Regulation of serine racemase activity by amino acids

Dunlop, David S.; Neidle, Amos

doi:10.1016/j.molbrainres.2004.10.027

Cited by 47 publications

(64 citation statements)

References 24 publications

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“…SR activ- ity is increased by Mg 2ϩ , ATP, and Ca 2ϩ , and by protein-protein interactions with the GluR-interacting protein (GRIP), protein interacting with C kinase 1 (PICK1), and Golgin subfamily A member 3 (Golga 3) (Baumgart and Rodríguez-Crespo, 2008). In contrast, SR activity is decreased by amino acids, such as glycine at a physiological level (Dunlop and Neidle, 2005), and by modification with S-nitrosylation (Mustafa et al, 2007). Thus, it is important to evaluate the contribution of SR to D-serine synthesis in the brain.…”

Section: Discussionmentioning

confidence: 99%

“…Enzymatic characterizations of purified SR suggest that the catalytic constant (k cat ) for D-serine in the racemization by mouse SR is ϳ1/400 of prokaryotic racemase, and the k cat /K m of SR in the dehydration of L-serine is higher than those in the racemization for serine (Yoshimura and Goto, 2008). The activity of SR is decreased by glycine at a physiological concentration (Dunlop and Neidle, 2005) and by modification with S-nitrosylation (Mustafa et al, 2007). Thus, the contribution of SR to D-serine production in the brain should be evaluated in vivo.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

NMDA- and β-Amyloid_1–42-Induced Neurotoxicity Is Attenuated in Serine Racemase Knock-Out Mice

Inoue¹,

Hashimoto²,

Harai³

et al. 2008

J. Neurosci.

146

117

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NMDA- and β-Amyloid_1–42-Induced Neurotoxicity Is Attenuated in Serine Racemase Knock-Out Mice

Inoue¹,

Hashimoto²,

Harai³

et al. 2008

J. Neurosci.

146

117

View full text Add to dashboard Cite

“…[19][20][21][22][23][24][25] Although the involvement of SR in pathological conditions and its potential druggability has preliminarily been validated through genetic techniques, [25] very little is known about small molecule inhibitors. [13,[26][27][28] Naturally occurring amino acids, such as glycine or l-aspartate, have physiological significance as inhibitors, [26] presumably by modulating the biosynthesis of D-Ser (1). Sulfhydryl containing amino acids, [13,26] and amino acids b-substituted with electron withdrawing groups are also SR inhibitors, [13,26] which covalently bind PLP.…”

Section: Introductionmentioning

confidence: 99%

Addressing the Conformational Flexibility of Serine Racemase by Combining Targeted Molecular Dynamics, Conformational Sampling and Docking Studies

Bruno

Amori

Costantino

2011

Molecular Informatics

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Serine racemase (SR) is a PLP-dependent enzyme catalyzing the racemization of L-Ser into D-Ser, which is now recognized as an endogenous co-agonist at the NMDA receptor complex. As indicated by available X-ray structures, SR undergoes significant conformational changes during ligand recognition, and it is conceivable that, in addition to the reported X-ray structures, other intermediate conformational states may have relevance in drug discovery studies. Targeted molecular dynamics (TMD) simulations are an effective tools to follow the conformational transition of a protein under the constrain of reaching a known target states. In this study we use TMD to simulate the transition between the open and closed form of SR in the presence of the endogenous substrate or an orthosteric inhibitor. The trajectories thus obtained are then clustered to collect an ensemble of intermediate conformational states. Docking of a small library of known SR inhibitors or closely related inactive analogs demonstrates that ensemble docking performs better than docking on available crystal structures, thus indicating that inclusion of conformational flexibility into ligand design strategies will be crucial for the development of new classes of SR inhibitors.

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“…The SR activity is enhanced by its interaction with the GluR-interacting protein (Kim et al, 2005), the presence of Mg 2ϩ and ATP , and Ca 2ϩ binding (Cook et al, 2002). In contrast, the enzymatic activity is suppressed by amino acids (Dunlop and Neidle, 2005) and S-nitrosylation (Mustafa et al, 2007).…”

mentioning

confidence: 99%

Serine racemase is predominantly localized in neurons in mouse brain

Miya

Inoue

Takata

et al. 2008

J of Comparative Neurology

223

211

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D-Serine is the endogenous ligand for the glycine binding site of the N-methyl-D-aspartate (NMDA)-type glutamate receptor (GluR) channel and is involved in the regulation of synaptic plasticity, neural network formation, and neurodegenerative disorders. D-Serine is synthesized from L-serine by serine racemase (SR), which was first reported to be localized in astrocytes. However, recently, SR mRNA and its protein have been detected in neurons. In this study, we examined the SR distribution in the brain during postnatal development and in cultured cells by using novel SR knockout mice as negative controls. We found that SR is predominantly localized in pyramidal neurons in the cerebral cortex and hippocampal CA1 region. Double immunofluorescence staining revealed that SR signals colocalized with those of the neuron-specific nuclear protein, but not with the astrocytic markers glial fibrillary acid protein and 3-phosphoglycerate dehydrogenase. In the striatum, we observed SR expression in gamma-aminobutyric acid (GABA)ergic medium-spiny neurons. Furthermore, in the adult cerebellum, we detected weak but significant SR signals in GABAergic Purkinje cells. From these findings, we conclude that SR is expressed predominantly in many types of neuron in the brain and plays a key role in the regulation of brain functions under physiological and pathological conditions via the production of the neuromodulator D-serine.

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Regulation of serine racemase activity by amino acids

Cited by 47 publications

References 24 publications

NMDA- and β-Amyloid_1–42-Induced Neurotoxicity Is Attenuated in Serine Racemase Knock-Out Mice

NMDA- and β-Amyloid_1–42-Induced Neurotoxicity Is Attenuated in Serine Racemase Knock-Out Mice

Addressing the Conformational Flexibility of Serine Racemase by Combining Targeted Molecular Dynamics, Conformational Sampling and Docking Studies

Serine racemase is predominantly localized in neurons in mouse brain

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Regulation of serine racemase activity by amino acids

Cited by 47 publications

References 24 publications

NMDA- and β-Amyloid1–42-Induced Neurotoxicity Is Attenuated in Serine Racemase Knock-Out Mice

NMDA- and β-Amyloid1–42-Induced Neurotoxicity Is Attenuated in Serine Racemase Knock-Out Mice

Addressing the Conformational Flexibility of Serine Racemase by Combining Targeted Molecular Dynamics, Conformational Sampling and Docking Studies

Serine racemase is predominantly localized in neurons in mouse brain

Contact Info

Product

Resources

About

NMDA- and β-Amyloid_1–42-Induced Neurotoxicity Is Attenuated in Serine Racemase Knock-Out Mice

NMDA- and β-Amyloid_1–42-Induced Neurotoxicity Is Attenuated in Serine Racemase Knock-Out Mice