Serine transhydroxymethylase

Tetrahydrofolate cofactors participate in one-carbon transfer reactions. As described above in the section on vitamin B12, one of these essential reactions produces the dTMP needed for DNA synthesis. In this reaction, the enzyme thymidylate synthase catalyzes the transfer of the one-carbon unit of N 5,N 10-methylenetetrahydrofolate to deoxyuridine monophosphate (dUMP) to form dTMP (Figure 33-2, reaction 2). Unlike all of the other enzymatic reactions that utilize folate cofactors, in this reaction the cofactor is oxidized to dihydrofolate, and for each mole of dTMP produced, one mole of tetrahydrofolate is consumed. In rapidly proliferating tissues, considerable amounts of tetrahydrofolate can be consumed in this reaction, and continued DNA synthesis requires continued regeneration of tetrahydrofolate by reduction of dihydrofolate, catalyzed by the enzyme dihydrofolate reductase. The tetrahydrofolate thus produced can then reform the cofactor N 5,N 10-methylenetetrahydrofolate by the action of serine transhydroxy- methylase and thus allow for the continued synthesis of dTMP. The combined catalytic activities of dTMP synthase, dihydrofolate reductase, and serine transhydroxymethylase are often referred to as the dTMP synthesis cycle. Enzymes in the dTMP cycle are the targets of two anticancer drugs methotrexate inhibits dihydrofolate reductase, and a metabolite of 5-fluorouracil inhibits thymidylate synthase (see Chapter 55 Cancer Chemotherapy). 

Scheme XII. Steric course of the serine transhydroxymethylase reaction.

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). 

Scheme L Serine transhydroxymethylase mechanism and experimental setup for...

The glyA mutation in Chinese hamster ovary cells in tissue culture makes these cells partially dependent on glycine. The mutation affects the mitochondrial form of serine transhydroxymethylase, which catalyzes the conversion of serine to glycine, with tetrahy-drofolate serving as an acceptor of the hydroxymethyl group. Would you expect heme synthesis to be adversely affected in glyA mutants Why ... 

The effect of D-cycloserine and cis-APD on SAM and SAH content in liver tissue of rodents is presented in Fig.2. A single injection of D-cycloserine into mice (4 gm/kg of body weight) producing within 4 hr moderate 40-50% decrease in activity of serine transhydroxy-methylase in liver tissue, leads to gradual 40% reduction of SAM level in the tissue. As the initial SAH content in the tissue within 4 hr after D-cycloserine administration does not change, the SAH/SAM ratio increases from about 0.45 to 0.75. Within 12 hr after D-cycloserine administration the activity of serine transhydroxymethylase and SAM and SAH content in liver tissue of mice return to normal. 

It shoud be noted that decaborane, the most active inhibitor of serine transhydroxymethylase in in vivo experiments, decreases the SAM and SAH content in liver tissue of rats no more than MTX does, namely by 50-55% as compared with the control (see Fig.3). 

Fig. 2. SAM and SAH content in liver tissue of mice and rats treated with D-cycloserine and cis-APD. D-Cycloserine was injected i.p. into mice (A) in dose a 4.0 gm/kg of body weight. cis-APD was injected i.p. into rats (B) three times with intervals of 2 hr, each time in a dose of 1.0 gm/kg of body weight. At the specifed time intervals after the injections of D-cycloserine or first injection of cis-APD the animals were killed for assay of SAM and SAH content and activity of serine transhydroxymethylase. Symbols (—Q—),SAM ...

Potentiating action of 4-vinylpyridoxal on inhibition of serine transhydroxymethylase by D-cycloserine and its dimer, Biochera. Pharmacol., 28 (in press, 1979). 

Serine transhydroxymethylase A. thaliana Somerville and Ogren (1981) Somer-... 

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