Methionine epinephrine

Detoxifica.tlon. Detoxification systems in the human body often involve reactions that utilize sulfur-containing compounds. For example, reactions in which sulfate esters of potentially toxic compounds are formed, rendering these less toxic or nontoxic, are common as are acetylation reactions involving acetyl—SCoA (45). Another important compound is. Vadenosylmethionine [29908-03-0] (SAM), the active form of methionine. SAM acts as a methylating agent, eg, in detoxification reactions such as the methylation of pyridine derivatives, and in the formation of choline (qv), creatine [60-27-5] carnitine [461-06-3] and epinephrine [329-65-7] (50). 

A particular interest for clinical applications was a possibility for detection of dopamine by its oxidation on nickel [19], cobalt [65], and osmium [66] hexacyanofer-ates. Except for oxidation of dopamine, cobalt and osmium hexacyanoferrates were active in oxidation of epinephrine and norepinephrine. For clinical analysis it is also important to carry out the detection of morphine on cobalt [67] and ferric [68] hexacyanoferrates, as well as the detection of oxidizable amino acids (cystein, methionine) by manganous [69] and ruthenium [70] hexacyanoferrate-modified electrodes. In general, oxidation of thiols was first shown for Prussian blue [71] and nickel hexacyanoferrate [72], This approach has been used for the detection of thiols in rat striatum microdialysate [73], Alternatively, the detection of thiocholine with Prussian blue was employed for pesticide determination in acetylcholine-esterase test [74],... 

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. 

The coenzyme tetrahydrofolate (THF) is the main agent by which Ci fragments are transferred in the metabolism. THF can bind this type of group in various oxidation states and pass it on (see p. 108). In addition, there is activated methyl, in the form of S-adenosyl methionine (SAM). SAM is involved in many methylation reactions—e. g., in creatine synthesis (see p. 336), the conversion of norepinephrine into epinephrine (see p. 352), the inactivation of norepinephrine by methylation of a phenolic OH group (see p. 316), and in the formation of the active form of the cytostatic drug 6-mercaptopurine (see p. 402). 

This enzyme [EC 2.1.1.28], also known as phenylethanol-amine A -methyltransferase, catalyzes the reaction of S-adenosyl-L-methionine with phenylethanolamine to produce 5-adenosyl-L-homocysteine and A -methylphenyl-ethanolamine. The enzyme will act on a number of phe-nylethanolamines and will catalyze the conversion of noradrenalin (or norepinephrine) into adrenalin (or epinephrine). 

The methyl transferases (MTs) catalyze the methyl conjugation of a number of small molecules, such as drugs, hormones, and neurotransmitters, but they are also responsible for the methylation of such macromolecules as proteins, RNA, and DNA. A representative reaction of this type is shown in Figure 4.1. Most of the MTs use S-adenosyl-L-methionine (SAM) as the methyl donor, and this compound is now being used as a dietary supplement for the treatment of various conditions. Methylations typically occur at oxygen, nitrogen, or sulfur atoms on a molecule. For example, catechol-O-methyltransferase (COMT) is responsible for the biotransformation of catecholamine neurotransmitters such as dopamine and norepinephrine. A-methylation is a well established pathway for the metabolism of neurotransmitters, such as conversion of norepinephrine to epinephrine and methylation of nicotinamide and histamine. Possibly the most clinically relevant example of MT activity involves 5-methylation by the enzyme thiopurine me thy Itransf erase (TPMT). Patients who are low or lacking in TPMT (i.e., are polymorphic) are at... 

Methylation A -adenosyl- methionine Transmethylases (cytosol) Catecholamines, phenols, amines Dopamine, epinephrine, pyridine, histamine, thiouracil... 

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. 

FIGURE 9.85 Biosynthesis of catecholamines. Tposine is used for the synthesis of various small molecules, which are used as hormones and neurotransmitters. The nutritional biochemist might be especially interested in the pathway of epinephrine bios)mthesis, as it requires the participation of four separate cofactors. These are (1) biopterin (2) pyridoxal phosphate (3) ascorbic acid and (4) S-adenosyl-methionine. 

Methionine, USP. An adequate diet should provide the methionine ncccs.sary for normal metabolism in the human.. Viethionine is considered an essential amino acid in humans. It is the precursor in the biosynthesis of -adcnosylnie(hio-niiic, which is an important methylating coenzyme involved In a variety of methylations (e.g.. N-me(hyla(ion of norepinephrine to form epinephrine and O-methylation of catecholamines catalyzed by ca(cchul-CI-mcthyl(iansfcra.ses). Adenosylmcthionine also participates in the methylation of pho.sphatidylcthanolaininc to form phosphatidylcholine, but this pathway is not efficient enough to provide all of the choline required hy higher animals hence, adequate dietary availability of choline is ncces.sary. ... 

S-Adenosylmethionine (SAM), which is produced from methionine and ATP, is involved in the transfer of methyl groups to compounds such as creatine, phosphatidylcholine, epinephrine, melatonin, and methylated polynucleotides. 

Methylation of norepinephrine in the adrenal medulla by S-adenosyl-g methionine forms the hormone epinephrine. 

This essential amino acid contains an R-group with a methyl group attached to sulfur. Methionine serves as donor of a methyl group in many transmethylation reactions, e.g., in the synthesis of epinephrine, creatine, and... 

Norepinephrine diifuses into the cytosol, where it is converted to epinephrine by methylation of its amino group. This reaction, in which the methyl group is donated by S-adenosylmethionine, is catalyzed by S-adenosyl-L-methionine phenylethanolamine-N-methyltransferase (PNMT). Epinephrine enters the granules and remains there until it is released. 

Outside of DNA synthesis, folate plays a role in methylation metabolism. The major methyl donor is S-adenosyl methionine (SAM), which is required for many reactions. For example, SAM is needed for the production of norepinephrine from epinephrine and for DNA methylation, which can influence gene transcription. After methyl group transfer, SAM is converted to S-adenosyl homocysteine (SAH), which is hydrolyzed to homocysteine and... 

Tyrosine is converted to dopa by the rate-limiting enzyme, tyrosine hydroxylase, which reqnires tetrahydro-biopterin and is inhibited by alpha-methyltyrosine. Dopa is decarboxylated to dopamine by L-aromatic amino acid decarboxylase, which reqnires pyridoxal phosphate (vitamin Bg) as a coenzyme. Carbidopa, which is used with l-dopa in the treatment of parkinsonism, inhibits this enzyme (see Figure 37). Dopamine is converted to norepinephrine by dopamine beta-hydroxylase, which requires ascorbic acid (vitamin C), and is inhibited by diethyldithiocarbamate. Norepinephrine is converted to epinephrine by phenyletha-nolamineN-melhyltransferase (PNMT), requiring S-adenosyl-methionine. The activity of PNMT is stimulated by corticosteroids. 

S-adenosylmethionine (SAM) SAM, produced from methionine and adenosine triphosphate (ATP), transfers the methyl group to precursors forming a number of compounds, including creatine, phosphatidylcholine, epinephrine, melatonin, methylated nucleotides, and methylated DNA. 

The relevance of the results obtained in vitro, in either liver slices or perfusates, to the general problem of lipoprotein biosynthesis in the intact animal remains to be established. In vivo synthesis of the protein moiety of serum 3-lipoprotein was studied in roosters by administration of S -methionine (Florsheim et al., 1963), followed by measurements of specific radioactivity of plasma 3-lipoprotein separated by dextran sulfate. Under these experimental conditions, enhancement of methionine incorporation was noted after pharmacological doses of ethanol, estrogens, and triiodothyronine. No significant effect was obtained after administration of epinephrine, cortisone, and thyroxine preparations. 

Enzymatic catalysis is also used in the synthesis of l-"C-labeled D-fructose and o-glucose firom mannitol and glucitol, respectively (Ogren and Langstrom 1998). The preparation of S-adenosyl-L-[ C]methionine (Guegen et al. 1982), [ C]epinephrine (Soussain et al. 1984), and [ C]daunorubicin (Eriks-Fluks et al. 1998) are other examples of enzyme catalysis. The nucleosides [ C]thymidine and [ C]-2 -arabino-2 -fluoro-P-5-methyl-uridine have been prepared by enzymes immobilized on hollow fiber membranes using [ C]formaldehyde as the labeled precursor (Hughes and Jay 1995). 

Norepinephrine is methylated in the presence of a specific enzyme (S-adenosylmethionine transferase) and a cofactor (S-adenosylmethionine) to form epinephrine. This reaction is analogous to the methyla-tion of guanidinoacetic acid, which occurs in liver. Two distinct enzyme reactions are involved methionine is converted to S-adenosylmethionine in the presence of a methionine-activating enzyme and ATP, in which reaction all the phosphates of ATP are lost, the terminal phosphorus of ATP is liberated as inorganic phosphate and the two internal phosphoryl groups yield pyrophosphate and (2) norepinephrine is then methylated in the presence of a specific enzyme S-adenosylmethionine transferase to form epinephrine. 

The methyl group of epinephrine can be provided by transmethylation from methionine. This was shown by du Vigneaud and co-workers by feeding methionine-C -CHs and isolating radioactive epinephrine from the adrenal glands. 

The utilization of the methyl group of methionine for the formation of the methyl group of methionine was first shown by Keller et al. (248). The conversion of norepinephrine to epinephrine was shown later by the isolation of radioactive epinephrine from rat adrenals after the injection of norepinephrine-C (248). Subsequent work has done much to fill in the details of the enzymic steps in this reaction sequence. 

Epinephrine (adrenalin see also Chapter 6 Opening) is produced in your body in a two-step process that accomplishes the transfer of a methyl group from methionine (Problem 70) to norepinephrine (see reactions 1 and 2 below), (a) Explain in detail what is going on mechanistically in these two reactions, and analyze the role played by the molecnle of ATP. (b) Would you expect methionine to react directly with norepinephrine Explain, (c) Propose a laboratory synthesis of epinephrine from norepinephrine. 

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