Methyl trap

It is the role of jV5-methyl THF which is key to understanding the involvement of cobalamin in megaloblastic anaemia. The metabolic requirement for N-methyl THF is to maintain a supply of the amino acid methionine, the precursor of S-adenosyl methionine (SAM), which is required for a number of methylation reactions. The transfer of the methyl group from jV5-methyl THF to homocysteine is cobalamin-dependent, so in B12 deficiency states, the production of SAM is reduced. Furthermore, the reaction which brings about the formation of Ns-methyl THF from N5,N10-methylene THF is irreversible and controlled by feedback inhibition by SAM. Thus, if B12 is unavailable, SAM concentration falls and Ah -methyl THF accumulates and THF cannot be re-formed. The accumulation of AT-methyl THF is sometimes referred to as the methyl trap because a functional deficiency of folate is created. 

Fig. 6 Methyl trap hypothesis 5,10-Methylenetetrahydrofolate is reduced to 5-methyltetiahy-drofolate in an irreversible reaction. When vitamin Bn is deficient, methyl groups are trapped as 5-methyltetrahydrofolate, resulting in decreased substrates for DNA synthesis and neural lipid methylation. MTHFR, methylenetetrahydrofolate reductase DHFR, dihydrofolate reductase MS, Methionine synthase TS, thymidylate synthase SAM, S-adenosyl-methionine dUMP, deoxyuridine 5 -monophosphate dTTP, deoxythymidine 5 -monophosphate...

Methyl trap The sequestering of tetrahydrofolate as N -methyl THF because of decreased conversion of homocysteine to methionine as a result of a deficiency of methionine synthase or its cofactor, cobalamin (vitamin B ). 

The hemopoietic problems associated with a B12 deficiency are identical to those observed in a folate deficiency and, in fact, result from a folate deficiency secondary to (i.e., caused by) the B12 deficiency (i.e., the methyl trap hypothesis). As the FH4 pool is exhausted, deficiencies of the tetrahydrofolate derivatives needed for purine and dTMP biosynthesis develop, leading to the characteristic megaloblastic anemia. 

If one analyzes the flow of carbon in the folate cycle, the equilibrium lies in the direction of the N -methyl FH4 form. This appears to be the most stable form of carbon attached to the vitamin. However, in only one reaction can the methyl group be removed from N -methyl FH4, and that is the methionine synthase reaction, which requires vitamin B12. Thus, if vitamin B12 is deficient, or if the methionine synthase enzyme is defective, N -methyl FH4 will accumulate. Eventually most folate forms in the body will become trapped in the N -methyl form. A functional folate deficiency results because the carbons cannot be removed from the folate. The appearance of a functional folate deficiency caused by a lack of vitamin B12 is known as the methyl-trap hypothesis, and its clinical implications are discussed in following sections. 

Scott, J.M., andD.G. Weir, 1981. The methyl trap. Aphysiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid induced exacerbation of subacute combined degeneration in pernicious anaemia. Lancet. 2, 337-340. 

The TT-allylpalladiLim complexes formed as intermediates in the reaction of 1,3-dienes are trapped by soft carbon nucleophiles such as malonate, cyanoacctate, and malononitrile[ 177-179). The reaction of (o-iodophenyl-methyl) malonate (261) with 1,4-cyclohexadiene is terminated by the capture of malonate via Pd migration to form 262. The intramolecular reaction of 263 generates Tr-allylpalladium, which is trapped by malononitrile to give 264. o-[odophenylmalonate (265) adds to 1,4-cyciohexadiene to form a Tr-allylpalladium intermediate via elimination of H—Pd—X and its readdition, which is trapped intramolecularly with malonate to form 266)176]. 

Allenes also react with aryl and alkenyl halides, or triflates, and the 7r-allyl-palladium intermediates are trapped with carbon nucleophiles. The formation of 283 with malonate is an example[186]. The steroid skeleton 287 has been constructed by two-step reactions of allene with the enol trillate 284, followed by trapping with 2-methyl-l,3-cyclopentanedione (285) to give 286[187]. The inter- and intramolecular reactions of dimethyl 2,3-butenylmalonate (288) with iodobenzene afford the 3-cyclopentenedicarboxylate 289 as a main product) 188]. 

The 7V-methylbenzo[( e]quinoline 426 was prepared by trapping the insertion product of an internal alkyne with a tertiary dimethylamine. One methyl group is eliminated. The dimethylaminonaphthalene-Pd complex 427 is an active catalyst and other Pd compounds are inactive[290a]. 

In addition to alcohols, some other nucleophiles such as amines and carbon nucleophiles can be used to trap the acylpalladium intermediates. The o-viny-lidene-/j-lactam 30 is prepared by the carbonylation of the 4-benzylamino-2-alkynyl methyl carbonate derivative 29[16]. The reaction proceeds using TMPP, a cyclic phosphite, as a ligand. When the amino group is protected as the p-toluenesulfonamide, the reaction proceeds in the presence of potassium carbonate, and the f>-alkynyl-/J-lactam 31 is obtained by the isomerization of the allenyl (vinylidene) group to the less strained alkyne. 

If the spent fuel is processed in a nuclear fuel reprocessing plant, the radioactive iodine species (elemental iodine and methyl iodide) trapped in the spent fuel elements ate ultimately released into dissolver off gases. The radioactive iodine may then be captured by chemisorption on molecular sieve 2eohtes containing silver (89). 

Cyanopyrrole undergoes photochemical rearrangement to 3-cyanopyrrole. If the analogous rearrangement of IV-methyl-2-cyanopyrrole (22) is carried out in methanol, in addition to the 3-cyanopyrrole (24) the bicyclic intermediate (23) is trapped as the methanol adduct (25) (78CC131). 

A similar intramolecular trapping of the intermediate (511) from the photolysis of the corresponding methyl tetrazole-l,5-dicarboxylate (510) gave methyl 5-methoxy-l,2,4-oxadiazole-3-carboxylate (512). 

However, when the molecules are converted into their anions, the cyclic pyrazolo[l,5- fjtetrazole (471) form predominates. It is possible to trap the cyclized anions such as (471) by methylation and to obtain stable azapentalenes (472) and (473). 

Thermolysis of 4-methyl(4-phenyl)isoxazolin-5-one produced a-cyanophenylacetic acid <67JHC533). The pyrolysis of 3-methylisoxazoline-4,5-dione 4-oxime generated fulminic acid, which was trapped in a liquid N2 cooled condenser for further study. Pyrolysis of metal salts such as Ag or Na produced the corresponding highly explosive salts of fulminic acid 79AG503). Treatment of the oxime with amines generated bis-a,/3-oximinopropionamides (Scheme 65) <68AC(R)189). 

Nitrile ylides derived from the photolysis of 1-azirines have also been found to undergo a novel intramolecular 1,1-cycloaddition reaction (75JA3862). Irradiation of (65) gave a 1 1 mixture of azabicyclohexenes (67) and (68). On further irradiation (67) was quantitatively isomerized to (68). Photolysis of (65) in the presence of excess dimethyl acetylenedicar-boxylate resulted in the 1,3-dipolar trapping of the normal nitrile ylide. Under these conditions, the formation of azabicyclohexenes (67) and (68) was entirely suppressed. The photoreaction of the closely related methyl-substituted azirine (65b) gave azabicyclohexene (68b) as the primary photoproduct. The formation of the thermodynamically less favored endo isomer, i.e. (68b), corresponds to a complete inversion of stereochemistry about the TT-system in the cycloaddition process. 

Fluoride ion attacks the sulfur atom in 2,3-diphenylthiirene 1,1-dioxide to give ck-1,2-diphenylethylenesulfonyl fluoride (23%) and diphenylacetylene (35%). Bromide or iodide ion does not react (80JOC2604). Treatment of S-alkylthiirenium salts with chloride ion gives products of carbon attack, but the possibility of sulfur attack followed by addition of the sulfenyl chloride so produced to the alkyne has not been excluded (79MI50600). In fact the methanesulfenyl chloride formed from l-methyl-2,3-di- -butylthiirenium tetrafluoroborate has been trapped by reaction with 2-butyne. A sulfurane intermediate may be indicated by NMR experiments in liquid sulfur dioxide. 

Methylvinyldiazirine (199) rearranges at room temperature in the course of some days. Formation of the linear isomer is followed by electrocyclic ring closure to give 3-methyl-pyrazole. The linear diazo compound could be trapped by its reaction with acids to form esters, while the starting diazirine (199) is inert towards acids (B-71MI50801). 

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