Abstract
In mammals, D-Ser is synthesized by serine racemase (SR) and degraded by D-amino acid oxidase (DAO). D-Ser acts as an endogenous ligand for N-methyl-D-aspartate (NMDA)- and δ2 glutamate receptors, and is involved in brain functions such as learning and memory. Although SR homologs are highly conserved in eukaryotes, little is known about the significance of D-Ser in non-mammals. In contrast to mammals, the slime mold Dictyostelium discoideum genome encodes SR, DAO, and additionally D-Ser specific degradation enzyme D-Ser dehydratase (DSD), but not NMDA- and δ2 glutamate receptors. Here, we studied the significances of D-Ser and DSD in D. discoideum. Enzymatic assays demonstrated that DSD is 460- and 1,700-fold more active than DAO and SR, respectively, in degrading D-Ser. Moreover, in dsd-null cells D-Ser degradation activity is completely abolished. In fact, while in wild-type D. discoideum intracellular D-Ser levels were considerably low, dsd-null cells accumulated D-Ser. These results indicated that DSD but not DAO is the primary enzyme responsible for D-Ser decomposition in D. discoideum. We found that dsd-null cells exhibit delay in development and arrest at the early culmination stage. The efficiency of spore formation was considerably reduced in the mutant cells. These phenotypes were further pronounced by exogenous D-Ser but rescued by plasmid-borne expression of dsd. qRT-PCR analysis demonstrated that mRNA expression of key genes in the cAMP signaling relay is perturbed in the dsd knockout. Our data indicate novel roles for D-Ser and/or DSD in the regulation of cAMP signaling in the development processes of D. discoideum.
Highlights
D-Serine (D-Ser) is highly concentrated in mammalian brain and plays important roles in brain functions such as memory and learning, by binding to N-methyl-D-aspartate (NMDA)- and δ2 glutamate receptors (Oliet and Mothet, 2009; Henneberger et al, 2010; Kakegawa et al, 2011)
Addition of other divalent metal ions such as Mg2+, Ca2+, Mn2+, Ni2+, and Fe2+ to the Ethylenediaminetetraacetic acid (EDTA)-treated enzyme did not restore enzyme activity (Figure 1B). These results indicate that the DDB0305709 protein, hereafter D-Ser dehydratase (DSD), is a PLPand Zn2+-dependent DSD
We studied the significances of D-Ser especially focusing on the enzymes responsible for D-Ser catabolism in D. discoideum
Summary
D-Serine (D-Ser) is highly concentrated in mammalian brain and plays important roles in brain functions such as memory and learning, by binding to N-methyl-D-aspartate (NMDA)- and δ2 glutamate receptors (Oliet and Mothet, 2009; Henneberger et al, 2010; Kakegawa et al, 2011). In tobacco and Arabidopsis, SR (and D-Ser) is reported to modulate glutamate-receptor-like channels, which regulate pollen-tube growth and morphogenesis by facilitating Ca2+ influx across the plasma membrane and thereby modulating the apical Ca2+ gradient (Michard et al, 2011). D-Ser is mainly degraded by a flavindependent enzyme, D-amino acid oxidase (DAO) (Pollegioni et al, 2007; Konno et al, 2010; Pollegioni and Sacchi, 2010), and D-Ser levels are tightly regulated by the combination of synthesis, degradation, uptake, and/or transport. In accordance with the physiological significance of D-Ser in the regulation of brain functions, altered levels of D-Ser in biological fluids were reported in various neuropsychiatric disorders such as schizophrenia (Bendikov et al, 2007; Cho et al, 2016), Alzheimer’s (Fisher et al, 1998), and ALS (Sasabe et al, 2007)
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