Novel role of serine racemase in anti-apoptosis and metabolism

Abstract

Background: Serine racemase (SR) catalyzes the production of d-serine, a co-agonist of the N-methyl-d-aspartate receptor (NMDAR). A previous report shows the contribution of SR in the NMDAR-mediated neuronal cell death process.

Methods and results: To analyze the intrinsic role of SR in the cell death process, we established the epithelial human embryonic kidney 293T (HEK293T) cell lines expressing wild-type SR (SR-WT), catalytically inactive mutant SR (SR-K56G), and catalytically hyperactive mutant SR (SR-Q155D). To these cell lines, staurosporine (STS), which induces apoptosis, was introduced. The cells expressing SR-WT and SR-Q155D showed resistance to STS-induced apoptosis, compared with nontransfected HEK293T cells and cells expressing SR-K56G. The SR-WT cells also showed a significant higher viability than the SR-QD cells. Furthermore, we detected elevated phosphorylation levels of Bcl-2 at serine-70 and Akt at serine-473 and threonine-308, which are related to cell survival, in the cells expressing SR-WT and SR-Q155D. From the results of metabolite analysis, we found elevated levels of acetyl CoA and ATP in cells expressing SR-WT.

Conclusion: Because SR has two enzymatic activities, namely, racemization and α, β-elimination, and SR-Q155D shows enhanced racemization and reduced α, β-elimination activities, we concluded that the racemization reaction catalyzed by SR may have a more protective role against apoptosis than the α, β-elimination reaction. Moreover, both of these activities are important for maximal survival and elevated levels of acetyl CoA and ATP.

General significance: Our findings reveal the NMDAR-independent roles of SR in metabolism and cell survival.

Keywords: Apoptosis; NMDA receptor; Serine racemase; d-Serine.