Serine racemase homologue of<i>Saccharomyces cerevisiae</i>has l-<i>threo</i>-3-hydroxyaspartate dehydratase activity

Wada, Masaaki; Nakamori, Shigeru; Takagi, Hiroshi

doi:10.1016/s0378-1097(03)00484-1

Cited by 23 publications

(25 citation statements)

References 21 publications

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“…For example, SR was isolated from the thermophilic archaeon Pyrobaculum islandicum [35]; it is present in the yeasts Schizosaccharomyces pombe and Saccharomyces cerevisiae [36,37]; and it can be found in plants like Arabidopsis thaliana [38,39], rice [40], and barley [41].…”

Section: Sr Distribution and Functionmentioning

confidence: 99%

“…Though also present in other tissue types, SR has been mainly studied in the CNS for its neurotransmitter producing ability. Along with DS, SR is found in hippocampus, amygdala, and various cortical regions [31,37]. The cellular distribution of SR is controversial.…”

Section: Sr Distribution and Functionmentioning

confidence: 99%

“…This observation has not been independently confirmed (unpublished observation). Notably, serine racemase homologs from the yeast Saccharomyces cerevisiae [37] and from soil bacteria Pseudomonas sp. T62 [82] have L-threo-3-hydroxyaspartate dehydratase activity and lack racemization activity.…”

Section: Sr Off-target Substrate Specificitymentioning

confidence: 99%

“…SR orthologs in yeast can act as hydroxyaspartate dehydratases [37]. We have shown that mammalian SR is also capable of efficient hydroxyaspartate elimination [86].…”

Section: Analogs Of Aspartic Acidmentioning

confidence: 99%

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Inhibition of Human Serine Racemase, an Emerging Target for Medicinal Chemistry

Jiraskova-Vanickova

Ettrich²,

Vorlová³

et al. 2011

CDT

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Proteins of glutamatergic NMDA receptor signaling pathways have been studied as targets for intervention in a variety of neuropathological conditions, including neurodegenerations, epilepsy, neuropathic pain, drug addiction, and schizophrenia. High activity NMDA-blocking agents have been designed to treat some of these disorders; however, their effect is often compromised by undesirable side effects. Therefore, alternative ways of modulating NMDA receptor function need to be sought after. The opening of the NMDA receptor ion channel requires occupation of two distinct binding sites, the glutamate site and the glycine site. It has been shown that D-serine, rather than glycine, can trigger the physiological NMDA receptor function. D-serine is a product of the activity of a specific enzyme, serine racemase (SR), which was identified a decade ago. SR has therefore emerged as a new potential target for the NMDA-receptor-based diseases. There is evidence linking increased levels of D-Ser to amyotrophic lateral sclerosis and Alzheimer's disease and decreased concentrations of D-serine to schizophrenia. SR is a pyridoxal-5'-phosphate dependent enzyme found in the cytosol of glial and neuronal cells. It is activated by ATP, divalent cations like Mg(2+) or Ca(2+), and reducing agents. This paper reviews the present literature on the activity and inhibition of mammalian SRs. It summarizes approaches that have been applied to design SR inhibitors and lists the known active compounds. Based on biochemical and docking analyses, i) we delineate for the first time the ATP binding site of human SR, and ii) we suggest possible mechanisms of action for the active compounds. In the end, we discuss the SR features that make the discovery of its inhibitors a challenging, yet very important, task of medicinal chemistry.

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Section: Sr Distribution and Functionmentioning

confidence: 99%

Section: Sr Distribution and Functionmentioning

confidence: 99%

Section: Sr Off-target Substrate Specificitymentioning

confidence: 99%

“…SR orthologs in yeast can act as hydroxyaspartate dehydratases [37]. We have shown that mammalian SR is also capable of efficient hydroxyaspartate elimination [86].…”

Section: Analogs Of Aspartic Acidmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Human Serine Racemase, an Emerging Target for Medicinal Chemistry

Jiraskova-Vanickova

Ettrich²,

Vorlová³

et al. 2011

CDT

View full text Add to dashboard Cite

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“…In addition, we used two sequences of THADH (A4F2N8, Pseudomonas sp. T62; P36007, Saccharomyces cerevisiae S288c; Murakami et al, 2009;Wada et al, 2003), which has a close phylogenetic relationship with eukaryotic SR but lacks SR activity. In this analysis, we hypothesized that gene products sharing more than 60 % similarity with THADH would lack SR activity.…”

Section: Methodsmentioning

confidence: 99%

Distribution of eukaryotic serine racemases in the bacterial domain and characterization of a representative protein in Roseobacter litoralis Och 149

et al. 2016

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Two distinct bacterial and eukaryotic serine racemases (SRs) have been identified based on phylogenetic and biochemical characteristics. Although some reports have suggested that marine heterotrophic bacteria have the potential to produce D-serine, the gene encoding bacterial SRs is not found in those bacterial genomes. In this study, using in-depth genomic analysis, we found that eukaryotic SR homologues were distributed widely in various bacterial genomes. Additionally, we selected a eukaryotic SR homologue from a marine heterotrophic bacterium, Roseobacter litoralis Och 149 (RiSR), and constructed an RiSR gene expression system in Escherichia coli for studying the properties of the enzyme. Among the tested amino acids, the recombinant RiSR exhibited both racemization and dehydration activities only towards serine, similar to many eukaryotic SRs. Mg 2+ and MgATP enhanced both activities of RiSR, whereas EDTA abolished these enzymatic activities. The enzymatic properties and domain structure of RiSR were similar to those of eukaryotic SRs, particularly mammalian SRs. However, RiSR showed lower catalytic efficiency for L-serine dehydration (k cat /K m 50.094 min 21 mM 21 ) than those of eukaryotic SRs reported to date (k cat /K m 50.6-21 min 21 mM 21 ). In contrast, the catalytic efficiency for L-serine racemization of RiSR (k cat /K m 53.14 min 21 mM 21 ) was 34-fold higher than that of L-serine dehydration. These data suggested that RiSR primarily catalysed serine racemization rather than dehydration.

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Enzyme Catalysis in Organic Synthesis

2012

186

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Serine racemase homologue ofSaccharomyces cerevisiaehas l-threo-3-hydroxyaspartate dehydratase activity

Cited by 23 publications

References 21 publications

Inhibition of Human Serine Racemase, an Emerging Target for Medicinal Chemistry

Inhibition of Human Serine Racemase, an Emerging Target for Medicinal Chemistry

Distribution of eukaryotic serine racemases in the bacterial domain and characterization of a representative protein in Roseobacter litoralis Och 149

Enzyme Catalysis in Organic Synthesis

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