Serine tetrahydrofolate conversion

Figure 10-5. Conversion of deoxyuridylate (dUMP) to deoxythymidylate (dTMP) by thymidylate synthetase. The importance of folate coenzymes in this reaction is illustrated. NADPH + H provide the necessary reducing equivalents and serine is the source of one-carbon units present on N, N °-methylene tetrahydrofolate (THF).

Side chain cleavage (Group c). In a third type of reaction the side chain of the Schiff base of Fig. 14-5 undergoes aldol cleavage. Conversely, a side chain can be added by (3 condensation. The best known enzyme of this group is serine hydroxymethyltransferase, which converts serine to glycine and formaldehyde.211-21313 The latter is not released in a free form but is transferred by the same enzyme specifically to tetrahydrofolic acid (Eq. 14-30), with which it forms a cyclic adduct. 

Cells making DNA must also be able to make deoxythymidine triphosphate (dTTP). The key step in the synthesis of dTTP is the conversion of dUMP to dTMP via thymidylate synthase. The reaction requires a source of N5,Nw-methylene tetrahydrofolate (see Sec. 15.7, Fig. 15-19) to provide the methyl group. In this reaction, the tetrahydrofolate is oxidized to dihydrofolate. Dihydrofolate must be reduced to tetrahydrofolate via the enzyme dihydrofolate reductase so that more Af5,A,l0-methylene tetrahydrofolate can be made from serine in a reaction catalyzed by serine hydroxymethyltransferase. These three reactions, which are essential for the formation of dTMP, are shown below. 

This interconversion is catalyzed by serine transhydroxymethylase, another PLP enzyme that is homologous to aspartate aminotransferase (Figure 24.11). The bond between the a- and P-carbon atoms of serine is labilized by the formation of a Schiff base between serine and PLP (Section 23.3.3). The side-chain methylene group of serine is then transferred to tetrahydrofolate. The conversion of serine into cysteine requires the substitution of a sulfur atom derived from methionine for the side-chain oxygen atom (Section 24.2.8). 

Thus, one-carhon units at each of the three oxidation levels are utilized in biosyntheses. Furthermore, tetrahydrofolate serves as an acceptor of one-carbon units in degradative reactions. The major source of one-carhon units is the facile conversion of serine into glycine, which yields N lO-methylenetetrahydrofolate. Serine can he derived from 3-... 

Folate (foUc acid) is an essential vitamin which, in its active form of tetrahydrofolate (THF, Figure 4-1), transfers 1-carbon groups to intermediates in metaboUsm. Folate plays an important role in DNA synthesis. It is required for the de novo synthesis of purines and for the conversion of deoxyuridine 5-monophosphate (dUMP) to deoxythymidine 5 -monophosphate (dTMP). Additionally, folate derivatives participate in the biosynthesis of choline, serine, glycine, and methionine. However, in situations of folate deficiency, symptoms are not observed from the lack of these products as adequate levels of chohne and amino acids are obtained from the diet. (See also Case 3.)... 

Serine - Serine has many important biological roles, including the biosynthesis of phosphopholipids and cysteine. Serine also contributes activated one-carbon units to the pool of tetrahydrofolate coenzymes. Serine can be made in a variety of ways, including the way shown here and Figure 21.24. Serine is catabolized by conversion to glycine or by action of serine-threonine dehydratase (Figure 21.25). 

Conversion of serine to glycine. This reaction requires tetrahydrofolate as an acceptor of a methylene group from Ser and utilizes pyridoxal phosphate as a cofactor. It results in the formation of 5,10-CH PteGlu, an essential coenzyme for the synthesis of thymidylate. 

Fig. 2. Tentative scheme for the conversion of glycine to serine associated with the inside of the inner membrane and matrix of plant mitochondria. E, Ej, E3, and E4 are regarded as enzyme proteins with pyridoxal phosphate, lipoyl, possibly tetrahydrofolate and FAD as prosthetic groups or cofactors. The scheme incorporates published information for similar systems in microorganisms, liver mitochondria, and plants and shows the three phosphorylations of ADP to ATP considered to be associated with the reaction in plants.

Tetrahydrofolic acid which was found to be a coenzyme acceptor of a single carbon unit for the conversion of serine to glycine also reacts with formaldehyde chemically to form a derivative which can serve as an enzymatic donor of an hydroxymethyl group -. Studies on the formaldehyde binding... 

A reduced form of folic acid (tetrahydrofolic acid, FH4) is active in so-called one-carbon metabolism. A formyl group may be substituted on N(5) or N(io) and the N(5)-N(io) methenyl derivative (Figure 36) is also active. Reactions involving the introduction of one-carbon fragments include the conversion of glycine to serine (Section V.C.3), ethanolamine to choline (Section V.C.3) and the introduction of C(8) of the purine nucleus (Section V.D.3). 

Folic acid (Fig. 6) is the precursor of a number of coenzymes vital for the synthesis of many important molecules. These derivatives of folic acid, referred to collectively as active formate and active formaldehyde , are responsible for the donation of one carbon fragments in the enzymatic synthesis of a number of essential molecules. In the formation of methionine from homocysteine, the folic acid coenzyme donates the S-methyl group, and in the conversion of glycine to serine it is necessary for the formation of the hydroxymethyl group. Folic add is converted into its active coenzyme forms by an initial two step reduction to tetra-hydrofolic add (Fig. 6) by means of two enzymes, folic reductase and dihydrofolic reductase. Conversion of tetrahydrofolic acid (THF) to an active coenzyme folinic acid subsequently occurs by ad tion of an Ns formyl group (Fig. 6). The formation of similar compounds such as an Nio formyl derivative, or the bridged Ns,Nio-methylenetetrahydrofolic acid, also leads to active coenzymes. 

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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