Carbon transfer reaction

Tetrahydrofolic acid (THF) Loose Folic acid Methyl group donor in one-carbon transfer reactions critical in biosynthesis of purines and pyrimidines... 

An asymmetric carbon-transfer reaction was also performed by using 2-(/>-tolyl)sulfmylmethyltetrahydro-l,3-oxa-zine 143 as the chiral aldehyde equivalent in the Pictet-Spengler ring closure with tryptamine, but only moderate diastereoselectivity ( 40% de) was observed in favor of the (l/ )-tetrahydro-/3-carboline 165, and the enantiopure main product could be isolated only in low yield (Scbeme 26) <2001H(55)1937, 2004T9171>. 

I I 3. The answer is c. (Hardman, pp 1243-1247.) Antimetabolites of folic acid such as methotrexate, which is an important cancer chemotherapeutic agent, exert their effect by inhibiting the catalytic activity of the enzyme dihydrofolate reductase. The enzyme functions to keep folic acid in a reduced state. The first step in the reaction is the reduction of folic acid to 7,8-dihydrofolic acid (FH2), which requires the cofactor nicotinamide adenine dinucleotide phosphate (NADPH). The second step is the conversion of FH2 to 5,6,7,8-tetrahydrofolic acid (FH ). This part of the reduction reaction requires nicotinamide adenine dinucleotide (NADH) or NADPH. The reduced forms of folic acid are involved in one-carbon transfer reactions that are required during the synthesis of purines and pyrimidine thymidylate. The affinity of methotrexate for dihydrofolate reductase is much greater than for the substrates of folic acid and FH2. The action of... 

Tetrahydrofolate cofactors participate in one-carbon transfer reactions. As described earlier in the discussion of vitamin B12, one of these essential reactions produces the dTMP needed for DNA synthesis. In this reaction, the enzyme... 

FIGURE 18-16 Some enzyme cofactors important in one-carbon transfer reactions. The nitrogen atoms to which one-carbon groups are attached in tetrahydrofolate are shown in blue. 

After removal of their amino groups, the carbon skeletons of amino acids undergo oxidation to compounds that can enter the citric acid cycle for oxidation to C02 and H20. The reactions of these pathways require a number of cofactors, including tetrahydrofolate and 5-adenosylmethionine in one-carbon transfer reactions and tetrahydrobiopterin in the oxidation of phenylalanine by phenylalanine hydroxylase. 

Tetrahydrofolates are cosubstrates for a variety of one-carbon transfer reactions. Tetrahydrofolates maintain formaldehyde and formate in chemically poised states, making them available for essential processes by specific enzymatic action. 

Tetrahydrofolate cofactors participate in one-carbon transfer reactions. As described above in the section on vitamin B12, one of these essential reactions produces the dTMP needed for DNA synthesis. In this reaction, the enzyme thymidylate synthase catalyzes the transfer of the one-carbon unit of N 5,N 10-methylenetetrahydrofolate to deoxyuridine monophosphate (dUMP) to form dTMP (Figure 33-2, reaction 2). Unlike all of the other enzymatic reactions that utilize folate cofactors, in this reaction the cofactor is oxidized to dihydrofolate, and for each mole of dTMP produced, one mole of tetrahydrofolate is consumed. In rapidly proliferating tissues, considerable amounts of tetrahydrofolate can be consumed in this reaction, and continued DNA synthesis requires continued regeneration of tetrahydrofolate by reduction of dihydrofolate, catalyzed by the enzyme dihydrofolate reductase. The tetrahydrofolate thus produced can then reform the cofactor N 5,N 10-methylenetetrahydrofolate by the action of serine transhydroxy- methylase and thus allow for the continued synthesis of dTMP. The combined catalytic activities of dTMP synthase, dihydrofolate reductase, and serine transhydroxymethylase are often referred to as the dTMP synthesis cycle. Enzymes in the dTMP cycle are the targets of two anticancer drugs methotrexate inhibits dihydrofolate reductase, and a metabolite of 5-fluorouracil inhibits thymidylate synthase (see Chapter 55 Cancer Chemotherapy). 

Impairment of methionine synthetase activity, for example, in vitamin B12 deficiency or after prolonged exposure to nitrous oxide (Section 10.9.7), will result in the accumulation of methyl-tetrahydrofolate. This can neither be utilized for any other one-carbon transfer reactions nor demethylated to provide free tetrahydrofolate. 

The four-coordinate sqnare planar iron(n) porphyrins discussed above are not only of great valne in heme protein model chemistry, but also in chemical applications, since they undergo a wealth of ligand addition reactions. For example it has been shown that TPPFe complexes are active catalysts for important carbon transfer reactions in organic chemistry and are found to catalyze the stereoselective cyclopropanation of aUcenes, olefin formation from diazoalkanes, and the efficient and selective olefination of aldehydes and other carbonyl compounds. The active species in these carbon transfer reactions are presumably iron porphyrin carbene complexes. " It was also found that ferrous hemin anchored to Ti02 thin films reduce organic halides, which can pose serious health problems and are of considerable environmental concern because of their prevalence in groundwater. ... 

Carbenes as Ligands. As mentioned above, TPPFe complexes have been reported to be active catalysts in carbon transfer reactions, in which the active species are assumed to be iron porphy-rin carbene complexes. " Since carbene complexes are typically synthesized as models of cytochrome P450 enzymes, they are discussed in the corresponding section on P450 models. Section 8.2. 

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. 

Inhibition of Dihydrofolate Reductase Folate-dependent reactions in the body are inhibited by folate analogues (or antagonists, e.g., methotrexate). Before it can function as a coenzyme in one-carbon transfer reactions, folate (F) must be reduced by dihydrofolate reductase to tetrahydrofolate (FH4). Dihydrofolate... 

Structure of folic acid showing its components. The numbered part participates in one-carbon transfer reactions. In nature, folate occurs largely as polyglutamyl derivatives in which the glutamate residues are attached by isopeptide linkages via the y-carboxyl group. The pteridine ring structure is also present in tetrahydrobiopterin, a coenzyme in the hydroxylation of phenylalanine, tyrosine, and tryptophan (Chapter 17). 

The various catalytic roles of folate-mediated one-carbon transfer reactions in anabolic and catabolic... 

One-carbon transfer reactions involving folate-derived carriers. Dashed arrows indicate multiple-step reaction pathways solid arrows represent direct, single-step reactions. 

The one-carbon transfer reaction (left) facilitated by the octahedral cobalt(III) complex Vitamin Bi2 (right) as coenzyme. Carbon-cobalt bonding of the substrate is involved in the mechanism, at the site designated by the R-group in the complex. 

Scheme III shows the experimental arrangement to study the second one-carbon transfer reaction we investigated, the formation of thymidylic acid from uridylic acid catalyzed by thymidy-late synthetase. In this reaction, the methyl group of thymidy-late is derived from the carbon and the two hydrogens of the methylene bridge plus H-6 of methylene-tetrahydrofolate. To study the stereochemistry of this reaction, we (5) synthesized serine stereospecifically labeled with tritium and deuterium at...

Metabolic interconversion of tetrahydrofolate derivatives and one-carbon transfer reactions 603... 

Trimethoprim exerts a synergistic effect with sulfonamides. It potently and selectively inhibits microbial dihydrofolate reductase, the enzyme that reduces dihydrofolate to tetrahydrofolate—the form required for one-carbon transfer reactions. Coadministration of a sulfonamide and trimethoprim thus introduces sequential blocks in the biosynthetic pathway for tetrahydrofolate (Figure 43-2). 

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