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Serine racemase

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https://www.readbyqxmd.com/read/28560262/decreased-free-d-aspartate-levels-are-linked-to-enhanced-d-aspartate-oxidase-activity-in-the-dorsolateral-prefrontal-cortex-of-schizophrenia-patients
#1
Tommaso Nuzzo, Silvia Sacchi, Francesco Errico, Simona Keller, Orazio Palumbo, Ermanno Florio, Daniela Punzo, Francesco Napolitano, Massimiliano Copetti, Massimo Carella, Lorenzo Chiariotti, Alessandro Bertolino, Loredano Pollegioni, Alessandro Usiello
It is long acknowledged that the N-methyl d-aspartate receptor co-agonist, d-serine, plays a crucial role in several N-methyl d-aspartate receptor-mediated physiological and pathological processes, including schizophrenia. Besides d-serine, another free d-amino acid, d-aspartate, is involved in the activation of N-methyl d-aspartate receptors acting as an agonist of this receptor subclass, and is abundantly detected in the developing human brain. Based on the hypothesis of N-methyl d-aspartate receptor hypofunction in the pathophysiology of schizophrenia and considering the ability of d-aspartate and d-serine to stimulate N-methyl d-aspartate receptor-dependent transmission, in the present work we assessed the concentration of these two d-amino acids in the post-mortem dorsolateral prefrontal cortex and hippocampus of patients with schizophrenia and healthy subjects...
2017: NPJ Schizophrenia
https://www.readbyqxmd.com/read/28533113/a-novel-serine-racemase-inhibitor-suppresses-neuronal-over-activation-in-vivo
#2
Hisashi Mori, Ryogo Wada, Satoyuki Takahara, Yoshikazu Horino, Hironori Izumi, Tetsuya Ishimoto, Tomoyuki Yoshida, Mineyuki Mizuguchi, Takayuki Obita, Hiroaki Gouda, Shuichi Hirono, Naoki Toyooka
Serine racemase (SRR) is an enzyme that produces d-serine from l-serine. d-Serine acts as an endogenous coagonist of NMDA-type glutamate receptors (NMDARs), which regulate many physiological functions. Over-activation of NMDARs induces excitotoxicity, which is observed in many neurodegenerative disorders and epilepsy states. In our previous works on the generation of SRR gene knockout (Srr-KO) mice and its protective effects against NMDA- and Aβ peptide-induced neurodegeneration, we hypothesized that the regulation of NMDARs' over-activation by inhibition of SRR activity is one such therapeutic strategy to combat these disease states...
May 11, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28487371/a-clostridium-difficile-alanine-racemase-affects-spore-germination-and-accommodates-serine-as-a-substrate
#3
Ritu Shrestha, Steve W Lockless, Joseph A Sorg
Clostridium difficile has become one of the most common bacterial pathogens in hospital-acquired infections in the United States. Although C. difficile is strictly anaerobic, it survives in aerobic environments and transmits between hosts via spores. C. difficile spore germination is triggered in response to certain bile acids and glycine. Although glycine is the most effective co-germinant, other amino acids can substitute with varying efficiencies. Of these, L-alanine is an effective co-germinant and is also a germinant for most bacterial spores...
May 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28435276/clinical-and-biochemical-study-of-d-serine-metabolism-among-schizophrenia-patients
#4
Hamdy N El-Tallawy, Tahia H Saleem, Abdallah Maa El-Ebidi, Mohammed H Hassan, Romany H Gabra, Wafaa Ma Farghaly, Nagwa Abo El-Maali, Hoda S Sherkawy
BACKGROUND: Schizophrenia is a typical N-methyl-d-aspartate receptor (NMDA-R) hypofunction disorder. Decreased d-serine (d-Ser) levels in the periphery occur in schizophrenia and may reflect decreased availability of d-Ser to activate NMDA-R in the brain. OBJECTIVE: The objective of this study was to investigate the role of d-Ser metabolism in the pathogenesis of schizophrenia via biochemical assays and correlates, the serum level of d-Ser, d-serine racemase (SR) (responsible for its formation from l-serine [l-Ser]) and d-amino acid oxidase (DAAO) (responsible for its catabolism), among different clinical types of schizophrenia patients...
2017: Neuropsychiatric Disease and Treatment
https://www.readbyqxmd.com/read/28290777/isolation-and-amino-acid-sequence-of-a-dehydratase-acting-on-d-erythro-3-hydroxyaspartate-from-pseudomonas-sp-n99-and-its-application-in-the-production-of-optically-active-3-hydroxyaspartate
#5
Hiroyuki Nagano, Kana Shibano, Yu Matsumoto, Atsushi Yokota, Masaru Wada
An enzyme catalyzing the ammonia-lyase reaction for the conversion of d-erythro-3-hydroxyaspartate to oxaloacetate was purified from the cell-free extract of a soil-isolated bacterium Pseudomonas sp. N99. The enzyme exhibited ammonia-lyase activity toward l-threo-3-hydroxyaspartate and d-erythro-3-hydroxyaspartate, but not toward other 3-hydroxyaspartate isomers. The deduced amino acid sequence of the enzyme, which belongs to the serine/threonine dehydratase family, shows similarity to the sequence of l-threo-3-hydroxyaspartate ammonia-lyase (EC 4...
June 2017: Bioscience, Biotechnology, and Biochemistry
https://www.readbyqxmd.com/read/28202572/differential-regulation-of-nmda-receptors-by-d-serine-and-glycine-in-mammalian-spinal-locomotor-networks
#6
David Acton, Gareth B Miles
Activation of N-methyl-d-aspartate receptors (NMDARs) requires the binding of a coagonist, either d-serine or glycine, in addition to glutamate. Changes in occupancy of the coagonist binding site are proposed to modulate neural networks including those controlling swimming in frog tadpoles. Here, we characterize regulation of the NMDAR coagonist binding site in mammalian spinal locomotor networks. Blockade of NMDARs by d(-)-2-amino-5-phosphonopentanoic acid (d-APV) or 5,7-dichlorokynurenic acid reduced the frequency and amplitude of pharmacologically induced locomotor-related activity recorded from the ventral roots of spinal-cord preparations from neonatal mice...
May 1, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28089597/magnesium-and-calcium-ions-differentially-affect-human-serine-racemase-activity-and-modulate-its-quaternary-equilibrium-toward-a-tetrameric-form
#7
Stefano Bruno, Marilena Margiotta, Francesco Marchesani, Gianluca Paredi, Valentina Orlandi, Serena Faggiano, Luca Ronda, Barbara Campanini, Andrea Mozzarelli
Serine racemase is the pyridoxal 5'-phosphate dependent enzyme that catalyzes both production and catabolism of d-serine, a co-agonist of the NMDA glutamate receptors. Mg(2+), or, alternatively, Ca(2+), activate human serine racemase by binding both at a specific site and - as ATP-metal complexes - at a distinct ATP binding site. We show that Mg(2+) and Ca(2+) bind at the metal binding site with a 4.5-fold difference in affinity, producing a similar thermal stabilization and partially shifting the dimer-tetramer equilibrium in favour of the latter...
April 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28051338/activity-dependent-sulfhydration-signal-controls-n-methyl-d-aspartate-subtype-glutamate-receptor-dependent-synaptic-plasticity-via-increasing-d-serine-availability
#8
Yuan-Long Li, Peng-Fei Wu, Jian-Guo Chen, Sheng Wang, Qian-Qian Han, Dan Li, Wen Wang, Xin-Lei Guan, Di Li, Li-Hong Long, Jian-Geng Huang, Fang Wang
AIMS: Reactive sulfur species, including hydrogen sulfide (H2S) and its oxydates, have been raised as novel redox signaling molecules. The present study aimed at examining whether endogenous sulfhydration signal is required for long-term potentiation (LTP), a cellular model for memory. RESULTS: In this study, we found that increased synaptic activity triggered sulfide generation and protein sulfhydration. Activity-triggered sulfide production was essential for N-methyl-D-aspartate subtype glutamate receptor (NMDAR)-dependent LTP via maintaining the availability of d-serine, a primary coagonist for synaptic NMDARs...
February 10, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/27986591/spinal-d-serine-increases-pkc-dependent-glun1-phosphorylation-contributing-to-the-sigma-1-receptor-induced-development-of-mechanical-allodynia-in-a-mouse-model-of-neuropathic-pain
#9
Sheu-Ran Choi, Ji-Young Moon, Dae-Hyun Roh, Seo-Yeon Yoon, Soon-Gu Kwon, Hoon-Seong Choi, Suk-Yun Kang, Ho-Jae Han, Alvin J Beitz, Jang-Hern Lee
We have recently shown that spinal sigma-1 receptor (Sig-1R) activation facilitates nociception via an increase in phosphorylation of the N-methyl-D-aspartate (NMDA) receptor GluN1 subunit (pGluN1). The present study was designed to examine whether the Sig-1R-induced facilitative effect on NMDA-induced nociception is mediated by D-serine, and whether D-serine modulates spinal pGluN1 expression and the development of neuropathic pain after chronic constriction injury (CCI) of the sciatic nerve. Intrathecal administration of the D-serine degrading enzyme, D-amino acid oxidase attenuated the facilitation of NMDA-induced nociception induced by the Sig-1R agonist, 2-(4-morpholinethyl)1-phenylcyclohexane carboxylate...
December 14, 2016: Journal of Pain: Official Journal of the American Pain Society
https://www.readbyqxmd.com/read/27880078/serine-racemase-is-expressed-in-islets-and-contributes-to-the-regulation-of-glucose-homeostasis
#10
Amber D Lockridge, Daniel C Baumann, Brian Akhaphong, Alleah Abrenica, Robert F Miller, Emilyn U Alejandro
NMDA receptors (NMDARs) have recently been discovered as functional regulators of pancreatic β-cell insulin secretion. While these excitatory receptor channels have been extensively studied in the brain for their role in synaptic plasticity and development, little is known about how they work in β-cells. In neuronal cells, NMDAR activation requires the simultaneous binding of glutamate and a rate-limiting co-agonist, such as D-serine. D-serine levels and availability in most of the brain rely on endogenous synthesis by the enzyme serine racemase (Srr)...
November 2016: Islets
https://www.readbyqxmd.com/read/27787586/bioinformatic-analysis-of-fold-type-iii-plp-dependent-enzymes-discovers-multimeric-racemases
#11
Anders M Knight, Alberto Nobili, Tom van den Bergh, Maika Genz, Henk-Jan Joosten, Dirk Albrecht, Katharina Riedel, Ioannis V Pavlidis, Uwe T Bornscheuer
Pyridoxal-5'-phosphate (PLP)-dependent enzymes are ubiquitous in nature and catalyze a variety of important metabolic reactions. The fold-type III PLP-dependent enzyme family is primarily comprised of decarboxylases and alanine racemases. In the development of a multiple structural alignment database (3DM) for the enzyme family, a large subset of 5666 uncharacterized proteins with high structural, but low sequence similarity to alanine racemase and decarboxylases was found. Compared to these two classes of enzymes, the protein sequences being the object of this study completely lack the C-terminal domain, which has been reported important for the formation of the dimer interface in other fold-type III enzymes...
February 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/27742076/the-rise-and-fall-of-the-d-serine-mediated-gliotransmission-hypothesis
#12
REVIEW
Herman Wolosker, Darrick T Balu, Joseph T Coyle
d-Serine modulates N-methyl d-aspartate receptors (NMDARs) and regulates synaptic plasticity, neurodevelopment, and learning and memory. However, the primary site of d-serine synthesis and release remains controversial, with some arguing that it is a gliotransmitter and others defining it as a neuronal cotransmitter. Results from several laboratories using different strategies now show that the biosynthetic enzyme of d-serine, serine racemase (SR), is expressed almost entirely by neurons, with few astrocytes appearing to contain d-serine...
November 2016: Trends in Neurosciences
https://www.readbyqxmd.com/read/27693471/serine-racemase-inhibition-induces-nitric-oxide-mediated-neurovascular-protection-during-cerebral-ischemia
#13
Akihiro Watanabe, Tsutomu Sasaki, Toshiro Yukami, Hideaki Kanki, Manabu Sakaguchi, Hiroshi Takemori, Kazuo Kitagawa, Hideki Mochizuki
There are no effective neuroprotectant drugs for acute cerebral ischemia. Serine racemase (SR) synthesizes d-serine, which is involved in N-methyl-d-aspartate (NMDA) receptor-induced neurotoxicity. Recently, SR deletion was reported to protect against focal cerebral ischemia. However, regulatory mechanisms controlling SR-activity in the neurovascular unit (NVU) during cerebral ischemia remain to be clarified. We investigated the effects of SR inhibition on neurovascular protection after ischemia. The SR inhibitor phenazine methosulfate (PMS) alleviated neuronal damage in an ex vivo ischemic model (oxygen glucose deprivation [OGD]) using primary neuronal cultures, and in an in vivo mouse model of ischemia (middle cerebral artery occlusion [MCAO])...
December 17, 2016: Neuroscience
https://www.readbyqxmd.com/read/27633914/endogenous-co-agonists-of-the-nmda-receptor-modulate-contextual-fear-in-trace-conditioning
#14
Alo C Basu, Matthew D Puhl, Joseph T Coyle
We have used mutant mice to probe the roles of the endogenous co-agonists of the NMDA receptor (NMDAR), D-serine and glycine, in fear learning and memory. Serine racemase knockout (SR-/-) mice have less than 15% of wild type forebrain levels of D-serine, whereas glycine transporter 1 heterozygous knockout (GlyT1+/-) mice have elevated synaptic glycine. While cued fear was normal in both delay and trace conditioned mice of both mutant genotypes, contextual fear was affected in trace conditioned subjects: SR-/- mice showed decreased contextual freezing, whereas GlyT1+/- mice showed elevated contextual freezing...
December 2016: Neurobiology of Learning and Memory
https://www.readbyqxmd.com/read/27585868/novel-role-of-serine-racemase-in-anti-apoptosis-and-metabolism
#15
Gourango Talukdar, Ran Inoue, Tomoyuki Yoshida, Tetsuya Ishimoto, Keisuke Yaku, Takashi Nakagawa, Hisashi Mori
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)...
January 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27544766/characterization-of-an-%C3%AE-amino-%C3%A9-caprolactam-racemase-with-broad-substrate-specificity-from-citreicella-sp-se45
#16
Wisarut Payoungkiattikun, Seiji Okazaki, Atsutoshi Ina, Aran H-Kittikun, Yasuhisa Asano
α-Amino-ε-caprolactam (ACL) racemizing activity was detected in a putative dialkylglycine decarboxylase (EC 4.1.1.64) from Citreicella sp. SE45. The encoding gene of the enzyme was cloned and transformed in Escherichia coli BL21 (DE3). The molecular mass of the enzyme was shown to be 47.4 kDa on SDS-polyacrylamide gel electrophoresis. The enzymatic properties including pH and thermal optimum and stabilities were determined. This enzyme acted on a broad range of amino acid amides, particularly unbranched amino acid amides including L-alanine amide and L-serine amide with a specific activity of 17...
August 20, 2016: Journal of Industrial Microbiology & Biotechnology
https://www.readbyqxmd.com/read/27493223/human-serine-racemase-is-allosterically-modulated-by-nadh-and-reduced-nicotinamide-derivatives
#17
Stefano Bruno, Francesco Marchesani, Luca Dellafiora, Marilena Margiotta, Serena Faggiano, Barbara Campanini, Andrea Mozzarelli
Serine racemase catalyzes both the synthesis and the degradation of d-serine, an obligatory co-agonist of the glutamatergic NMDA receptors. It is allosterically controlled by adenosine triphosphate (ATP), which increases its activity around 7-fold through a co-operative binding mechanism. Serine racemase has been proposed as a drug target for the treatment of several neuropathologies but, so far, the search has been directed only toward the active site, with the identification of a few, low-affinity inhibitors...
October 15, 2016: Biochemical Journal
https://www.readbyqxmd.com/read/27458110/characterization-of-a-homologue-of-mammalian-serine-racemase-from-caenorhabditis-elegans-the-enzyme-is-not-critical-for-the-metabolism-of-serine-in%C3%A2-vivo
#18
Masumi Katane, Yuki Saitoh, Keita Uchiyama, Kazuki Nakayama, Yasuaki Saitoh, Tetsuya Miyamoto, Masae Sekine, Kouji Uda, Hiroshi Homma
Free d-serine (d-Ser) plays a crucial role in regulating brain function in mammals. In various organisms, including mammals, d-Ser is biosynthesized by Ser racemase, a synthetic enzyme that produces d-Ser from l-Ser. Ser racemase also exhibits dehydratase activity toward several hydroxyamino acids. Thus, this enzyme is unique in that it possesses the capability to both synthesize and degrade d-Ser; however, the physiological significance of its degradative activity remains unclear. In contrast to the physiological roles of d-Ser in mammals, little is known about the role of this amino acid in lower organisms, including the nematode Caenorhabditis elegans...
September 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/27438592/molecular-cloning-and-enzymological-characterization-of-pyridoxal-5-phosphate-independent-aspartate-racemase-from-hyperthermophilic-archaeon-thermococcus-litoralis-dsm-5473
#19
Tsubasa Washio, Shiro Kato, Tadao Oikawa
We succeeded in expressing the aspartate racemase homolog gene from Thermococcus litoralis DSM 5473 in Escherichia coli Rosetta (DE3) and found that the gene encodes aspartate racemase. The aspartate racemase gene consisted of 687 bp and encoded 228 amino acid residues. The purified enzyme showed aspartate racemase activity with a specific activity of 1590 U/mg. The enzyme was a homodimer with a molecular mass of 56 kDa and did not require pyridoxal 5'-phosphate as a coenzyme. The enzyme showed aspartate racemase activity even at 95 °C, and the activation energy of the enzyme was calculated to be 51...
September 2016: Extremophiles: Life Under Extreme Conditions
https://www.readbyqxmd.com/read/27394076/the-inverse-link-between-genetic-risk-for-schizophrenia-and-migraine-through-nmda-n-methyl-d-aspartate-receptor-activation-via-d-serine
#20
Sandra Van der Auwera, Alexander Teumer, Johannes Hertel, Georg Homuth, Uwe Völker, Michael J Lucht, Franziska Degenhardt, Thomas Schulze, Marcella Rietschel, Markus M Nöthen, Ulrich John, Matthias Nauck, Hans Jörgen Grabe
Schizophrenia has a considerable genetic background. Epidemiological studies suggest an inverse clinical association between schizophrenia and migraine. However, it is unclear to what extent this inverse comorbidity can be explained by genetic mechanisms or by schizophrenia-related behavioral factors. For both disorders hypotheses of glutamate N-methyl-D-aspartate (NMDA) receptor dysfunction have been developed in the past. We hypothesized that both conditions share common genetic factors with inverse effects, primary in the glutamatergic system and genes involved in NMDA activation...
September 2016: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
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