Methionine choline methyl groups from

The question therefore arose about the fate of the methyl group from methionine. When minimal amounts of methionine were used to supplement the diet of rats given homocysteine as their main source of sulfur, the rats did not usually thrive, and at death had fatty accumulations in their livers. Best and his co-workers had earlier reported the efficacy of choline as a lipotropic agent, facilitating the mobilization of fat from the liver. Du Vigneaud therefore tried supplementing homcys-... 

Animals also derive methyl groups from dietary choline, which can partially substitute for the methionine nutritional requirement. An oxidation product of choline, betaine, is the actual methyl donor to homocysteine. This probably represents a salvage pathway for methyl groups in the catabolism of choline, but it can be of considerable importance if the capacity for de novo methyl synthesis is limited. 

On the other hand, if we wanted to describe this reaction to a biochemist fer reaction. Biochemists have described many similar reactions this way, for transfers a methyl group from S-adenosy/methionine AM) to a tertiary amine to make choline. Choline is incorporated into the phospholipids of our cell membranes, and it is the hydrolysis product of acetylcholine, an important neurotransmitter. (Crystals of acetylcholine are shoum in the polarized light microscopy image above.)... 

Creatine was first isolated in 1835 by Chevreul 20 years later Dessaignes showed it to contain a methyl group. Choline was obtained from lecithin in bile by Strecker in 1849 and methionine isolated by Mueller in 1922. That methionine contained a methyl group linked to sulfur was demonstrated by Barger and Coyne in 1928. 

The anaemia in B deficiency is caused by an inability to produce sufficient of the methylating agent S-adenosyhnethionine. This is required by proliferating cells for methyl group transfer, needed for synthesis of the deoxythymidine nucleotide for DNA synthesis (see below and Chapter 20). This leads to failure of the development of the nucleus in the precursor cells for erythrocytes. The neuropathy, which affects peripheral nerves as well as those in the brain, is probably due to lack of methionine for methyl transfer to form choline from ethanolamine, which is required for synthesis of phosphoglycerides and sphingomyelin which are required for formation of myelin and cell membranes. Hence, the neuropathy results from a... 

Homocysteine (Hey) metabolism is closely linked to that of the essential amino acid methionine and thus plays a central role in several vital biological processes. Methionine itself is needed for protein synthesis and donates methyl groups for the synthesis of a broad range of vital methylated compounds. It is also a main source of sulphur and acts as the precursor for several other sulphur-containing amino acids such as cystathionine, cysteine and taurine. In addition, it donates the carbon skeleton for polyamine synthesis [1,2]. Hey is also important in the metabolism of folate and in the breakdown of choline. Hey levels are determined by its synthesis from methionine, which involves several enzymes, its remethylation to methionine and its breakdown by trans-sulphuration. 

Aminopterin and amethopterin are 4-amino analogues of folic acid (Fig. 11.5) and as such are potent inhibitors of the enzyme dihydrofolate reductase (EC 1.5.1.3) (Blakley, 1969). This enzyme catalyses the reduction of folic acid and dihydrofolic acid to tetrahy-drofolic acid which is the level of reduction of the active coenzyme involved in many different aspects of single carbon transfer. As is clear from Fig. 11.6, tetrahydrofolate is involved in the metabolism of (a) the amino acids glycine and methionine (b) the carbon atoms at positions 2 and 8 of the purine ring (c) the methyl group of thymidine and (d) indirectly in the synthesis of choline and histidine. 

Choiine. Choline is a component of many biomem-hranes and plasma phospholipids. Dietary sources include eggs. fish, liver, milk, and vegetables. These sources provide choline primarily as the phospholipid lecithin. Lecithin is hydrolyzed to glycerophosphorylcholinc by the intestinal mucosa before absorption. The liver liberates choline. Choline can be biosynthesized by humans con.sequcntly. it cannot be con.sidcred a (rue vitamin. Biosynthesis involves methylation of cthanolamine. The methyl groups arc provided by methionine or by a reaction involving vitamin B12 and folic acid. Therefore, deficiencies can occur only if all methyl donors are excluded from the diet. 

The widespread co-occurrence of noradrenaline and adrenaline in itself suggests that noradrenaline is the immediate adrenaline precursor. This had been considered probable even before the natural occurrence of noradrenaline was known (70, 71), and the methylation of noradrenaline has since been shown both in vitro in adrenal preparations (110) and in vivo on perfusing the surviving adrenal (111). The methyl group can arise from methionine, probably formed from choline, in which the adrenal is extremely rich. A large proportion of the activity of administered (methyl-C ) methionine appears in the adrenal (460, 569). 

The importance of SAM in metabolism is reflected in the several mechanisms that provide for the synthesis of sufficient amounts of its precursor, methionine, when the latter molecule is temporarily absent from the diet. For example, choline is used as source of methyl groups to convert homocysteine into methionine. Homocysteine can also be methylated in a reaction utilizing N5-methyl THF. This latter reaction is a bridge between the THF and SAM pathways (Figure 14.17). 

The methyl group on the pyrrolidine nitrogen of nicotine is derivable from methionine, where it is transferred as such (397, 398), from choline, which is probably first oxidized to betaine (399, 400), from formaldehyde (401), from glycine and from glycolic acid, of which the a-carbon is transferred (402, 403), and from serine (402) and from glycolic acid (403), from both of which the /3-carbon is transferred. 

Triglyceride and phospholipid formation. This figure depicts the formation of triacylglycerol from a-glycerolphosphate and fatty-acyl CoA. The formation of phosphatidylethanolamine and phosphatidylcholine from scratch (i.e., from serine and methionine methyl groups) is also shown. The formation of phosphatidylcholine, starting with choline, is also depicted and is the major pathway for phosphatidylcholine synthesis. 

Lipotrophic factors are those required for transportation of triacylglycerol from the liver to the adipose tissue for storage. These factors are those that cannot be synthesized from nonlipotrophic components of the diet. The major role of lipotrophic factors is the formation of phosphatidylcholine, which is critical in VLDL formation. One of the lipotrophic factors obviously would be choline, which can be incorporated into phosphatidylcholine. Two other lipotrophic factors are related to the potential de novo synthesis of choline. The first and foremost is methionine, which can be used to donate the methyl groups for choline formation in the absence of dietary choline, thus allowing lipids to be moved from liver to adipose tissue (Fig. 18.7). 

A second lipothrophic factor is betaine, which is effective because the transfer of at least one of its methyl groups to homocysteine is very efficient and can replenish methionine for choline formation. In the absence of sufficient lipotrophic factors, a fatty liver develops, and there is insufficient movement of fats either ingested or synthesized in the liver to the adipose tissue. As fats enter or are synthesized in the liver, they are repackaged or packaged as VLDLs to be moved out for transport from the blood to adipose tissue. The VLDLs contain protein, triacylglycerol, cholesterol, cholesterol esters, and phospholipids, especially phosphatidylcholine (lecithin). If one has either a protein deficiency or a lipotrophic factor deficiency, the movement of triacylglycerol s from the liver to adipose is ineffective and a fatty liver can develop. Choline can be present in the diet and need not be synthesized de novo. Phospholipid synthesis has been discussed previously (Chapter 15). 

The reducing property of ascorbic acid also assists another vitamin, folic acid (Figure 5.18). This is an essential co-factor in various one-carbon transfers for example the methyl group originating from the essential amino acid methionine is required in the formation of a wide variety of compounds including purines, the pyrimidine thymine, the amino acid serine, choline, carnitine, creatine, adrenalin, and many others. In its functional state, folic acid must be in its most reduced tetrahydrofolate form and this is brought about and/or maintained by ascorbic acid. 

Other compounds involved in one-carbon metabolism are derived from degradation products of choline. Choline, an essential component of certain phospholipids, is oxidized to form betaine aldehyde, which is further oxidized to betaine (trimethylglycine). In the liver, betaine can donate a methyl group to homocysteine to form methionine and dimethyl glycine. This allows the liver to have two routes for homocysteine conversion to methionine. Under conditions in which SAM accumulates, glycine can be methylated to form sarcosine (N-methyl glycine). This route is used when methionine levels are high and excess methionine needs to be metabolized. 

The remethylation cycle allows the conversion of homocysteine back to methionine by two pathways. The first and major pathway is catalyzed by the enzyme, methionine synthase, and links the folate cycle with homocysteine metabolism. Methionine synthase requires the cofactor, meth-ylcobalamin. The second pathway utilizes the enzyme, betaine-homocysteine methyltransfer-ase [8]. This pathway remethylates homocysteine using a methyl group derived from betaine, formed via oxidation of choline, and is presumably responsible for up to 50 % of homocysteine remethylation [10]. Both methionine and homocysteine play important roles in protein synthesis, folding, and function. 

Lipotropic substances compounds directly or indirectly involved in fat metabolism, which can prevent or correct fatty degeneration of the liver. They serve as substrates of phosphatide biosynthesis, or contribute (e.g. by methylation) to the synthesis of these substrates. Thus choline and any substance capable of contributing methyl groups for choline synthesis (e.g. methionine) are L.s. Liver is the major site of synthesis of plasma phosphoglycerides when the availability of choline is restricted, the rate of phosphatidylcholine synthesis decreases, and the rate of removal of fatty acids from the liver falls below normal. If the rate of supply of fatty acids (free and esterified) to the liver remains normal, the resulting accumulation of fat gives rise to the condition of fatty liver, or fatty degeneration of the liver. 

Methionine differs from the other methyl donors in being a simple thioether, whereas the others are sulfonium compounds or quarternary ammonium compounds. Onium compounds with an anionic group appear to be the only methyl donors choline, an onium compound, is inert as a donor until it is oxidized to betaine. Methionine was found to transfer its methyl group only in the presence of ATP. Cantoni has... 

Further experiments were carried out in the intact animal to determine the role of dimethyl- and monomethylaminoethanol in the transmethylation reaction. The methyl groups of dimethylaminoethauol were found to be used very efficiently in the synthesis of choline. Thus, about 45 % of the methyl groups of the tissue choline were derived from deutero-dimethylamiuocthanol on three weeks of feeding a diet containing homocystine in place of methionine as compared to (i0% when deuteroclioline was fed with homocystine. Monomethylaminoethanol also appeared to be a precursor of choline. ... 

The formation of the methyl groups of choline and methionine has been demonstrated to occur from formate-C in the intact rat and in liver slices. ... 

The demethylation reactions so far outlined take us to dimethylglycine. Nothing concrete is known on the further demethylation of this compound. Since N -betaine has been shown to be converted to labeled glycine the demethylation must go to completion. Similarly the role of sarcosine in the proposed cycle is obscure. In feeding experiments sarcosine was found not to be an effective methyl donor for choline formation. " This also was observed for the synthesis of methionine from homocysteine with liver slices and homogenates. The oxidation of the sarcosine methyl to formaldehyde, on the other hand, is a very active process and sarcosine oxidase is very widely distributed. This reaction could serve as a pathway for the catabolism of surplus methyl groups in the body. 

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