Betaine, methyl transfer

One-carfaon cycle a cycle of methyl transfer and methyl oxidation involving glycine, sarcosine, dimethylglycine, betaine and choline, first proposed in 1958 from observations on the oxidation of dimethylglycine and sarcosine by rat liver mitochondria [Mackenzie Frisell, J. Biol. Chem. 232 (1958) 417-427]. The existence of a 0-c.c. is now confirmed it involves choline oxidation in mitochondria and phosphatidylcholine synthesis in the endoplasmic reticulum (Fig.). [A.J. Wittwer C.Wagner J. Biol. Chem. 256 (1981) 4102- 108, 4109-4115]... 

The relationship between DMGDH deficiency and the muscle symptoms in the index case are unclear. DMG has been used as a performance enhancer in athletes as well as to treat autistic children, with little evidence of efficacy. Prior to the use of NMR spectroscopy, DMG was detected by dedicated GC-MS methods and by HPLC with appropriate derivatization [13]. Increased levels of DMG in plasma and urine have been observed during betaine therapy and in some individuals with folate deficiency, because of impaired methyl transfer reactions [10]. 

In other methyl transfers, there is no net proton production. For example, with betaine as methyl donor to homocysteine, the general reaction according to Eq. (5) [in this case Eq. (15a)] is balanced at pH 7.0 in aqueous solution by proton uptake by the product dimethylglydne ... 

Refluxing 3-aryl-3-dimethyUiydrazono- l,l,l-trifluoro-2-propanones in toluene (or p-xylene) afforded 4-aryl-l-methyl-5-trifluoromethylimidazoles via 5-aryl-6-trifluoromethyl-3,6-dihydro-2/f-[l,3,4]oxadiazine intermediates (Scheme 44) [58]. Retro Diels-Alder reaction of these oxadiazines afforded 3-imino-1,1,1-trifluoro-2-propanones and A-methyformimine that underwent cycloaddition to produced betaines. Proton transfer and subsequent dehydration gave the corresponding 5-trifluoromethylimidazoles. 

Although this is not an anabolic process, discussion of the reactions involved is included here to complete the presentation of the steps of the cycle shown in Fig. 2. The process is initiated by the oxidation of choline to betaine. Evidence that methyl transfer involves betaine, not choline was indicated by the work of Dubnofif (78), who observed that methyl transfer can occur from betaine anaerobically, but from choline only aerobically. More definite proof was provided by Muntz (79), who demonstrated that incubation of choline and homocysteine with liver homogenates yielded dimethylglycine and not dimethylaminoethanol. The former would be expected if betaine was demethylated, the latter if it was choline. 

The final step in our understanding of transmethylation followed from the observation by Cantoni (1951) that betaine and dimethylthetin only acted as methyl donors in the presence of homocysteine, i.e. after the methyl group had been transferred to give methionine. Methionine would only transmethylate if ATP was available. S-adenosyl methionine was therefore proposed as the primary methyl donor, a suggestion confirmed after the compound had been synthesized by Baddiley and Jamieson in 1954. 

The product of transmethylation, S-adenosylhomocysteine, is converted (step g) into homocysteine in an unusual NAD-dependent hydrolytic reaction (Eq. 15-14) by which adenosine is removed (step g).302c Homocysteine can be reconverted to methionine, as indicated by the dashed line in Fig. 24-16. This can be accomplished by the vitamin B12-and tetrahydrofolate-dependent methionine synthase, (Eq. 16-43), which transfers a methyl group from methyl-tetrahydrofolate303 303b by transfer of a methyl group from betaine, a trimethylated glycine (Eq. 24-33)304, or by remethylation with AdoMet (Fig. 24-16).304a... 

The activity of 6-alkyl substituents is well shown by the ease with which 6-methyl- and 6-ethylphenanthridinium-5-enol betaines (215) (R = Me and Et) undergo cyclodehydration to pyrrolophenanthridines (238) (R = H or Me) on heating, since the first step presumably involves proton transfer from the a-carbon atom of the alkyl substituent.285... 

Homocysteine can be recycled back to methionine either by transfer of a methyl group from betaine catalyzed by betaine-homocysteine methyltransferase, or from N -methyltetrahydrofolate(N -methyl-FH4)catalyzedbyN -methyl-FH4-methyltransferase, which requires methyl cobalamin ... 

Similar effects are observed for phosphonium ylides18 (see also Vol. El, p 704) which are able to transfer their alkylidenc unit to a,/ -unsaturated esters. The ring closure of the intermediate betaine proceeds under steric control and preferentially generates the less hindered cyclopropane derivatives, for example, ethylidene triphenylphosphorane and methyl (E)-2-butenoate furnish a 93 7 mixture of methyl 2,3-dimethylcyclopropanecarboxylate 519. 

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. 

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). 

Adenosylmethionine (SAM) is the main agent for the transfer of methyl groups, although in some cells chgline, betaine, and related compounds also play such a role. Some methyltransferases are very specific with respect to the acceptor substrate while others are unspecific. In all, a very wide variety of acceptors have been identified. The nucleotide product of methylation is [Pg.43]

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... 

Porco et al. reported the synthesis of ( ) methyl rocaglate using [3 + 2] dipolar photocycloaddition reaction of an oxidopyrylium betaine derived from excited state intramolecular proton transfer reaction of 3-hydroxyflavin and methyl cinnamate [144]. Methyl rocaglate was obtained by a base-mediated a-ketol rearrangement followed by hydroxy-directed reduction sequence. They subsequently succeeded in the asymmetric synthesis of methyl rocaglate using functionalized TADDOL derivative (34) (Figure 2.30) as a chiral Bronsted acid (Scheme 2.77) [145]. 

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