Novel tetrahydrofolate-dependent D-serine dehydratase activity of serine hydroxymethyltransferases

D-Serine plays vital physiological roles in the functional regulation of the mammalian brain, where it is produced from L-serine by serine racemase and degraded by D-amino acid oxidase. In the present study, we identified a new D-serine metabolizing activity of serine hydroxymethyltransferase (SHMT) in bacteria as well as mammals. SHMT is known to catalyze the conversion of L-serine and tetrahydrofolate (THF) to glycine and 5,10-methylenetetrahydrofolate, respectively. In addition, we found that human and Escherichia coli SHMTs have D-serine dehydratase activity, which degrades D-serine to pyruvate and ammonia. We characterized this enzymatic activity along with canonical SHMT activity. Intriguingly, SHMT required THF to catalyze D-serine dehydration and did not exhibit dehydratase activity toward L-serine. Furthermore, SHMT did not use D-serine as a substrate in the canonical hydroxymethyltransferase reaction. The D-serine dehydratase activities of two isozymes of human SHMT were inhibited in the presence of a high concentration of THF, whereas that of E. coli SHMT was increased. The pH and temperature profiles of D-serine dehydratase and serine hydroxymethyltransferase activities of these three SHMTs were partially distinct. The catalytic efficiency (k(cat)/K-m) of dehydratase activity was lower than that of hydroxymethyltransferase activity. Nevertheless, the D-serine dehydratase activity of SHMT was physiologically important because d-serine inhibited the growth of an SHMT deletion mutant of E. coli, increment glyA, more than that of the wild-type strain. Collectively, these results suggest that SHMT is involved not only in L-but also in d-serine metabolism through the degradation of D-serine.