacterial fatty acids sometimes contain branched-chain fatty acids. In contrast, polyketide synthesis in bacteria uses malonyl, methylmalonyl, and ethylmalonyl units as extenders. In the polyketide synthase, respective extender units are used at every step of the condensation. The polyketide synthase in fungi uses malonyl units as extenders and methyl groups at a positions are added by C-methylation using 5-adenosyl-L-methionine. 

Here we limit ourselves to an example of a 4Fe-4S center from the radical 5 -adenosyl-L-methionine (SAM) enzyme oxygen-independent coproporphyrinogen III oxidase HemN. This enzyme catalyzes the oxidative decarboxylation of coproporphyrinogen III to protoporphyrinogen IX during bacterial heme biosynthesis. The crystal structure of Escherichia coT/HemN revealed the presence of an unusually coordinated Iron-sulfur cluster and two molecules of SAM. 

Methylation is rarely of quantitative importance in the metabolization of xenobiotics. The methyl group is transferred from the nucleotide 5-adenosyl-L-methionine (SAM) by means of a methyl transferase. The functional groups include primary, secondary, and tertiary amines, pyridines, phenols, catechols, thiophenols, etc. The azahe-terocycle pyridine is metabolized to the A -methylpyridi-nium ion, which is more toxic than pyridine itself (Fig. 32.18). The binding properties of the ionized metabolite are disturbed by the loss of its hydrophobic feature, resulting from the polarity inversion. 

Abbreviations PP, pyridoxal phosphate PQQ, pyrroloquinoline quinone SAM, 5-adenosyl-L-methionine. A. Ramos et al, manuscript in preparation. 

An alternate pathway to guaiacyl lignin was later proposed following the characterization of 5-adenosyl-L-methionine iraras-caffeoyl-coenzyme A 3-(9-... 

K. Eto and H. Kimura, The production of hydrogen sulfide is regulated by testosterone and 5-adenosyl-L-methionine in mouse brain. J. Neurochem. 83, 80-86 (2002). 

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