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Information on EC 5.1.1.18 - serine racemase and Organism(s) Mus musculus and UniProt Accession Q9QZX7
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5.1.1.18 serine racemaseIUBMB Comments
A pyridoxal-phosphate protein that is highly selective for L-serine as substrate. D-Serine is found in type-II astrocytes in mammalian brain, where it appears to be an endogenous ligand of the glycine site of N-methyl-D-aspartate (NMDA) receptors [1,2]. The reaction can also occur in the reverse direction but does so more slowly at physiological serine concentrations .
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Word Map
- 5.1.1.18
- d-serine
- n-methyl-d-aspartate
-
co-agonist
-
nmdars
- astrocyte
-
d-amino
-
schizophrenia
-
neurotransmission
- pyridoxal
-
hypofunction
- d-aspartate
-
glutamatergic
-
5'-phosphate-dependent
-
nmda-type
- d-ser
-
plp-dependent
-
nmdar-mediated
- pharmacology
- medicine
-
alanine-serine-cysteine
- drug development
-
glycine-binding
-
n-methyl-d
-
vante
-
brain-enriched
-
gliotransmitter
-
nmdar-dependent
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
serine racemase, srace, ser racemase, t01h8.2, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
L-serine = D-serine
reaction mechanism, the enzyme catalyzes the racemization of serine, but also the alpha,beta-elimination of serine forming pyruvate. Mechanicistically, the racemization and alpha,beta-elimination reactions share the same intermediate, represented by a resonance-stabilized carbanion. The intermediate forms a partition between the two pathways. L-Serine binds to pyridoxal 5'-phosphate, yielding an external aldimine intermediate, followed by the abstraction of the alpha-proton by Lys56 and formation of a planar resonance-stabilized carbanion. At this point, protonation in the opposite side of the carbanion intermediate (mediated by the Ser84-OH group) generates D-serine. Since the proton abstraction and the reprotonation steps are performed by different residues (Lys56 and Ser84) that work as acid/base catalysts, serine racemase racemization is consistent with a two-base mechanism
L-serine = D-serine
SRR catalyses Ser racemization via a two-base mechanism in which two catalytic residues, Lys56 and Ser84 play vital roles in the abstraction and donation of alpha-proton of L-Ser and D-Ser, respectively
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PATHWAY SOURCE
PATHWAYS
BRENDA
-
-, -
SYSTEMATIC NAME
IUBMB Comments
serine racemase
A pyridoxal-phosphate protein that is highly selective for L-serine as substrate. D-Serine is found in type-II astrocytes in mammalian brain, where it appears to be an endogenous ligand of the glycine site of N-methyl-D-aspartate (NMDA) receptors [1,2]. The reaction can also occur in the reverse direction but does so more slowly at physiological serine concentrations [4].
CAS REGISTRY NUMBER
COMMENTARY
77114-08-0
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
beta-chloro-L-alanine
pyruvate + NH3 + ?
-
the artificial serine racemase substrate is degraded via alpha,beta-elimination
-
-
?
L-serine O-sulfate
pyruvate + NH3 + ?
-
the artificial serine racemase substrate is degraded via alpha,beta-elimination
-
-
?
L-threo-3-hydroxyaspartate
pyruvate + NH3 + ?
-
the artificial serine racemase substrate is degraded via alpha,beta-elimination
-
-
?
L-aspartate
D-aspartate
enzyme SRR catalyses Asp racemization by a mechanism similar to Ser racemization. Lys56 performs the alpha-proton abstraction/donation of L-Asp and Ser84 is responsible for alpha-proton transferring for D-Asp
-
-
r
L-serine
D-serine
D-serine is a coagonist with glutamate at NMDA receptors, postsynaptic stimulation of nitric-oxide formation feeds back to presynaptic cells to S-nitrosylate SR and decrease D-serine availability to postsynaptic NMDA receptors, enzyme regulation, mechanism, overview
-
-
?
L-serine
D-serine
enzyme SRR catalyses Ser racemization via a two-base mechanism in which two catalytic residues, Lys and Ser play vital roles in the abstraction and donation of alpha-proton of L-Ser and D-Ser, respectively
-
-
r
L-serine
D-serine
-
-
-
-
?
L-serine
D-serine
-
-
D-serine is an important modulator of the N-methyl-D-aspartate receptor function
-
?
L-serine
D-serine
-
developmental regulation of enzyme expression in neuronal ganglion cells of the retina, overview, D-serine is the endogenous ligand for the glycine modulatory binding site of the NMDA receptor
-
-
?
L-serine
D-serine
-
D-serine is stored primarily within astrocytes ensheathing neuronal synapses containing NMDA receptors, model of D-serine signalling in the brain, overview
-
-
?
additional information
?
-
racemization and elimination activities reside at the same active site of enzyme. Racemization activity is specific to serine, elimination activity has a broader specificity for L-amino acids with a suitable leaving group at the beta-carbon
-
-
?
additional information
?
-
-
racemization and elimination activities reside at the same active site of enzyme. Racemization activity is specific to serine, elimination activity has a broader specificity for L-amino acids with a suitable leaving group at the beta-carbon
-
-
?
additional information
?
-
enzyme SRR recognizes L-Asp as an in vivo substrate in addition to L- and D-Ser
-
-
?
additional information
?
-
reactions catalyzed by serine racemase are racemization and alpha,beta-elimination, mechanisms, overview
-
-
?
additional information
?
-
the enzyme has two enzymatic activities, namely, racemization and alpha,beta-elimination
-
-
?
additional information
?
-
wild-type enzyme SRR and SRR mutant S84A show Ser dehydratase activity. SRR-catalysed Asp racemization is less efficient and 550fold lower than that of Ser racemization
-
-
?
additional information
?
-
-
enzyme modulates physiologic regulation of cerebellar granule cell migration
-
-
?
additional information
?
-
-
enzyme product may serve as a ligand for setting the sensitivity of N-methyl-D-aspartate receptors under physiological conditions
-
-
?
additional information
?
-
-
ratio of elimination reaction/racemization reaction for substrate L-serine is 3.7
-
-
?
additional information
?
-
-
ratio of synthesized pyruvate/D-serine is about 3
-
-
?
additional information
?
-
-
serine racemase is the major enzyme for D-serine production in the brain, D-serine is the predominant endogenous coagonist of the NMDA receptor in the forebrain, and D-serine may be involved in controlling the extent of NMDA receptor-mediated neurotoxic insults observed in disorders including Alzheimers disease.
-
-
?
additional information
?
-
-
enzyme additionally catalyzes eleimination reaction of D-/L-serine and of L-serine-O-sulfate
-
-
?
additional information
?
-
-
the enzyme binds to the glutamate receptor interacting protein, to protein interacting with C kinase 1, and Golgi-localized protein Golga 3. The carboxy terminus of both the mouse and human enzyme contains an amino acid domain that binds to PSD-95/DlgA/zo-1 (PDZ)-containing proteins, such as GRIP and PICK1, which subsequently activates the racemase. The PDZ domain is an important protein-protein interaction motif
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
L-serine
D-serine
D-serine is a coagonist with glutamate at NMDA receptors, postsynaptic stimulation of nitric-oxide formation feeds back to presynaptic cells to S-nitrosylate SR and decrease D-serine availability to postsynaptic NMDA receptors, enzyme regulation, mechanism, overview
-
-
?
L-serine
D-serine
-
-
D-serine is an important modulator of the N-methyl-D-aspartate receptor function
-
?
L-serine
D-serine
-
developmental regulation of enzyme expression in neuronal ganglion cells of the retina, overview, D-serine is the endogenous ligand for the glycine modulatory binding site of the NMDA receptor
-
-
?
L-serine
D-serine
-
D-serine is stored primarily within astrocytes ensheathing neuronal synapses containing NMDA receptors, model of D-serine signalling in the brain, overview
-
-
?
additional information
?
-
enzyme SRR recognizes L-Asp as an in vivo substrate in addition to L- and D-Ser
-
-
?
additional information
?
-
-
enzyme modulates physiologic regulation of cerebellar granule cell migration
-
-
?
additional information
?
-
-
enzyme product may serve as a ligand for setting the sensitivity of N-methyl-D-aspartate receptors under physiological conditions
-
-
?
additional information
?
-
-
serine racemase is the major enzyme for D-serine production in the brain, D-serine is the predominant endogenous coagonist of the NMDA receptor in the forebrain, and D-serine may be involved in controlling the extent of NMDA receptor-mediated neurotoxic insults observed in disorders including Alzheimers disease.
-
-
?
additional information
?
-
-
the enzyme binds to the glutamate receptor interacting protein, to protein interacting with C kinase 1, and Golgi-localized protein Golga 3. The carboxy terminus of both the mouse and human enzyme contains an amino acid domain that binds to PSD-95/DlgA/zo-1 (PDZ)-containing proteins, such as GRIP and PICK1, which subsequently activates the racemase. The PDZ domain is an important protein-protein interaction motif
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
Mg2+
Ca2+
Mg2+
Mn2+
additional information
Mg2+
activates the enzyme independently from ATP, the effect due to divalent ion and ATP is additive
Ca2+
-
or Mn2+, required, binding konstant 0.0062 mM. Possible glutamatergic-mediated regulation of enzyme via intracellular calcium concentration
additional information
Mg2+ or Ca2+ cations interact with similar affinity to a specific site of the enzyme, the formers might represent the physiological ligand since the free Mg2+ concentration in the cells is several orders of magnitude higher than the Ca2+ concentration. The racemase activity is independently stimulated by both Mg2+ and ATP
additional information
-
activation of serine racemase by divalent cations has been assumed to be a side-effect associated with ATP binding, activation mechanisms and ligand binding, molecular modelling with the human enzyme, overview
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
beta-haloalanine
reacts with pyridoxal 5'-phosphate to yield thiazolidine derivative
cysteine
reacts with pyridoxal 5'-phosphate to yield thiazolidine derivative
homocysteine
reacts with pyridoxal 5'-phosphate to yield thiazolidine derivative
nitric oxide
nitric oxide physiologically S-nitrosylates the enzyme at Cys113, mediating feedback inhibition of D-serine, which is enhanced by the NMDA receptor through activation of neuronal nitric oxide synthase
L-aspartic acid beta-hydroxamate
-
a competitive and selective serine racemase inhibitor
phosphatidylinositol-4,5-bisphosphate
-
i.e. PIP2, a physiological inhibitor of the enzyme, competes with activator ATP for enzyme binding. Activation of metabotropic glutamate receptors on glia leads to phospholipase C-mediated degradation of PIP2, relieving SR inhibition
additional information
Asp racemization is inhibited by EDTA and hydroxylamine
-
additional information
EDTA impairs only the alpha,beta-elimination reaction, not the racemization. Several dicarboxylic acids are strong, competitive inhibitors of the enzyme
-
additional information
-
small aliphatic hydroxamic acids as potent serine racemase inhibitors, interaction with the pyridoxal-5'-phosphate cofactor, mechanistic analysis, overview. Some of these hydroxamic acids can act as nonspecific inhibitors of pyridoxal 5'-phosphate-dependent enzymes, the nonspecific effect is likely due to irreversible interaction of the hydroxamic acid moiety with pyridoxal 5'-phosphate to form aldoxime species
-
additional information
-
S-nitrosylation or membrane binding inhibit racemase activity
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
glycine
active site ligand glycine increases the enzyme's affinity for ATP by 22fold and abolishes cooperativity while ATP increases the noncooperative glycine binding 15fold
hydroxylamine
activates Ser racemase activity, but inhibits Asp racemase activity
metabotropic glutamate receptor
-
i.e. mGluR5, on glia, activation mechanism of the D-serine synthesis needed for NMDA neurotransmission, overview
-
protein interacting with C kinase 1
-
i.e. PICK1, the carboxy terminus of the mouse enzyme contains an amino acid domain that binds to PSD-95/DlgA/zo-1 (PDZ)-containing proteins, such as PICK1, which subsequently activates the racemase. The PDZ domain is an important protein-protein interaction motif
-
ATP
activates the enzyme independently from Mg2+, the nucleotide increases serine racemase activity even in the presence of EDTA, and the effect due to divalent ion and ATP is additive. In the presence of 1 mM ATP, the Km for L-serine is decreased 10fold with little change in Vmax
ATP
-
1 mM, decrease of Km-value for racemization by 85%, allosteric mechanism. Inhibitory to L-serine O-sulfate dehydration reaction
ATP
-
competes with inhibitor phosphatidylinositol(4,5)-bisphosphate for enzyme binding
glutamate receptor interacting protein
-
i.e. GRIP, a multi-PSD-95/discs large/ZO-1 domain protein, that is usually coupled to the GluR2/3 subunits of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid Ca2+ channel, in vivo activation by full-length GRIP, determination of required length and domains of the protein for activation, activation mechanism, overview
-
glutamate receptor interacting protein
-
i.e. GRIP, the carboxy terminus of the mouse enzyme contains an amino acid domain that binds to PSD-95/DlgA/zo-1 (PDZ)-containing proteins, such as GRIP, which subsequently activates the racemase. The PDZ domain is an important protein-protein interaction motif
-
additional information
no effect on Ser racemase activity by EDTA, KCl, and NaCl. Asp racemization is activated by divalent cations and nucleotide complexes
-
additional information
-
activation of enzyme by glutamate neurotransmission involving alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors
-
additional information
-
activation of serine racemase by divalent cations has been assumed to be a side-effect associated with ATP binding, activation mechanisms and ligand binding, molecular modelling with the human enzyme, overview
-
additional information
-
the glutamate transmission activates the enzyme by degrading phospholipids
-
additional information
-
the enzyme is activated by nucleotides. Serine racemase can also be activated by phosphorylation
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.49
L-serine O-sulfate
pH 8.0, 37°C, presence of 1 mM ATP, elimination reaction
additional information
additional information
kinetic parameters of Ser dehydratase activity and Asp racemase activity of wild-type and mutant enzymes
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.49
L-serine O-sulfate
pH 8.0, 37°C, presence of 1 mM ATP, elimination reaction
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
bifunctional enzyme, racemization of serine and elimination of L-serine and L-serine-O-sulfate to form pyruvate
Swissprot
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
developmental regulation of enzyme expression, in situ hybridization analysis, overview, D-serine levels are quite high in ganglion cells of neonatal retinas and decreasing rapidly postnatally
-
localization of the enzme protein in the granular and cornified layer of the epidermis
additional information
glial cells of brain, highest levels of enzyme in astrocyte-enriched cultures
-
astrocyte glia, activation of enzyme by glutamate neurotransmission involving alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors
-
expression of serine racemase and of protein interacting with C-kinase, PICK1 are developmentally regulated. In neonatal mice with knock-out of protein interacting with C-kinase, PICK1 the levels of D-serine are selectively decreased in the forebrain
-
adult cerebellum, weak but significant expression in gamma-aminobutyrate, i.e. GABAergic Purkinje cells
-
adult, weak but significant enzyme signals are detected in GABAergic Purkinje cells
-
pyramidal neuron of cerebral cortex and hippocampal CA1 region, predominant localization
-
expression in gamma-aminobutyrate, i.e. GABAergic medium-spine neuron
-
pyramidal neuron of cerebral cortex and hippocampal CA1 region, predominant localization
-
pyramidal neuron of cerebral cortex and hippocampal CA1 region, predominant localization. Serine racemase co-localizes with neuron-specific nuclear protein
-
primarily, pyramidal neurons of the cerebral cortex and hippocampal CA1 region
-
intact retina of 1-3 day, 3 week, and 18 week old mouse. Robust expression of serine racemase, levels are developmentally regulated, with high levels during the early postnatal period, but diminishing considerably in the mature retina. D-Serine levels are regulated accordingly.
additional information
-
the enzyme colocalizes with neuron-specific nuclear protein, but not with astrocytic markers, namely, glial fibrillary acidic protein, and 3-phosphoglycerate dehydrogenase
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
membrane association via phospholipid binding. The enzyme is prominently associated with the plasma membrane but also is detected in granular structures that may be vesicles associated with the plasma membrane or other cellular components
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
SerRs and AspRs are not separated by their racemase functions and form a serine/aspartate racemase family cluster based on phylogenetic analysis
malfunction
physiological function
malfunction
physiological function
additional information
malfunction
D-Asp levels are significantly lower in the hippocampi and frontal cortices of SRR-knockout mice, approximately half the levels recorded from wild-type mice. These results are consistent with those from a previous study. In contrast, D-Asp abundance is not altered in the cerebellums or testes of SRR-knockout mice
malfunction
HEK-293T cells expressing the wild-type enzyme and hyperactive mutant Q155D show resistance to staurosporine-induced apoptosis, compared with nontransfected HEK-293T cells and cells expressing the catalytically-dead enzyme mutant K56G. The wild-type enzyme-expressing cells also show a significant higher viability than the cells expressing hyperactive mutant Q155D enzyme mutant. Elevated phosphorylation levels of Bcl-2 at Ser70 and Akt at Ser473 and Thr308, which are related to cell survival, occur in the cells expressing wild-type enzyme and mutant Q155D, elevated levels of acetyl CoA and ATP in cells expressing the wild-type enzyme. Phenotypes, overview
physiological function
serine racemase catalyzes the production of D-serine, a co-agonist of the N-methyl-D-aspartatereceptor (NMDAR), contribution of the enzyme in the NMDAR-mediated neuronal cell death process. The racemization reaction catalyzed by serine racemase may have a more protective role against apoptosis than the alpha,beta-elimination reaction
physiological function
serine racemase is a key player in apoptosis and necrosis
physiological function
serine racemase, SRR, is involved in D-aspartate biosynthesis, SRR is responsible for D-Asp production in certain organs and/or tissues
malfunction
-
serine racemase is associated with schizophrenia susceptibility in a mouse model, abnormal N-methyl-D-aspartate receptor function is implicated in the pathophysiology of schizophrenia
malfunction
-
enzyme knockout mice show increased expression of involucrin and keratin 10 in the epidermis compared to wild-type mice
malfunction
-
enzyme KO mutant mice show reduced D-serine contents, reduced N-methyl-D-aspartate receptor activity, and impaired learning and memory abilities, altered morphological features of brain of SR-KO mice, altered behaviur and neurodegeneration in KO mice, phenotypes of three SR-KO mouse strains, overview. Enzyme expression in the liver is upregulated in nSR-KO_ITC mice
malfunction
-
mice genetically deficient in the serine racemase gene have decreased levels of D-serine in the brain. Serine racemase KO mice show no obvious defects, but neurotransmission and behavior mediated by the NMDA receptors are altered in these mice. The KO mice exhibit a schizophrenia-like phenotype and have impaired spatial memory, reduced prepulse inhibition, decreased sociability, and elevated anxiety. KO mice have a decreased level of D-serine, which protected against overstimulation of NMDA receptors
malfunction
-
repeated administration of methamphetamine results in behavioral sensitization in wild-type, but not in knockout mutant Srr-KO mice, while METH-induced acute hyperlocomotion is similar in wild-type and mutant mice. Pretreatment with D-serine does not affect the development of behavioral sensitization after repeated methamphetamine administration
physiological function
-
the enzyme is responsible for the biosynthesis of the neurotransmitter D-serine, which activates N-methyl-D-aspartate receptors in the central nervous system
physiological function
-
serine racemase catalyses the synthesis of the transmitter/neuromodulator D-serine, which plays a major role in synaptic plasticity and N-methyl D-aspartate receptor neurotoxicity
physiological function
-
D-serine is an endogenous coagonist of the N-methyl-D-aspartate-type glutamate receptor in the central nervous system and its synthesis is catalyzed by serine racemase
physiological function
-
role of D-serine as an endogenous agonist of N-methyl-D-aspartate receptors (NMDARs). D-Serine is required for NMDAR activity during normal neurotransmission as well as NMDAR overactivation that takes place in neurodegenerative conditions
physiological function
-
serine racemase activity is regulated by several physiological pathways. D-Serine binds to the coagonist site of the NMDA receptors and enhances neurotransmission
physiological function
-
serine racemase is an enzyme which synthesizes D-serine, an endogenous co-agonist of N-methyl-D-aspartate (NMDA) receptors. N-methyl-D-aspartate receptors play a role in behavioral abnormalities observed after administration of the psychostimulant, methamphetamine. Role of serine racemase in behavioral sensitization in mice after repeated administration of methamphetamine, overview
additional information
role of individual residues at position 150-152, overview
additional information
-
role of individual residues at position 150-152, overview
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). SRR_MOUSE
339
0
36359
Swiss-Prot
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37500
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
phosphoprotein
-
serine racemase is phosphorylated at Thr71 and Thr227, Thr71 phosphorylation increases serine racemase activity
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C113S
site-directed mutagenesis, the mutant is resistant to regulation by nitrosylation by NO
H150S
site-directed mutagenesis, the mutant shows altered substrate specificity and activity compared to the wild-type enzyme
H150S/N152S
site-directed mutagenesis, the mutant shows altered substrate specificity and activity compared to the wild-type enzyme
H150S/P151S
site-directed mutagenesis, the mutant shows altered substrate specificity and activity compared to the wild-type enzyme
H150S/P151S/N152S
site-directed mutagenesis, the mutant shows altered substrate specificity and activity compared to the wild-type enzyme
K51A
site-directed mutagenesis, the K51A mutant shows substantially less ATP binding and reduced activity compared to the wild-type enzyme
K56G
N152S
site-directed mutagenesis, the mutant shows altered substrate specificity and activity compared to the wild-type enzyme
P151S
site-directed mutagenesis, the mutant shows altered substrate specificity and activity compared to the wild-type enzyme
P151S/N152S
site-directed mutagenesis, the mutant shows altered substrate specificity and activity compared to the wild-type enzyme
Q155D
site-directed mutagenesis, catalytically hyperactive mutant, the mutant shows enhanced racemization and reduced alpha,beta-elimination activities
S84A
site-directed mutagenesis, SRR mutant S84A shows Ser dehydratase activity, but no Ser racemase activity, the S84A mutation completely abolishes racemization activity for both Ser and Asp. Mutation S84A results in the loss of the enzyme's D-Ser dehydrase activity without changing L-Ser dehydrase activity
H152S
-
ratio of elimination reaction to racemization is 1.4 compared to 3.7 in wild-type
N154F
-
ratio of elimination reaction to racemization is 0.33 compared to 3.7 in wild-type
P153S
-
ratio of elimination reaction to racemization is 0.24 compared to 3.7 in wild-type
Q155D
-
ratio of elimination reaction to racemization is 0.25 compared to 3.7 in wild-type
additional information
additional information
introducing the triple serine loop region into SerRs promotes aspartate racemization
additional information
-
introducing the triple serine loop region into SerRs promotes aspartate racemization
additional information
-
in neonatal mice with knock-out of protein interacting with C-kinase, PICK1 the levels of D-serine are selectively decreased in the forebrain
additional information
-
serine racemase knock-out mice show a 90% decrease in forebrain D-serine content and a reduced neurotoxicity induced by NMDA- and beta-amyloid1-42-peptide injections in the forebrain
additional information
-
targeted disruption of serine racemase results in profoundly altered glutamatergic neurotransmission and subtle but significant behavioral abnormailites that reflect hyperactivity and impaired spatial memory, and that are consistent with elevated anxiety
additional information
-
enzyme mutants that cannot bind phosphatidylinositol(4,5)-bisphosphate lose their membrane localizations and display a 4fold enhancement of catalytic activity. Moreover, metabotropic glutamate receptors activation of the enzyme activity is abolished by inhibiting phospholipase C
additional information
-
generation of mice with an ENU-induced mutation, SrrY269stop, that results in a complete loss of Srr activity and dramatically reduced D-serine levels. Mutant mice display behaviors relevant to schizophrenia, including impairments in prepulse inhibition, sociability and spatial discrimination. Behavioral deficits are exacerbated by an NMDAR antagonist and ameliorated by D-serine or the atypical antipsychotic clozapine. Expression profiling reveals that the Srr mutation influences several genes that are linked to schizophrenia and cognitive ability, expression pattern of the enzyme in mutant brain tissues, detailed phenotype, overview
additional information
-
targeted deletion of the enzyme lead to markedly diminished nitric oxide formation and neurotoxicity in the brain, NO formation and nitrosylation of NO targets are reduced. Knockout mice show highly diminished infarct volume following middle cerebral artery occlusion in several regions of the brains, while the number and sensitivity of the NMDA receptors are increased, phenotype, overview
additional information
-
generation of enzyme knockout mutant mice, phenotypes, overview
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged wild-type and mutant enzymes from Escherichia coli strain BL21(DE3) by nickel affinity chromatography and dialysis
recombinant His6-tagged wild-type and mutant enzymes from Escherichia coli strain BL21(DE3) using Talon resin chromatography
recombinant enzyme from Escherichia coli strain MC1061 by hydrophobic interaction and anion exchange chromatography, followed by ATP affinity chromatography and dialysis
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of His6-tagged wild-type and mutant enzymes in Escherichia coli strain BL21(DE3)
gene Srr, recombinant expression of wild-type and mutant enzymes in Rattus norvegicus PC-12 cells, recombinant expression of N-terminally His-tagged wild-type and mutant enzymes in Escherichia coli strain BL21(DE3). SRR-overexpressing PC-12 cells produce endogenous D-Asp and D-Ser
recombinant expression of His-tagged wild-type and mutant enzymes in HEK-293T cells
expression of GST-tagged fusion protein containing amino acid residue 150-190 of the mouse enzyme, expression of His-tagged enzyme in Cavia porcellus and Oryctolagus cuniculus, quantitative real-time PCR enzyme expression analysis
-
expression of untagged and of N-terminally His6-tagged and C-terminally FLAG-tagged enzyme in COS-7 cells, co-expression with glutamate receptor interacting protein or FLAG-tagged glutamate receptor interacting protein domain PDZ6
-
HEK293 cells transfected with wild-type enzyme and metabotropic glutamate receptor display a 4fold increase in enzyme activity upon treatment with the metabotropic glutamate receptor agonist dihydroxyphenylglycine
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
-
serine racemase is the major enzyme for D-serine production in the brain, D-serine is the predominant endogenous coagonist of the NMDA receptor in the forebrain, and D-serine may be involved in controlling the extent of NMDA receptor-mediated neurotoxic insults observed in disorders including Alzheimer's disease.
medicine
-
targeted disruption of serine racemase results in profoundly altered glutamatergic neurotransmission and subtle but significant behavioral abnormailites that reflect hyperactivity and impaired spatial memory, and that are consistent with elevated anxiety
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Wang, L.Z.; Zhu, X.Z.
Spatiotemporal relationships among D-serine, serine racemase, and D-amino acid oxidase during mouse postnatal development
Acta Pharmacol. Sin.
24
965-974
2003
Mus musculus
Strisovsky, K.; Jiraskova, J.; Mikulova, A.; Rulisek, L.; Konvalinka, J.
Dual substrate and reaction specificity in mouse serine racemase: identification of high-affinity dicarboxylate substrate and inhibitors and analysis of the beta-eliminase activity
Biochemistry
44
13091-13100
2005
Mus musculus (Q9QZX7), Mus musculus
Dunlop, D.S.; Neidle, A.
Regulation of serine racemase activity by amino acids
Brain Res. Mol. Brain Res.
133
208-214
2005
Mus musculus
Strisovsky, K.; Jiraskova, J.; Barinka, C.; Majer, P.; Rojas, C.; Slusher, B.S.; Konvalinka, J.
Mouse brain serine racemase catalyzes specific elimination of L-serine to pyruvate
FEBS Lett.
535
44-48
2003
Mus musculus (Q9QZX7), Mus musculus
Cook, S.P.; Galve-Roperh, I.; Martinez del Pozo, A.; Rodriguez-Crespo, I.
Direct calcium binding results in activation of brain serine racemase
J. Biol. Chem.
277
27782-27792
2002
Mus musculus
Foltyn, V.N.; Bendikov, I.; De Miranda, J.; Panizzutti, R.; Dumin, E.; Shleper, M.; Li, P.; Toney, M.D.; Kartvelishvily, E.; Wolosker, H.
Serine racemase modulates intracellular D-serine levels through an alpha,beta-elimination activity
J. Biol. Chem.
280
1754-1763
2005
Mus musculus
Neidle, A.; Dunlop, D.S.
Allosteric regulation of mouse brain serine racemase
Neurochem. Res.
27
1719-1724
2002
Mus musculus
Stevens, E.R.; Esguerra, M.; Kim, P.M.; Newman, E.A.; Snyder, S.H.; Zahs, K.R.; Miller, R.F.
D-serine and serine racemase are present in the vertebrate retina and contribute to the physiological activation of NMDA receptors
Proc. Natl. Acad. Sci. USA
100
6789-6794
2003
Ambystoma tigrinum, Mus musculus, Rattus norvegicus
Kim, P.M.; Aizawa, H.; Kim, P.S.; Huang, A.S.; Wickramasinghe, S.R.; Kashani, A.H.; Barrow, R.K.; Huganir, R.L.; Ghosh, A.; Snyder, S.H.
Serine racemase: activation by glutamate neurotransmission via glutamate receptor interacting protein and mediation of neuronal migration
Proc. Natl. Acad. Sci. USA
102
2105-2110
2005
Mus musculus
Wolosker, H.; Blackshaw, S.; Snyder, S.H.
Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission
Proc. Natl. Acad. Sci. USA
96
13409-13414
1999
Mus musculus (Q9QZX7)
De Miranda, J.; Panizzutti, R.; Foltyn, V.N.; Wolosker, H.
Cofactors of serine racemase that physiologically stimulate the synthesis of the N-methyl-D-aspartate (NMDA) receptor coagonist D-serine
Proc. Natl. Acad. Sci. USA
99
14542-14547
2002
Mus musculus
Baumgart, F.; Mancheno, J.M.; Rodriguez-Crespo, I.
Insights into the activation of brain serine racemase by the multi-PDZ domain glutamate receptor interacting protein, divalent cations and ATP
FEBS J.
274
4561-4571
2007
Mus musculus
Dun, Y.; Duplantier, J.; Roon, P.; Martin, P.M.; Ganapathy, V.; Smith, S.B.
Serine racemase expression and D-serine content are developmentally regulated in neuronal ganglion cells of the retina
J. Neurochem.
104
970-978
2007
Mus musculus, Mus musculus C57/BL6J
Mustafa, A.K.; Kumar, M.; Selvakumar, B.; Ho, G.P.; Ehmsen, J.T.; Barrow, R.K.; Amzel, L.M.; Snyder, S.H.
Nitric oxide S-nitrosylates serine racemase, mediating feedback inhibition of D-serine formation
Proc. Natl. Acad. Sci. USA
104
2950-2955
2007
Mus musculus (Q9QZX7)
Hikida, T.; Mustafa, A.K.; Maeda, K.; Fujii, K.; Barrow, R.K.; Saleh, M.; Huganir, R.L.; Snyder, S.H.; Hashimoto, K.; Sawa, A.
Modulation of D-serine levels in brains of mice lacking PICK1
Biol. Psychiatry
63
997-1000
2008
Mus musculus
Miya, K.; Inoue, R.; Takata, Y.; Abe, M.; Natsume, R.; Sakimura, K.; Hongou, K.; Miyawaki, T.; Mori, H.
Serine racemase is predominantly localized in neurons in mouse brain
J. Comp. Neurol.
510
641-654
2008
Mus musculus
Inoue, R.; Hashimoto, K.; Harai, T.; Mori, H.
NMDA- and beta-amyloid1-42-induced neurotoxicity is attenuated in serine racemase knock-out mice
J. Neurosci.
28
14486-14491
2008
Mus musculus
Basu, A.C.; Tsai, G.E.; Ma, C.L.; Ehmsen, J.T.; Mustafa, A.K.; Han, L.; Jiang, Z.I.; Benneyworth, M.A.; Froimowitz, M.P.; Lange, N.; Snyder, S.H.; Bergeron, R.; Coyle, J.T.
Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior
Mol. Psychiatry
14
719-727
2008
Mus musculus
Hoffman, H.E.; Jiraskova, J.; Ingr, M.; Zvelebil, M.; Konvalinka, J.
Recombinant human serine racemase: enzymologic characterization and comparison with its mouse ortholog
Protein Expr. Purif.
63
62-67
2009
Homo sapiens, Mus musculus
Labrie, V.; Fukumura, R.; Rastogi, A.; Fick, L.J.; Wang, W.; Boutros, P.C.; Kennedy, J.L.; Semeralul, M.O.; Lee, F.H.; Baker, G.B.; Belsham, D.D.; Barger, S.W.; Gondo, Y.; Wong, A.H.; Roder, J.C.
Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model
Hum. Mol. Genet.
18
3227-3243
2009
Homo sapiens, Mus musculus, Mus musculus C57BL/6JJcl
Hoffman, H.E.; Jiraskova, J.; Cigler, P.; Sanda, M.; Schraml, J.; Konvalinka, J.
Hydroxamic acids as a novel family of serine racemase inhibitors: mechanistic analysis reveals different modes of interaction with the pyridoxal-5'-phosphate cofactor
J. Med. Chem.
52
6032-6041
2009
Mus musculus
Mustafa, A.K.; Ahmad, A.S.; Zeynalov, E.; Gazi, S.K.; Sikka, G.; Ehmsen, J.T.; Barrow, R.K.; Coyle, J.T.; Snyder, S.H.; Dore, S.
Serine racemase deletion protects against cerebral ischemia and excitotoxicity
J. Neurosci.
30
1413-1416
2010
Mus musculus
Mustafa, A.K.; van Rossum, D.B.; Patterson, R.L.; Maag, D.; Ehmsen, J.T.; Gazi, S.K.; Chakraborty, A.; Barrow, R.K.; Amzel, L.M.; Snyder, S.H.
Glutamatergic regulation of serine racemase via reversal of PIP2 inhibition
Proc. Natl. Acad. Sci. USA
106
2921-2926
2009
Mus musculus
Wolosker, H.
Serine racemase and the serine shuttle between neurons and astrocytes
Biochim. Biophys. Acta
1814
1558-1566
2011
Mus musculus
Foltyn, V.N.; Zehl, M.; Dikopoltsev, E.; Jensen, O.N.; Wolosker, H.
Phosphorylation of mouse serine racemase regulates D-serine synthesis
FEBS Lett.
584
2937-2941
2010
Mus musculus
Ding, X.; Ma, N.; Nagahama, M.; Yamada, K.; Semba, R.
Localization of D-serine and serine racemase in neurons and neuroglias in mouse brain
Neurol. Sci.
32
263-267
2011
Mus musculus
Wolosker, H.; Mori, H.
Serine racemase: an unconventional enzyme for an unconventional transmitter
Amino Acids
43
1895-1904
2012
Mus musculus, Mus musculus C57BL/6
Balu, D.T.; Takagi, S.; Puhl, M.D.; Benneyworth, M.A.; Coyle, J.T.
D-Serine and serine racemase are localized to neurons in the adult mouse and human forebrain
Cell. Mol. Neurobiol.
34
419-435
2014
Homo sapiens, Mus musculus
Ohide, H.; Miyoshi, Y.; Maruyama, R.; Hamase, K.; Konno, R.
D-Amino acid metabolism in mammals: biosynthesis, degradation and analytical aspects of the metabolic study
J. Chromatogr. B
879
3162-3168
2011
Homo sapiens, Mus musculus, Rattus norvegicus
Inoue, R.; Yoshihisa, Y.; Tojo, Y.; Okamura, C.; Yoshida, Y.; Kishimoto, J.; Luan, X.; Watanabe, M.; Mizuguchi, M.; Nabeshima, Y.; Hamase, K.; Matsunaga, K.; Shimizu, T.; Mori, H.
Localization of serine racemase and its role in the skin
J. Invest. Dermatol.
134
1618-1626
2014
Mus musculus, Mus musculus C57BL/6
Horio, M.; Kohno, M.; Fujita, Y.; Ishima, T.; Inoue, R.; Mori, H.; Hashimoto, K.
Role of serine racemase in behavioral sensitization in mice after repeated administration of methamphetamine
PLoS ONE
7
e35494
2012
Mus musculus
Uda, K.; Abe, K.; Dehara, Y.; Mizobata, K.; Edashige, Y.; Nishimura, R.; Radkov, A.D.; Moe, L.A.
Triple serine loop region regulates the aspartate racemase activity of the serine/aspartate racemase family
Amino Acids
49
1743-1754
2017
Acropora millepora, Crassostrea gigas (A0A0U5AKI6), Mus musculus (Q9QZX7), Mus musculus, Penaeus monodon (A0A0U4MRI4)
Talukdar, G.; Inoue, R.; Yoshida, T.; Ishimoto, T.; Yaku, K.; Nakagawa, T.; Mori, H.
Novel role of serine racemase in anti-apoptosis and metabolism
Biochim. Biophys. Acta
1861
3378-3387
2017
Mus musculus (Q9QZX7)
Canu, N.; Ciotti, M.T.; Pollegioni, L.
Serine racemase a key player in apoptosis and necrosis
Front. Synaptic Neurosci.
6
9
2014
Homo sapiens (Q9GZT4), Mus musculus (Q9QZX7)
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