Tetrahydrofolate 1-carbon carriers

Thymidylate synthase (E.C. 2.1.1.45) is the enzyme that methylates UMP to thymidine, using methylene tetrahydrofolate as the carbon carrier. The enzyme can be inhibited directly by analogues of uracil such as 5-fluorouracil (8.34, 5-FU). The antimetabolite must be in the 5-fluorodeoxyuridine monophosphate (FdUMP) form to become active, and the capability of cells to achieve this transformation is a major determinant of their sensitivity to such drugs. 

The other major class of antimalarials are the folate synthesis antagonists. There is a considerable difference in the drug sensitivity and affinity of dihydrofolate reductase enzyme (DHFR) between humans and the Plasmodium parasite. The parasite can therefore be eliminated successfully without excessive toxic effects to the human host. DHFR inhibitors block the reaction that transforms deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) at the end of the pyrimidine-synthetic pathway. This reaction, a methylation, requires N °-methylene-tetrahydrofolate as a carbon carrier, which is oxidized to dihydrofolate. If the dihydrofolate cannot then be reduced back to tetrahydrofolate (THF), this essential step in DNA synthesis will come to a standstill. 

Histidine is converted into 4-imidazolone 5-propionate (Figure 23.24). The amide bond in the ring of this intermediate is hydrolyzed to the TV-formimino derivative of glutamate, which is then converted into glutamate by transfer of its formimino group to tetrahydrofolate, a carrier of activated one-carbon units (Section 24.2.6). 

Serine is the precursor of glycine and cysteine. In the formation of glycine, the side-chain methylene group of serine is transferred to tetrahydrofolate, a carrier of one-carbon units that will be discussed shortly. 

Tetrahydrofolate, a carrier of activated one-carbon units, plays an important role in the metabolism of amino acids and nucleotides. This coenzyme carries one-carbon units at three oxidation states, which are interconvertible most reduced—methyl intermediate—methylene and most oxidized—formyl, formimino, and methenyl. The major donor of activated methyl groups is -adenosylmethionine, which is synthesized by the transfer of an adenosyl group from ATP to the sulfur atom of methionine. -Adenosylhomocysteine is formed when the activated methyl group is transferred to an acceptor. It is hydrolyzed to adenosine and homocysteine, the latter of which is then methylated to methionine to complete the activated methyl cycle. 

Dihydrofolate Reductase Catalyzes the Regeneration of Tetrahydrofolate, a One-Carbon Carrier... 

There are several one-carbon derivatives of folate (of different redox states) that function as one-carbon carriers in different metabolic processes. In all of these reactions, the one-carbon moiety is carried in a covalent linkage to one or both of the nitrogen atoms at the 5- and 10-positions of the pteroic acid portion of tetrahydrofolate. Six known forms of carrier are shown in Figure 27-4. Folinic acid (N -formyl FH4), also called leucovorin or citrovorum factor, is chemically stable and is used clinically to prevent or reverse the toxic effect of folate antimetabolites, such as methotrexate and pyrimethamine. The formation and interconversion of some metabolites of... 

Figure 4-2. Structures of the various 1-carbon carriers of tetrahydrofolate (THF). THF can carry one-carbon units in the oxidation states of methanol (N -methyl THF), formaldehyde (N, N °-methylene THF) or formic acid (remaining structures).

Tetrahydrofolate Tetrahydrofolate, which is produced from the vitamin folate, is the primary one-carbon carrier in the body. This vitamin obtains one-carbon units from serine, glycine, histidine, formaldehyde, and formate (Fig. 40.1). While these carbons are attached to FH4 they can be either oxidized or reduced. Because of this, folate can exist in a variety of chemical forms. Once a carbon has been reduced to the methyl level (methyl-FHf, however, it cannot be re-oxidized. Collectively, these one-carbon groups attached to their carrier FH4 are known as the one-carbon pool. The term folate is used to represent a water-soluble B-complex vitamin that functions in transferring single-carbon groups at various stages of oxidation. 

The addition of a methyl group to uracil to produce thymine requires tetrahydrofolate as the one-carbon carrier. This process is a target for cancer chemotherapy. 

Tetrahydrofolates (THF) interconvert several one-carbon compounds or fragments. As is indicated in Fig. 18, formaldehyde released from the PLP-dependent cleavage of serine is immediately trapped by THF (Fig. 14). Nitrogen N1 adds to formaldehyde to form a carboxymethyl (—CH2—COOH) derivative which can than react reversibly with loss of water to form a cyclic adduct (Fig. 18). This compound can be oxidized to the N °-methyl form. Both of these are important intermediates in a variety of biosynthetic processes. The third one-carbon carrier is vitamin B12 which can act as an acceptor, taking the methyl group from methyl-THF to form... 

Folic acid derivatives (folates) are acceptors and donors of one-carbon units for all oxidation levels of carbon except that of CO2 (where biotin is the relevant carrier). The active coenzyme form of folic acid is tetrahydrofolate (THF). THF is formed via two successive reductions of folate by dihydrofolate reductase (Figure 18.35). One-carbon units in three different oxidation states may be bound to tetrahydrofolate at the and/or nitrogens (Table 18.6). These one-carbon units... 

Group-transfer reactions often involve vitamins3, which humans need to have in then-diet, since we are incapable of realizing their synthesis. These include nicotinamide (derived from the vitamin nicotinic acid) and riboflavin (vitamin B2) derivatives, required for electron transfer reactions, biotin for the transfer of C02, pantothenate for acyl group transfer, thiamine (vitamin as thiamine pyrophosphate) for transfer of aldehyde groups and folic acid (as tetrahydrofolate) for exchange of one-carbon fragments. Lipoic acid (not a vitamin) is both an acyl and an electron carrier. In addition, vitamins such as pyridoxine (vitamin B6, as pyridoxal phosphate), vitamin B12 and vitamin C (ascorbic acid) participate as cofactors in an important number of metabolic reactions. 

Tetrahydrofolic acid then functions as a carrier of one-carbon groups for amino acid and nucleotide metabolism. The basic ring system is able to transfer methyl, methylene, methenyl, or formyl groups, and it utilizes slightly different reagents as appropriate. These are shown here for convenience, we have left out the benzoic acid-glutamic acid portion of the structure. These compounds are all interrelated, but we are not going to delve any deeper into the actual biochemical relationships. 

The pyruvate carboxylase reaction requires the vitamin biotin (Fig. 16-16), which is the prosthetic group of the enzyme. Biotin plays a key role in many carboxyla-tion reactions. It is a specialized carrier of one-carbon groups in their most oxidized form C02. (The transfer of one-carbon groups in more reduced forms is mediated by other cofactors, notably tetrahydrofolate and 5-adenosylmethionine, as described in Chapter 18.)... 

Tetrahydrofolate functions as a carrier of one-carbon units. There are numerous metabolic reactions that require either the addition or removal of a one-carbon unit of some specific oxidation state. THF binds one-carbon units of three oxidation levels the methanol, formaldehyde, and formate states. These are shown in Table 6.4 along with their origins and uses. The various one-carbon units are interconvertible, as shown in Figure 6.5. Nicotinamide coenzymes are involved. In addition, the one-carbon unit may be released as C02. The methanol-level THF-bound one-carbon unit 5-methyl-THF is the storage and transport form. Once formed, its main pathway of metabolism is to form methionine from homocysteine, a reaction that requires vitamin B12 in the form of methylcobalamin (see Figure 6.2 and Chapter 20) ... 

Tetrahydrofolate (THF) The active form of the vitamin folic acid. THF is one of the major carriers of one-carbon units at various oxidation states for biosynthetic reactions. It is required for the synthesis of the nucleotide thymidylate (dTMP). Although bacteria can synthesize folic acid, eukaryotes must obtain folate from the diet. Dietary sources of folate include leafy green vegetables (e.g., spinach and turnip greens), citrus fruits, and legumes. Many breakfast cereals, breads, and other grain products are fortified with folate. 

Tetrahydrofolate (THF) is the major source of 1-carbon units used in the biosynthesis of many important biological molecules. This cofactor is derived from the vitamin folic acid and is a carrier of activated 1-carbon units at various oxidation levels (methyl, methylene, formyl, formimino, and methenyl). These compounds can be interconverted as required by the cellular process. The major donor of the 1-carbon unit is serine in the foUowing reaction ... 

Folic acid An essential vitamin composed of a pteridine ring bound to p-aminobenzoate, which is in an amide linkage to one or more glutamate residues. The active form of the enzyme is tetrahydrofolate (THF, FH ), which is an important carrier of 1-carbon units in a variety of oxidation... 

Tetrahydrofolate, the biologically active form of folic acid, and S-adenosylmethio-nine are important carriers of single carbon atoms in a variety of synthetic reactions. 

Amino acids are precursors of many phy siologically important biomolecules. Many of the processes that synthesize these molecules involve the transfer of carbon groups. Because many of these transfers involve one-carbon groups (e.g., methyl, methylene, methenyl, and formyl), the overall process is referred to as one-carbon metabolism. S-Adenosylmethionine (SAM) and tetrahydrofolate (THF) are the most important carriers of one-carbon groups. 

The one-carbon unit transferred in this reaction is bound to tetrahydrofolate, forming A ,A/ °-methylenetetrahydrofolate, in which the methylene (one-carbon) unit is bound to two of the nitrogens of the carrier (Figure 23.12). Tetrahydrofolate is not the only carrier of one-carbon units. We have already encountered biotin, a carrier of GOg, and we have discussed the role that biotin plays in gluconeogenesis (Section 18.2) and in the anabolism of fatty acids (Section 21.6). 

It is worth noting that we have now seen three important carriers of one-carbon units biotin, a carrier of GOg tetrahydrofolate (FH4), a carrier of methylene and formyl groups and 5 adenosylmethionine, a carrier of methyl groups. 

What are some common features in amino acid biosynthesis In the anabolism of amino acids, transamination reactions play an important role. Glutamate and glutamine are frequently the amino-group donors. The enzymes that catalyze transamination reactions frequently require pyridoxal phosphate as a coenzyme. One-carbon transfers also operate in the anabolism of amino acids. Carriers are required for the one-carbon groups transferred. Tetrahydrofolate is a carrier of methylene and formyl groups, and S-adenosylmethionine is a carrier of methyl groups. 

What is conversion of dUTP to dTTP Another reaction specifically needed to produce substrates for DNA synthesis is the conversion of uracil to thymine. This pathway, which requires a tetrahydrofolate derivative as the carrier for one-carbon transfer, is a target for cancer chemotherapy. 

Tetrahydrofolate is a carrier of carbon groups. Two of the carbons in the purine ring are donated by tetrahydrofolate. 

Folate is reduced to tetrahydrofolate (THF), which is a carrier of 1-carbon units ... 

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