Introduction to Human Nutrition

172 Introduction to Human Nutrition

and choline. Serine is the most important source of

substituted folates for biosynthetic reactions, and

the activity of serine hydroxymethyltransferase is

regulated by the state of folate substitution and the

availability of folate. The reaction is freely reversible,

and under appropriate conditions in liver it functions

to form serine from glycine as a substrate for

gluconeogenesis.

Methylene-, methenyl-, and 10-formyl-tetrahydro-

folates are freely interconvertible. This means that

when one-carbon folates are not required for syn-

thetic reactions, the oxidation of formyl-tetrahydro-

folate to carbon dioxide and folate provides a means

of maintaining an adequate tissue pool of free

folate.

By contrast, the reduction of methylene-tetra-

hydrofolate to methyl-tetrahydrofolate is irreversible,

and the only way in which free folate can be formed

from methyl-tetrahydrofolate is by the reaction of

methionine synthetase (see below).

Thymidylate synthetase and

dihydrofolate reductase

The methylation of dUMP to thymidine monophos-

phate (TMP), catalyzed by thymidylate synthetase, is

essential for the synthesis of DNA, although pre-

formed TMP arising from the catabolism of DNA can

be reutilized.

The methyl donor for thymidylate synthetase is

methylene-tetrahydrofolate; the reaction involves

reduction of the one-carbon fragment to a methyl

group at the expense of the folate, which is oxidized

to dihydrofolate. Dihydrofolate is then reduced to

tetrahydrofolate by dihydrofolate reductase.

Thymidylate synthase and dihydrofolate reductase

are especially active in tissues with a high rate of cell

division, and hence a high rate of DNA replication

and a high requirement for thymidylate. Because of

this, inhibitors of dihydrofolate reductase have been

exploited as anticancer drugs (e.g. methotrexate).

Chemotherapy consists of alternating periods of

Methylene-THF

Methenyl-THF

Formyl-THF

Histidine Formimino-THF

Methyl-THF Methionine

Serine

TMP + Dihydrofolate

Purines

CO 2

Formate

Glycine

Serine

Choline

Sources of one-carbon units Synthesis using one-carbon units

(a) (b)

Figure 8.15 Interconversion of the principal one-carbon substituted folates; sources of one-carbon fragments are shown on the left, and pathways

in which one-carbon units are used and free tetrahydrofolate is regenerated on the right. (a) Methylene-tetrahydrofolate reductase (EC 1.5.1.20);

(b) methionine synthetase (EC 2.1.1.13).