Sources of Substituted Folates

The major point of entry for one-carbon fragments into substituted folates is methylene-tetrahydrofolate, which is formed by the catabolism of glycine, serine, and choline. Serine Hydroxymethyltransferase Serinehydroxymethyltrans-ferase is a pyridoxal phosphate-dependent aldolase that catalyzes the cleavage of serine to glycine and methylene-tetrahydrofolate (as shown in Figure 10.5). Serine is the major source of one-carbon substituted folates for biosynthetic reactions. At times of increased cell proliferation, the activities of serine hydroxymethyltransferase and the enzymes of the serine biosynthetic pathway are increased. The other product of the reaction, glycine, is also required in increased amounts under these conditions (for de novo synthesis of purines).

There are two isoenzymes of serine hydroxymethyltransferase; the cytosolic enzyme is involved in the provision of one-carbon fragments for biosynthetic reactions, whereas the mitochondrial enzyme is important in the fasting state as a source of serine for gluconeogenesis. The activity of the cytosolic enzyme is regulated by the state of folate substitution and the availability of folate, rather than by the state of serine metabolism. Methyl-tetrahydrofolate is a potent inhibitor, so when there is an adequate concentration of substituted folates from other sources, serine can be spared for energy-yielding metabolism or gluconeogenesis (Snell et al., 2000). The other reactions leading to the formation of one-carbon substituted tetrahydrofolate shown in Figure 10.4 are

Figure 10.3. One-carbon substituted tetrahydrofolic acid derivatives. THF, tetrahy-drofolate.

primarily catabolic reactions and are not subject to feedback inhibition by methyl-tetrahydrofolate.

When the glycine formed by serine hydroxymethyltransferase is not required for purine synthesis, it undergoes cleavage to carbon dioxide and ammonium, catalyzed by the glycine cleavage system. This is a multienzyme

Figure 10.4. Sources and uses of one-carbon units bound to folate. THF, tetrahydrofo-late.

complex with a number of similarities to the thiamin-dependent 2-oxo-acid dehydrogenases (Section 6.3.1), although it does not contain thiamin. It consists of the following:

1. a pyridoxal phosphate-dependent glycine decarboxylase;

2. a lipoamide-containing aminomethyltransferase, which acts to oxidize the one-carbon fragment to a methylene residue at the expense of reducing lipoamide to the disulfhydryl form;

3. a methylene-tetrahydrofolate synthesizing enzyme that transfers the one-carbon fragment onto tetrahydrofolate, releasing the nitrogen as ammonium; and

4. an NAD-dependent flavoprotein, dihydrolipoyl dehydrogenase, that oxidizes disulfhydryl lipoamide back to the disulfide. Histidine Catabolism As shown in Figure 10.6, the catabolism of histidine leads to the formation of formiminoglutamate (FIGLU). The ch2oh ch-nh3+


methylene-THF THF

serine hydroxymethyltransferase ch2-coo"

methylene-THF thf

glycine cleavage system

Figure 10.5. Reactions of serine hydroxymethyltransferase (EC and the glycine cleavage system (EC THF, tetrahydrofolate.

COO" glutamate

Figure 10.6. Catabolism of histidine - basis of the FIGLU test for folate status. Histi-dase, EC; urocanase, EC; FIGLU formiminotransferase, EC THF, tetrahydrofolate.

COO" glutamate

Figure 10.6. Catabolism of histidine - basis of the FIGLU test for folate status. Histi-dase, EC; urocanase, EC; FIGLU formiminotransferase, EC THF, tetrahydrofolate.

formimino group is transferred onto tetrahydrofolate to form formimino -tetrahydrofolate, which is subsequently deaminated to form methenyl-tetrahydrofolate.

A single bifunctional enzyme catalyzes the FIGLU formiminotransferase and formiminofolate cyclodeaminase reactions, so there is little or no free formimino-tetrahydrofolate in tissues under normal conditions. The two catalytic sites are separate, and with tetrahydrofolate monoglutamate, there is release of the formimino derivative. However, when polyglutamates are used, there is channeling of the intermediate between the two sites, and no release of the formimino derivative (Mackenzie and Baugh, 1980; Paquin et al., 1985).

Although catabolism of histidine is not a major source of substituted folate, the reaction is of interest because it has been exploited as a means of assessing folate nutritional status. In folate deficiency, the activity of the formimi-notransferase is impaired by lack of cofactor. Alter a loading dose of histidine, there is impaired oxidative metabolism of histidine and accumulation of FIGLU, which is excreted in the urine (Section 10.10.4). Other Sources of One-Carbon Substituted Folates As shown in Figure 14.4, choline is oxidized to betaine (trimethylglycine), then the first methyl group is transferred directly to homocysteine, forming methionine. The resultant dimethylglycine is demethylated to methylglycine (sarcosine) by an iron-flavoprotein, dimethylglycine dehydrogenase, which oxidizes the methyl group to formaldehyde before transferring it to tetrahydrofolate to form methylene-tetrahydrofolate. The demethylation of sarcosine to glycine yields methylene-tetrahydrofolate in the same way.

Formylglutamate can transfer its formyl group directly onto tetrahydro-folate to yield 5-formyl-tetrahydrofolate. Formyl-glutamate is not a normal physiological intermediate, and the formation of 5-formyl-tetrahydrofolate is probably a side reaction of FIGLU formiminotransferase.

Free formate can react with tetrahydrofolate to form 10-formyl-tetrahy-drofolate; the plasma concentration of formate rises in folate deficiency, and the ability to metabolize [14C]formate has been used as an index of folate depletion in experimental animals.

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