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Serine racemase

Joseph T Coyle, Darrick T Balu
The N-methyl-d-aspartate receptor (NMDAR) is unique in requiring two agonists to bind simultaneously to open its cation channel: the neurotransmitter, glutamate, and the coagonists, glycine, or d-serine. The Snyder laboratory was the first to clone serine racemase (SR), the enzyme that synthesizes d-serine, and to localize it immunocytochemically. Our laboratory has focused on the role of d-serine in brain disorders. Silencing the expression of SR, a risk gene for schizophrenia (SCZ), in mice (SR-/-), results in a phenotype that closely resembles SCZ including: cortical atrophy, reduced dendritic spine density and complexity, downregulation of parvalbumin-positive cortical GABAergic neurons, and cognitive impairments...
2018: Advances in Pharmacology
Herman Wolosker
d-Serine is a physiological coagonist of NMDA receptors involved in synaptic plasticity, neurodevelopment, and neurodegeneration. d-Serine is synthesized by the enzyme serine racemase, which converts l- to d-serine. Recent studies indicate that the supply of l-serine by astroglia fuels the neuronal synthesis of d-serine. This pathway, named the serine shuttle, highlights the importance of the glia-neuron metabolic crosstalk for regulating NMDA receptor activity. Dysfunction of different components of the serine shuttle pathway leads to neurodevelopmental defects, neurodegeneration, and may be involved in psychiatric diseases...
2018: Advances in Pharmacology
Francesco Marchesani, Stefano Bruno, Gianluca Paredi, Samanta Raboni, Barbara Campanini, Andrea Mozzarelli
Serine racemase is a pyridoxal 5'‑phosphate dependent enzyme responsible for the synthesis of d‑serine, a neuromodulator of the NMDA receptors. Its activity is modulated by several ligands, including ATP, divalent cations and protein interactors. The murine orthologue is inhibited by S-nitrosylation at Cys113, a residue adjacent to the ATP binding site. We found that the time course of inhibition of human serine racemase by S-nitrosylation is markedly biphasic, with a fast phase associated with the reaction of Cys113...
January 30, 2018: Biochimica et Biophysica Acta
Hua Tao, Xu Zhou, Qian Xie, Zhonghua Ma, Fuhai Sun, Lili Cui, Yujie Cai, Guoda Ma, Jiawu Fu, Zhou Liu, You Li, Haihong Zhou, Jianghao Zhao, Yanyan Chen, Hui Mai, Ying Chen, Jun Chen, Wei Qi, Chaowen Sun, Bin Zhao, Keshen Li
D-serine is a predominant N-methyl-D-aspartate receptor co-agonist with glutamate, and excessive activation of the receptor plays a substantial role in epileptic seizures. Serine racemase (SRR) is responsible for transforming L-serine to D-serine. In this study, we aimed to investigate the genetic roles of SRR and a neighbouring gene, nonsense-mediated mRNA decay factor (SMG6), in temporal lobe epilepsy (TLE). Here, a total of 496 TLE patients and 528 healthy individuals were successfully genotyped for three SRR tag single nucleotide polymorphisms...
January 24, 2018: Journal of Cellular and Molecular Medicine
Yeong-Chan Ahn, Conrad Fischer, Marco J van Belkum, John C Vederas
O-Ureidoserine racemase (DcsC) is a PLP-independent enzyme in the biosynthetic route to the antibiotic d-cycloserine. Here we present the recombinant expression and characterization of a significantly more active DcsC variant featuring an N-terminal SUMO-tag. Synthesis of enantiomeric pure inhibitors in combination with site-specific mutation of active site cysteines to serines of this enzyme offers closer insights into the mechanism of this transformation. Homology modelling with a close relative (diaminopimelate epimerase, DapF) inspired C- and N-terminal truncation of DcsC to produce a more compact yet still active enzyme variant...
January 24, 2018: Organic & Biomolecular Chemistry
Hugo Girard, Olivier Potvin, Scott Nugent, Caroline Dallaire-Théroux, Stephen Cunnane, Simon Duchesne
Sporadic Alzheimer's disease (AD), as opposed to its autosomal dominant form, is likely caused by a complex interaction of genetic, environmental, and health lifestyle factors. Twin studies indicate that sporadic AD heritability could be between 58% and 79%, around half of which is explained by the ε4 allele of the apolipoprotein E (APOE4). We hypothesized that genes associated with known risk factors for AD, namely hypertension, hypercholesterolemia, obesity, diabetes, and cardiovascular disease, would contribute significantly to the remaining heritability...
December 7, 2017: Neurobiology of Aging
Suyan Li, Yota Uno, Uwe Rudolph, Johanna Cobb, Jing Liu, Thea Anderson, Deborah Levy, Darrick T Balu, Joseph T Coyle
D-Serine is a co-agonist at forebrain N-methyl-D-aspartate receptors (NMDAR) and is synthesized by serine racemase (SR). Although D-serine and SR were originally reported to be localized to glia, recent studies have provided compelling evidence that under healthy physiologic conditions both are localized primarily in neurons. However, in pathologic conditions, reactive astrocytes can also express SR and synthesize D-serine. Since cultured astrocytes exhibit features of reactive astrocytes, we have characterized D-serine synthesis and the expression of enzymes involved in its disposition in primary glial cultures...
January 3, 2018: Biochemical Pharmacology
Hironori Ozaki, Ran Inoue, Takako Matsushima, Masakiyo Sasahara, Atsushi Hayashi, Hisashi Mori
Diabetic retinopathy (DR) is a leading cause of blindness. DR is recognized as a microvascular disease and inner retinal neurodegeneration. In the course of retinal neurodegeneration, N-methyl-D-aspartate receptor (NMDAR)-mediated excitotoxicity is involved. Full activation of NMDAR requires binding of agonist glutamate and coagonist glycine or D-serine. D-Serine is produced from L-serine by serine racemase (SRR) and contributes to retinal neurodegeneration in rodent models of DR. However, the involvement of SRR in both neurodegeneration and microvascular damage in DR remains unclear...
2018: PloS One
Satoyuki Takahara, Kiyomi Nakagawa, Tsugumi Uchiyama, Tomoyuki Yoshida, Kazunori Matsumoto, Yasuo Kawasumi, Mineyuki Mizuguchi, Takayuki Obita, Yurie Watanabe, Daichi Hayakawa, Hiroaki Gouda, Hisashi Mori, Naoki Toyooka
Most of the endogenous free d-serine (about 90%) in the brain is produced by serine racemase (SR). d-Serine in the brain is involved in neurodegenerative disorders and epileptic states as an endogenous co-agonist of the NMDA-type glutamate receptor. Thus, SR inhibitors are expected to be novel therapeutic candidates for the treatment of these disorders. In this study, we solved the crystal structure of wild-type SR, and tried to identify a new inhibitor of SR by in silico screening using the structural information...
December 13, 2017: Bioorganic & Medicinal Chemistry Letters
Isil Ezgi Eryilmaz, Yakup Kordan, Berna Aytac Vuruskan, Onur Kaygısız, Berrin Tunca, Gulsah Cecener
Genetic rearrangements involving androgen-regulated transmembrane protease serine 2 (TMPRSS2) and genes from the ETS transcription factor family, most commonly ERG and ETV1, result in alteration that responsible for oncogenic activity in prostate cancer (PC). The aims of the present study were to: 1) investigate the frequency of these fusion transcripts in prostate tissue samples obtained from patients diagnosed with atypical small acinar proliferation (ASAP), 2) determine any clinical significance of T2E expression at the RNA level in predicting PC detection in subsequent biopsies, and 3) evaluate expression of the PC marker, alpha-methylacyl-CoA racemase (AMACR), according to T2E status by real-time quantitative reverse transcription PCR (RT-qPCR)...
December 22, 2017: Gene
Gianluca Molla
D-amino acid oxidase (DAAO) catalyzes the oxidative deamination of several neutral D-amino acids and is the enzyme mainly responsible (together with serine racemase) for degrading D-serine (D-Ser) in the central nervous system of mammals. This D-amino acid, which binds the coagonist site of the N-methyl-D-aspartate receptor, is thus a key neuromodulator of glutamatergic neurotransmission. Altered D-Ser metabolism results in several pathological conditions (e.g., amylotrophic lateral sclerosis or schizophrenia, SZ) for which effective "broad spectrum" pharmaceutical drugs are not yet available...
2017: Frontiers in Molecular Biosciences
Taichi Mizobuchi, Risako Nonaka, Motoki Yoshimura, Katsumasa Abe, Shouji Takahashi, Yoshio Kera, Masaru Goto
Aspartate racemase (AspR) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that is responsible for D-aspartate biosynthesis in vivo. To the best of our knowledge, this is the first study to report an X-ray crystal structure of a PLP-dependent AspR, which was resolved at 1.90 Å resolution. The AspR derived from the bivalve mollusc Scapharca broughtonii (SbAspR) is a type II PLP-dependent enzyme that is similar to serine racemase (SR) in that SbAspR catalyzes both racemization and dehydration. Structural comparison of SbAspR and SR shows a similar arrangement of the active-site residues and nucleotide-binding site, but a different orientation of the metal-binding site...
December 1, 2017: Acta Crystallographica. Section F, Structural Biology Communications
Darrick T Balu, Joseph T Coyle
cAMP-response-element-binding protein (CREB) is a transcription factor ubiquitously expressed in the brain that regulates neuroplasticity by modulating gene expression. The influx of calcium through N-methyl-d-aspartate receptors (NMDARs) is a well-defined mechanism that leads to the increased expression of CREB-dependent genes, including brain derived neurotrophic factor (BDNF), microRNA-132, and activity-regulated cytoskeleton-associated protein (Arc). These molecules are implicated in the pathophysiology of schizophrenia...
November 27, 2017: ACS Chemical Neuroscience
Hoon-Seong Choi, Dae-Hyun Roh, Seo-Yeon Yoon, Sheu-Ran Choi, Soon-Gu Kwon, Suk-Yun Kang, Ji-Young Moon, Ho-Jae Han, Alvin J Beitz, Jang-Hern Lee
BACKGROUND AND PURPOSE: Although we have recently demonstrated that spinal astrocyte gap junctions mediate the development of mirror-image pain (MIP), it is still unclear which astrocyte-derived factor is responsible for the development of MIP and how its production is controlled. In the present study, we focused on the role of ipsilateral versus contralateral D-serine in the development of MIP and investigated the possible involvement of σ1 receptors and gap junctions in astrocyte D-serine production...
February 2018: British Journal of Pharmacology
Matthew D Puhl, Rajeev I Desai, Shunsuke Takagi, Kendall T Presti, Michelle R Doyle, Rachel J Donahue, Samantha M Landino, Jack Bergman, William A Carlezon, Joseph T Coyle
Both schizophrenia (SZ) and substance abuse (SA) exhibit significant heritability. Moreover, N-methyl-d-aspartate receptors (NMDARs) have been implicated in the pathophysiology of both SZ and SA. We hypothesize that the high prevalence of comorbid SA in SZ is due to dysfunction of NMDARs caused by shared risk genes. We used transgenic mice with a null mutation of the gene encoding serine racemase (SR), the enzyme that synthesizes the NMDAR co-agonist d-serine and an established risk gene for SZ, to recreate the pathology of SZ...
November 23, 2017: Addiction Biology
Masahito Murakami, Makoto Saito, Hirokazu Yokobori, Katsushi Nishimura, Minoru Tanigawa, Yoko Nagata
Pyrobaculum islandicum is a hyperthermophilic archaeon that grows optimally at 95-100 °C. In the previous study, we extensively purified a serine racemase from this organism and cloned the gene for overexpression in Escherichia coli (Ohnishi et al. 2008). This enzyme also exhibits highly thermostable L-serine/L-threonine dehydratase activity. In the present study, we aimed to elucidate the molecular mechanisms underlying the high thermostability of this enzyme. A recombinant variant of this enzyme, PiSRvt, constructed by truncating the C-terminal 72 amino acids, was compared with the native enzyme, PiSR...
November 9, 2017: Extremophiles: Life Under Extreme Conditions
Darrick T Balu, Kendall Taylor Presti, Cathy C Y Huang, Kevin Muszynski, Inna Radzishevsky, Herman Wolosker, Guia Guffanti, Kerry J Ressler, Joseph T Coyle
BACKGROUND: The amygdala is a central component of the neural circuitry that underlies fear learning. N-methyl-D-aspartate receptor-dependent plasticity in the amygdala is required for pavlovian fear conditioning and extinction. N-methyl-D-aspartate receptor activation requires the binding of a coagonist, D-serine, which is synthesized from L-serine by the neuronal enzyme serine racemase (SR). However, little is known about SR and D-serine function in the amygdala. METHODS: We used immunohistochemical methods to characterize the cellular localization of SR and D-serine in the mouse and human amygdala...
August 26, 2017: Biological Psychiatry
Sayuri Ishiwata, Asami Umino, Toru Nishikawa
It has been well accepted that d-serine may be an exclusive endogenous coagonist for the N-methyl-d-aspartate (NMDA)-type glutamate receptor in mammalian forebrain regions. We have recently found by using an in vivo dialysis method that an intra-medial prefrontal cortex infusion of S-α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (S-AMPA), a selective AMPA-type glutamate receptor agonist, causes a reduction in the extracellular levels of d-serine in a calcium-permeable AMPA receptor antagonist-sensitive manner...
September 28, 2017: Neurochemistry International
He Zhang, Liping Song, Yuhua Chang, Mengjuan Wu, Xiuli Kuang, Haiyan Jiang, Shengzhou Wu
Inward migration of cerebellar granule cells (CGCs) after birth is critical for lamination in the cerebellar cortex. N-methyl-d-aspartate (NMDA) subtype of glutamate receptor (NMDAR) tethering CGCs into Bergmann glial fibers mediates the inward movement during the glial-dependent migratory phase. Activation of NMDAR depends on simultaneous binding of the GluN2 subunit by glutamate, and of the GluN1 subunit by d-serine or glycine; d-serine is believed to be an endogenous ligand of NMDAR. We hypothesized that lamination of the cerebellar cortex may be compromised in Srr (the gene for serine racemase (SR)) mutated mice (Srrnull) because of significantly low levels of d-serine per se...
September 20, 2017: Molecular and Cellular Neurosciences
Haiyan Jiang, Mengjuan Wu, Yimei Liu, Liping Song, Shifeng Li, Xianwei Wang, Yun-Feng Zhang, Junxu Fang, Shengzhou Wu
Choroidal neovascularization (CNV) is a leading cause of blindness in age-related macular degeneration. Production of vascular endothelial growth factor (VEGF) and macrophage recruitment by retinal pigment epithelial cells (RPE) significantly contributes to the process of CNV in an experimental CNV model. Serine racemase (SR) is expressed in retinal neurons and glial cells, and its product, d-serine, is an endogenous co-agonist of N-methyl-d-aspartate receptor. Activation of the receptor results in production of nitric oxide ((...
November 2017: Journal of Neurochemistry
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