Choline, and methionine

Vitamin Bj 2 is concerned in the biosynthesis of methyl groups of choline and methionine. 

Fig. 1. The choline and methionine cycles showing the origin and disposition of labile methyl groups. FAH = tetrahydrofolic acid CH3BJ2 = methylated...

A methyl group, when grafted on a nitrogen or sulfur atom, can transform this latter in an onium, able to act as methyl donor. In living organisms the usual suppliers of methyl rests are choline and methionine. Methionine is first activated in vivo by combination with adenosine to yield 5-adenosyl-methionine (SAM Figure 20.8). 

Rushmore, T. H., Lim, Y. R, Farber, E., and Ghoshal, A. K., Rapid lipid peroxidation in the nuclear fraction of rat liver induced by a diet deficient in choline and methionine, Cancer Lett., 24, 251, 1984. 

Ghoshal, A. K. and Farber, E., The induction of liver cancer by dietary deficiency of choline and methionine without added carcinogens, Carcinogenesis, 5, 1367, 1984. 

Newberne, P. M., (1977). Effect of folic acid, Bi2 choline, and methionine on immunocompetence and cel1-mediated immunity, in Suskind, R.M. (ed.) Malnutrition.and the Immune Response (New York Raven Press) 376-386. 

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. ... 

Wells, I. C. Role of choline and methionine antagonists in metabolism. Amer. J. clin. Nutr. 6, 254 (1958). 

Cirrhosis of the liver in man is often found in chronic alcoholism and is probably due to dietary deficiency. In active fatty alcoholic cirrhosis, choline administration has been shown to lead to a decrease in liver fat. An increase in the rate of phospholipid turnover, following administration of 10 g. of choline or methionine, has been demonstrated in patients with cirrhosis who had evidence of fatty infiltration of the liver as shown by biopsy. In animals, vitamin B12 and folic acid are intimately related to choline and methionine metabolism and are important in the prevention of fatty livers under certain conditions. Whether these vitamins are related to accumulation of fat in the liver and cirrhosis in man remains to be ascertained. The value of high protein diets in the prevention and treatment of experimental dietary cirrhosis in animals is well established there is much evidence that such is also true in man (see also p. 521). 

Numerous tracer experiments on the intact animal and with liver slices have demonstrated an extensive conversion of labeled formate (62-64), formaldehyde (63-66), and methanol (62, 63) to the methyl groups of choline and methionine. However, no cell-free preparation has been obtained that could convert the above Ci compounds to choline methyl whereas enz3Tne systems have been obtained that can catalyze the synthesis of the methyl group of methionine (66-69) and of thymine (70, 71) from formaldehyde or formaldehyde precursors. 

Choline occupies a key position between energy and protein metabolism. Two types of choline functions are known as choline per se, for which the choline moiety is required, and in the function of a methyl donor. Choline per se plays a major role in lipid metabolism, particularly in lipid transport, as lipotropic agent, but it is also an important source of labile methyl groups for the biosynthesis of other methylated compounds. Based on this second function, choline and methionine pathways partially overlap in providing methyl groups in a variety of reactions. Based on these assumptions we investigated the effects of rumen protected choline administration on milk production in dairy cows. To achieve this pourpose a meta-analysis was carried out to summarize available scientific evidence for the effect of oral rumen protected choline (RPC) supplementation in dairy cows. 

In terms of amino acids bacterial protein is similar to fish protein. The yeast s protein is almost identical to soya protein fungal protein is lower than yeast protein. In addition, SCP is deficient in amino acids with a sulphur bridge, such as cystine, cysteine and methionine. SCP as a food may require supplements of cysteine and methionine whereas they have high levels of lysine vitamins and other amino acids. The vitamins of microorganisms are primarily of the B type. Vitamin B12 occurs mostly hi bacteria, whereas algae are usually rich in vitamin A. The most common vitamins in SCP are thiamine, riboflavin, niacin, pyridoxine, pantothenic acid, choline, folic acid, inositol, biotin, B12 and P-aminobenzoic acid. Table 14.4 shows the essential amino acid analysis of SCP compared with several sources of protein. 

Neuschwander-Tetri et al., 1992) and pancreatitis induced by a choline-deficient methionine-supplemented diet is less severe when mice are treated with a new synthetic ascorbic-acid derivative (CV 3611) (Nonaka et al., 1991). 

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. 

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. 

Methionine is intimately related to lipid metabolism in the liver. Methionine deficiency is one of the causes of the fatty liver syndrome. Lack of methionine prevents the methylation of phosphatidylethanolamine to phosphatidylcholine, resulting in an ability by the liver to build and export very low density lipoprotein. The syndrome can be treated by the administration of choline, and for this reason, choline has often been referred to as the lipotropic factor. 

Methionine, through subsequent conversion to 5-adenosylmethionine (see Fig. 28-4), is also required for the synthesis of choline and... 

The one-carbon units are methyl, methylene, methenyl, formyl or formimino groups. These one-carbon transfer reactions are required in the biosynthesis of serine, methionine, glycine, choline and the purine nucleotides and dTMP. 

FIGURE 20.8 Methyl donors and alkylating compounds choline 1, methionine 2, S-adenosyl-methionine 3, dimethyl sulfate 4 and butane-1,4-diol bis-methane sulfonate 5 (busulfan). 

Folate (foUc acid) is an essential vitamin which, in its active form of tetrahydrofolate (THF, Figure 4-1), transfers 1-carbon groups to intermediates in metaboUsm. Folate plays an important role in DNA synthesis. It is required for the de novo synthesis of purines and for the conversion of deoxyuridine 5-monophosphate (dUMP) to deoxythymidine 5 -monophosphate (dTMP). Additionally, folate derivatives participate in the biosynthesis of choline, serine, glycine, and methionine. However, in situations of folate deficiency, symptoms are not observed from the lack of these products as adequate levels of chohne and amino acids are obtained from the diet. (See also Case 3.)... 

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. 

Phosphatidylcholine is the major phospholipid on the surface monolayer of all lipoproteins, including VLDLs. In the liver, phosphatidylcholine is synthesized by two biosynthetic pathways the CDP-choline pathway and the phosphatidylethanolamine A -methyltransferase pathway (Chapter 8). Choline is an essential biosynthetic precursor of phosphatidylcholine via the CDP-choline pathway. When cells or animals are deprived of choline, plasma levels of TG and apo B are markedly reduced and TG accumulates in the liver, resulting in fatty liver. These observations led to the widely held view that the fatty liver caused by choline deficiency is due to inhibition of PC synthesis, which in turn would decrease VLDL secretion. This hypothesis was tested in primary rat hepatocytes cultured in medium lacking choline. Upon removal of choline/methionine from culture medium, the TG content of hepatocytes was increased 6-fold, and the secretion of TG and apo B in VLDL was markedly reduced. The interpretation of these experiments was that hepatic VLDL secretion requires the synthesis of phosphatidylcholine from either the CDP-choline or methylation pathways which require choline or methionine, respectively, as precursors (D.E. Vance, 1988). However, since choline deprivation was induced in a background of methionine insufficiency, it was not clear whether the lack of choline per se, and inhibition of the choline pathway for phosphatidylcholine synthesis, decreased VLDL secretion. More recent experiments have shown, surprisingly, that deficiency of choline in primary mouse hepatocytes does not reduce, but increases, phosphatidylcholine synthesis via the CDP-choline pathway, and does not decrease VLDL secretion (J.E. Vance, 2004). Thus, a deficiency of dietary choline reduces plasma TG and apo B levels by a mechanism that does not involve reduction of phosphatidylcholine synthesis. 

---