Biotechnologie et biomatériaux

Abstrait

Comprehensive analysis of molecular mechanism of Serine deficiency by computational approach

Momoko Hamano

L -serine (L-Ser), a dispensable amino acid, is synthesized via de novo synthesis from the glycolytic intermediate 3-phosphoglycerate with
3-phosphoglycerate dehydrogenase (Phgdh) catalyzing the first reaction step. L-Ser serves as a necessary precursor for the synthesis of proteins,
sphingolipids, folate metabolites, and amino acids such as D-serine and glycine. Previous in vivo study demonstrated that severe L-Ser deficiency
in mice with systemic targeted disruption of Phgdh, resulted in intrauterine growth retardation, multiple organ malformation, and embryonic lethality.
L-Ser biosynthesis defects in humans resulting from PHGDH mutations were identified to be a cause of L-Ser deficiency disorders and Neu–
Laxova syndrome, the symptoms of which include severe fetal growth retardation, microcephaly, still birth and/or perinatal lethality. These findings
have demonstrated that de novo L-Ser synthesis is essential for embryonic development and survival in mice and humans. Moreover, resent study
demonstrate that the decrease of L-Ser availability appears to correlate with symptoms of metabolic diseases and psychiatric diseases. These
studies raise the possibility that elucidation of the pathological mechanisms underlying L-Ser deficiency could provide an opportunity to develop
new therapies to alleviate symptoms of various diseases associated with reduced L-Ser availability. In this study, I aim to elucidate the molecular
mechanism of cytotoxicity induced by Ser deficiency under pathological condition. To understand the physiological significance of Ser in the brain,
I extracted characteristic gene expression pattern using microarray data and detected the active/inactive pathways caused by Ser deficiency.