Methionine 5 -methylthioadenosine

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). 

In addition to ACC, ACS produces 5 -methylthioadenosine (MTA), which is recycled through methionine cycle to methionine (see Scheme 1). Recycling of MTA back to methionine requires only the available ATP. A constant concentration of cellular methionine is maintained even when ethylene is rapidly synthesized or when the pool of free methionine is small. The methionine cycle involves the following subsequent intermediates MTA, 5-methylthioribose (MTR), 5-methylthioribose-1-phosphate (MTR-l-P), 2-keto-4-methylthiobutyrate (KMB), and then the recycled methionine. ... 

Scheme 1 The ethylene biosynthetic pathway. The enzymes catalyzing each step are shown above the arrows. SAM S-adenosyl-L-methionine SAMS S-adenosyl-i-methionine synthetase ACC 1-aminocyclopropane-1-carboxylic acid ACS 1-aminocyclopropane-1-carboxylate synthase ACO 1-aminocyclopropane-1-carboxylate oxidase Ade adenine MTA methylthioadenosine. The atoms of SAM recycled to methionine through methionine cycle are marked in red and the atoms of methionine converted to ethylene are marked in bold. For details see text.

This enzyme [EC 3.3.1.2], also referred to as -adenosyl-methionine cleaving enzyme and methylmethionine-sulfonium-salt hydrolase, catalyzes the hydrolysis of -adenosylmethionine to produce methylthioadenosine and homoserine. The enzyme will also convert methyl-methionine sulfonium salt to dimethyl sulfide and homoserine. 

Adams and Yang (10) have suggested that the S atom of methionine is recycled in the ethylene reaction pathway, as shown in Fig. 2. In this scheme, 5 -methylthioadenosine, the residual molecule which derives from the reaction converting SAM to ACC, is further metabolized to 5 -methylthioribose, which then transfers the S-methyl group to homoserine to form methionine. This scheme is hypothetical, and the enzymes necessary for all these reactions have not as yet been demonstrated. 

During polyamine and ethylene biosynthesis, 5 -adenosyl-methionine (AdoMet) is converted to methylthioadenosine. 

A salvage pathway. Another product of S-adenosylmethionine is 5 -methylthioadenosine, which can be formed by an internal displacement on the y-methylene group by the carboxylate group (step I, Fig. 24-16). Methylthioadenosine also arises during formation of the compoimds spermidine (Fig. 24-12) and ACC (Fig. 24-16). Mammalian tissues convert methylthioadenosine back to methionine by the sequence shown in Eq. 24-34. It imdergoes phosphorol-ysis to 5 -methylthioribose whose ring is opened and... 

FIG. 55 Methionine salvage pathway via 5 -methylthioadenosine (MTA). 1, MTA phosphorylase 2, MTA nucleosidase 3, 5-methylthioritese kinase. 

The purine requirement for this enzyme is unknown and it is likely that an AdoMet analog based on purine or methionine could affect both polyamine and methylation reactions. In trypanosomatids, the salvage enzyme methylthioadenosine (MTA) phosphorylase has been found to have a broad substrate requirement (Fig. 7.1)... 

A unique feature of this cyclic pathway (the methionine cycle) is that the methylthiodadenosine released on ACC formation from AdoMet is recycled to produce methionine. Adams and Yang [37] found that when [ SJraethionine was supplied to tissue plugs from climacteric apple fruits these produced both radioactive 5 methylthioadenosine (MTA) and 5 methylthioribose (MTR) but tissue plugs from preclimacteric fruits did not. 

AdoMet is an important metabolic intermediate in all organisms, from bacteria to higher animals and plants. It supplies the methyl group to nucleic acids, phenolic substances and alkaloids, or the propylamine moiety to polyamines after decarboxylation. The methionine cycle operates in animals and microorganisms in relation to polyamine synthesis. Thus, enzymes which catalyse all of these reactions are present in all organsims. However, two enzymes in the ACC pathway, ACC synthase (AdoMet methylthioadenosine-lyase) and ACC oxidase, are unique to higher plants. ACC is also malonylated to form N-malonyl ACC, which does not serve as a precursor of ethylene [48,49]. 

The more complex sulphur requirements of the marine animals are met largely by cysteine, cystine, methionine, biotin, and thiamine (Young and Maw, 1958) (Fig. 4). Cysteine is a component of the tripeptide glutathione and a precursor of taurine. Methionine is as an essential amino acid involved in biosynthesis of proteins, creatine and adrenaline. Adenosylmethionine is considered to be the active part in transmethylation, e.g. of choline. Methionine is part of the pathways to homocysteine, cystathionine and methylthioadenosine (Young and Maw, 1958). Various organisms convert cysteine and/or cystine into mercapturic acids, cysteine sulphinic acid, and thiazolidine derivatives (Zobell, 1963). 

S ATP + 5-methylthioribose (<1> enzyme may be involved in an alternative pathway of methionine synthesis in plant tissues [1] <2> may be a primary enzyme involved in the recycling of the methylthio group of 5-methylthioribose back into methionine [2,3] <3> key step in recycling of methionine from 5 -methylthioadenosine a co-product of polyamine biosynthesis, expression of methylthioribose kinase may be under control of the methionine regulon [4]) (Reversibility [1-4, 6]) [1-4, 6, 7]... 

In the ensuing sections, we will focus on (a) the biosynthesis of homocysteine, the immediate precursor of the four-carbon and sulfur-containing moi-ety of methionine, (b) the biosynthesis of AdoMet and its nucleoside products AdoHcy and 5 -methylthioadenosine, and (c) the regulation of methionine biosynthesis. 

Adenosine triphosphate is the specific nucleotide of this reaction. Active methionine is the methyl donor to various acceptors, e.g., nicotinamide, glycocyamine, adrenaline. Transmethylations are catalyzed by specific methylpherases The product of transmethylation is usually the iV-methyl derivative of the acceptor while active methionine is converted to (S-adenosylhomocysteine. Active methionine may undergo hydrolytic cleavage in yeast to yield 5 -methylthioadenosine and homoserine 96). The reaction may not be enzymic. This adenosine derivative had been isolated long before active methionine was known 96). Betaine and certain sul-fonium compounds structurally related to active methionine, e.g., dimethyl-/8-propiothetin [(CHs)2= S—CH —CHj—COOH] 97), can also act as methyl donors for homocysteine in liver suspensions 98). 

Methylthioadenosine (MTA) represents one of the main products of S-adenosylmethionine (Ado-Met) metabolism and is distributed ubiquitously in micromolar amounts in several prokaryotes and eukaryotes . Although the chemical structure of this thioether was elucidated in 1924, its biological role as product of methionine metabolism was demonstrated by Schlenk in 1952, even before the discovery of its precursor Ado-Met. ... 

The specificity of human 5 -methylthioadenosine phosphorylase is rather strict if compared with that of the enzyme purified from E. coli The replacement of the sulfur atom of 5 -methylthioade-nosine by selenium and the replacement of the methyl group by an ethyl one are the only substrate modifications compatible with enzymic activity. The rate of breakdown of 5 -methylselenoadenosine equals that of 5 -methylthioadenosine (see Fig. 8). This finding agrees with the generally accepted view that the enzyme systems that normally utilize sulfur metabolites also convert their selenium analogues, i.e. the interchangeability of methionine and selenomethionine has been demonstrated in protein synthesisas well as that of S-adenosylmethionine and Se-adenosylselenomethionine in polyamine biosynthesis. 

Pascale, R.M., Simile, M.M., Satta, G., Seddaiu, M.A., Daino, L., Pinna, G., Vmci, M.A., Gaspa, L., and Feo, F. (1991). Comparative effects of L-methionine, S-adenosyl-L-methionine and 5 -methylthioadenosine on the growth of preneoplastic lesions and DNA methylation in rat liver during the early stages of hepatocarcinogenesis. Anticancer Res. 11,1617-1624. 

Fig, 7. Pathways for the metabolism of methionine to 5 -methylthioadenosine (MTA) and recycling of MTA to methionine. Methionine can serve as a carbon source for the synthesis of polyamines and, in some tissues, ethylene. 5 -Methylthioadenosine is a product of both processes. Only the methylthio group of methionine is recycled, the C4 moiety for the resynthesis of methionine being derived from the ribosyl moiety of ATP. The enzymes involved are (1) SAM synthetase, (2) SAM decarboxylase, (3) various C3 transfer enzymes of polyamine biosynthesis, (4) MTA nucleosidase, (5) methylthioribose kinase, (6) three( ) uncharacterized enzymes, (7) aminotransferase, and (8) aminocyciopropane carboxylate synthase. 

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