Folic acid coenzymes, reactions involving

Vitamin B12. Figure 2 Selected reactions in which folic acid coenzymes are involved. 

The number of vitamin B 12-dependent reactions is not large. Most of these involve rearrangements of the carbon skeletons of metabolites. Such reactions are important in linking some aspects of fatty acid metabolism to the citric acid cycle. In another form, a vitamin Bi2-derived coenzyme is involved, along with folic acid coenzymes, in the metabolism of one-carbon fragments, including the biosynthesis of methionine. 

In summary it can be seen that relatively little is yet known about the biosynthesis of pteroylglutamic acid although this is an active field of research. Enzyme studies with tissues from higher animals have established that PGA is reduced to FH4 and that this reduced form of folic acid plays a key role in accepting either —CHO or —CH OH by mechanisms cUscussed above and is thus equipped to carry out functions of single-carbon transfer. Table II and Figs. 5 and 6 summarize the enzymic reactions involving various folic acid coenzymes. 

The coenzyme forms of folic acid are derivatives of tetrahydrofolic acid, FH4. See Fig. 7. Folic acid functions as a coenzyme in enzyme reactions which involve the transfer of one-carbon fragments at various levels of... 

Methotrexate [meth oh TREX ate] (MTX) is structurally related to folic acid and acts as an antagonist of that vitamin by inhibiting dihydrofolate reductase1, the enzyme that converts folic acid to its active, coenzyme form, tetrahydrofolic acid (FH4) it therefore acts as an antagonist of that vitamin. Folate plays a central role in a variety of metabolic reactions involving the transfer of one-carbon units. (Figure 38.7)2. 

The rapid technological progress in X-ray crystallography has enabled the structural analysis of numerous enzymes involved in coenzyme biosynthesis. Complete sets of structures that cover all enzymes of a given pathway are available in certain cases such as riboflavin, tetrahydrobiopterin, and folic acid biosynthesis. Stmctures of orthologs from different taxonomic groups have been reported in certain cases. X-ray structures of enzymes in complex with substrates, products, and analogs of substrates, products, or intermediates have been essential for the elucidation of the reaction mechanisms. Structures of some coenzyme biosynthesis enzymes have been obtained by NMR-structure analysis. 

The metabolism of folic acid involves reduction of the pterin ting to different forms of tetrahydrofolylglutamate. The reduction is catalyzed by dihydtofolate reductase and NADPH functions as a hydrogen donor. The metabolic roles of the folate coenzymes are to serve as acceptors or donors of one-carbon units in a variety of reactions. These one-carbon units exist in different oxidation states and include methanol, formaldehyde, and formate. The resulting tetrahydrofolylglutamate is an enzyme cofactor in amino acid metabolism and in the biosynthesis of purine and pyrimidines (10,96). The one-carbon unit is attached at either the N-5 or N-10 position. The activated one-carbon unit of 5,10-methylene-H folate (5) is a substrate of T-synthase, an important enzyme of growing cells. 5-10-Methylene-H folate (5) is reduced to 5-methyl-H,j folate (4) and is used in methionine biosynthesis. Alternatively, it can be oxidized to 10-formyl-H folate (7) for use in the purine biosynthetic pathway. 

Folic acid or the folate coenzyme [6] is a nutritional factor both for the parasites and the hosts. It exists in two forms, viz. dihydro- and tetrahydrofolic acids [4,5] which act as cofactors involved in the transfer of one carbon units like methyl, hydroxymethyl and formyl. The transfer of a one carbon unit is associated with de novo synthesis of purines, pyrimidines and amino acids. Mammals can not synthesize folate and, therefore, depend on preformed dietary folates, which are converted into dihydrofolate by folate reductase. Contrary to this, a number of protozoal parasites like plasmodia, trypanosomes and leishmania can not utilize exogenous folate. Consequently, they carry out a de novo biosynthesis of their necessary folate coenzymes [12]. The synthesis of various folates follows a sequence of reactions starting from 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine (1), which is described in Chart 4 [13,14]. 

Tyrosine is not an essential amino acid in animals because it is synthesized from phenylalanine in a hydroxylation reaction. The enzyme involved, phenylala-nine-4-monoxygenase, requires the coenzyme tetrahydrobiopterin (Section 14.3), a folic acid-like molecule derived from GTP. Because this reaction also is a first step in phenylalanine catabolism, it is discussed further in Chapter 15. 

The well-publicized substance known as Coenzyme QIO, or CoQlO, receives favorable mention as an anticancer agent in an article by Christi Yerby appearing in the October 2005 issue of Life Extension. He states that low levels of CoQlO were found in patients with myeloma, lymphoma, and cancers of the breast, lung, prostate, pancreas, colon, kidney, head, and neck. In one case study, a woman with breast cancer experienced a stabilized tumor from taking 90 mg/day of CoQlO. When the daily dose was increased to 390 mg, the tumor disappeared. It was mentioned that CoQlO is synthesized from the amino acids tyrosine and phenylalanine in a cascade of reactions that involve vitamin C and the B vitamins B2, B3, B5, B6, B12, plus folic acid. Although the body produces CoQlO naturally, this is sometimes not enough. An earlier reference is S.T. Sinatra s The Coenzyme QIO Phenomenon, published in 1998. 

The stereochemistry of many of the biological reactions involving serine and its derivatives has been studied using the labeled compounds prepared above. The carbon atom, C-3, of serine acts as a source of the one carbon unit transferred by the coenzyme tetrahydrofolic acid 87 (95) (Scheme 24). It is initially transferred to the coenzyme 87 to give 5,10-methylenetetrahydro-folic acid 56a and glycine 23 in a reaction catalyzed by the enzyme serine... 

The conversion of serine to glycine involves the transfer of a one-carbon unit from serine to an acceptor. This reaction is catalyzed by senne hydroxymethylase, with pyridoxal phosphate as a coenzyme. The acceptor in this reaction is tetra-hydrofolate, a derivative of folic acid and a frequently encountered carrier of one-carbon units in metabolic pathways. Its structure has three parts a substituted pteridine ring, /(-aminobenzoic acid, and glutamic acid (Figure 23.11). Folic acid is a vitamin that has been identified as essential in preventing birth defects consequently, it is now a recommended supplement for all women of... 

The finding in 1946 by T. Spies and colleagues that thymine can substitute the functions of folic acid and vitamin B12 led to the understanding that both folic acid and vitamin B12 are involved in methyl transfer reactions (Vilter et al. 1950). Donaldson and Keresztesy showed that folic acid can exist in various forms with one-carbon group attached. The coenzyme methylcobalamin was discovered in 1964 (Lindstrand 1964). 

It may be possible that the folic acid component of the various coenzymes involved in single-carbon transfer reactions occurs in combination with additional amino acids attached by peptide linkage to the glutamic add group. Di-, tri-, and heptaglutamates of folic acid have been isolated from various natural sources (1). 

The N-5 position is considerably more basic than the N-10 position, and this basicity is one of several factors that control certain preferences in the course of reactions involving tetrahydrofolate. Thus, for-mylation occurs more readily at N-10 while alkylation occurs more readily at N-5. Benkovic and Bullard (1973) have reviewed evidence for an iminium cation at N-5 as the active donor in formaldehyde oxidation-level transfers. Recently, Barrows et al. (1976) have further studied such a mechanism for folic acid. The interconversion of these forms of folate coenzymes by enzymatic means has been reviewed by Stokstad and Koch (1967), and the reader is directed there for further details. Folate coenzymes are involved in a wide variety of biochemical reactions. These include purine and pyrimidine synthesis, conversion of glycine to serine, and utilization and generation of formate. In addition, the catabolism of histidine, with the formation of formiminoglu-tamic acid (FIGLU), is an important cellular reaction involving folate. 

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