Novel tetrahydrofolate‐dependent <scp>d</scp>‐serine dehydratase activity of serine hydroxymethyltransferases
Tetsuya Miyamoto, Shinya Fushinobu, Yasuaki Saitoh, Masae Sekine, Masumi Katane, Kumiko Sakai‐Kato, Hiroshi Homma
Abstract
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 , ∆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.