Any feedback?
Information on EC 5.1.1.18 - serine racemase and Organism(s) Rattus norvegicus and UniProt Accession Q76EQ0
for references in articles please use BRENDA:EC5.1.1.18Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
EC Tree
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 .
Specify your search results
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: Rattus norvegicus
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, t01h8.2, ser racemase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
L-serine = D-serine
analysis of the catalytic reaction mechanism and intermediate stabilization in mammalian serine racemase using multiscale quantum-classical simulations, hybrid quantum mechanics/molecular mechanics molecular dynamics simulations in conjunction with umbrella sampling are performed, overview. The unprotonated pyridoxal 5'-phosphate-substrate intermediate is stabilized mostly due to solvation effects contributed by water molecules and active-site residues, as well as long-range electrostatic interactions with the enzyme environment
L-serine = D-serine
racemase and dehydratase reaction mechanism of serine racemase, overview
-
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
L-serine
D-serine
-
D-serine is an endogenous N-methyl-D-aspartate, NMDA, receptor coagonist
-
?
L-serine
D-serine
D-serine, an endogenous co-agonist of N-methyl-D-aspartate receptors in vertebrate retina, modulates glutamate sensitivity of retinal neurons, overview
-
-
?
L-serine
D-serine
-
mechanisms regulating D-serine production by the enzyme serine racemase via translocation from cytosol to membranes, overview
D-serine is a physiological coagonist of N-methyl D-aspartate receptors, NMDARs, that plays a major role in several NMDAR-dependent events
-
?
additional information
?
-
regulation of the D-serine content in the forebrain and in C6 glioma cells, that lack the main degerative enzyme D-amino acid oxidase, might act via mechanisms including SRR operating in alpha,beta-eliminase mode, converting D-serine to pyruvate, and regulation by serine transport, in which the alanine-serine-cysteine transporter ASCT2 is implicated, overview. D-serine transport mediated by ASCT2 contributes prominently to D-serine homeostasis when DAO activity is absent
-
-
?
additional information
?
-
analysis of enzyme-substrate-cofactor interactions in the active site, overview
-
-
?
additional information
?
-
-
enzyme product may serve as a ligand for setting the sensitivity of N-methyl-D-aspartate receptors under physiological conditions
-
-
?
additional information
?
-
-
role for D-serine in peripheral nerve transduction
-
-
?
additional information
?
-
-
serine racemase may negatively regulate cellular differentiation through the inhibition of sry-typeHMGbox 9, i.e.Sox9 transcriptional activity in chondrocytes
-
-
?
additional information
?
-
-
the enzyme binds to the Golgi-localized protein Golga 3. The N-terminal of serine racemase contains residues that bind to Golga 3, which results in inhibition of ubiqitin-proteosomal serine racemase degradation
-
-
?
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 an endogenous N-methyl-D-aspartate, NMDA, receptor coagonist
-
?
L-serine
D-serine
D-serine, an endogenous co-agonist of N-methyl-D-aspartate receptors in vertebrate retina, modulates glutamate sensitivity of retinal neurons, overview
-
-
?
L-serine
D-serine
-
mechanisms regulating D-serine production by the enzyme serine racemase via translocation from cytosol to membranes, overview
D-serine is a physiological coagonist of N-methyl D-aspartate receptors, NMDARs, that plays a major role in several NMDAR-dependent events
-
?
additional information
?
-
regulation of the D-serine content in the forebrain and in C6 glioma cells, that lack the main degerative enzyme D-amino acid oxidase, might act via mechanisms including SRR operating in alpha,beta-eliminase mode, converting D-serine to pyruvate, and regulation by serine transport, in which the alanine-serine-cysteine transporter ASCT2 is implicated, overview. D-serine transport mediated by ASCT2 contributes prominently to D-serine homeostasis when DAO activity is absent
-
-
?
additional information
?
-
-
enzyme product may serve as a ligand for setting the sensitivity of N-methyl-D-aspartate receptors under physiological conditions
-
-
?
additional information
?
-
-
role for D-serine in peripheral nerve transduction
-
-
?
additional information
?
-
-
serine racemase may negatively regulate cellular differentiation through the inhibition of sry-typeHMGbox 9, i.e.Sox9 transcriptional activity in chondrocytes
-
-
?
additional information
?
-
-
the enzyme binds to the Golgi-localized protein Golga 3. The N-terminal of serine racemase contains residues that bind to Golga 3, which results in inhibition of ubiqitin-proteosomal serine racemase degradation
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
no inhibition by Triton X-100. Association of serine racemase to brain membranes inhibits D-serine synthesis. Feedback inactivation of D-serine synthesis by NMDA receptor-elicited translocation of serine racemase to the membrane, and this effect is averted by blockade of NMDA receptors
-
additional information
-
S-nitrosylation or membrane binding inhibit racemase activity
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
morphine
chronic administration significantly augments both serine racemase mRNA and protein expression in all brain regions and leads to slight but significant elevation in the concentration of D-serine in the cortex, striatum, and hippocampus
additional information
-
ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, ketamine, transiently enhances the expression of the enzyme in the brain in all the brain areas, overview
-
additional information
-
non-competitive N-methyl-D-aspartate receptor antagonist MK-801 causes an increase of serine racemase and D-serine levels in almost all brain areas, e.g. in striatum, hippocampus, cortex, diencephalon, midbrain, pons-medulla, and cerebellum, overview
-
additional information
-
the amyloid beta-peptide and secreted forms, liberated by alpha- or beta-secretase, of beta-amyloid precursor protein induce enzyme expression and lead to elevated D-serine levels in microglia, overview
-
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
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
a retinal Mueller cell line, enzyme expression analysis, uptake of D-serine in Mueller cells is specific for neutral amino acids and excludes anionic and cationic amino acids, specificity and activity of transporters, overview
-
mRNA is ubiquitously expressed in all cell layers of proliferating to hypertrophic chondrocytes
-
vestibular sensory epithelium, in transitional cells therein, which are parasensory cells located between the sensory epithelium and the dark cells, and in dark cells
-
Schwann cell and other endoneural components of spinal nerve, lysates of sciatic nerve
-
of neonatal rat, mRNA is ubiquitously expressed in all cell layers of proliferating to hypertrophic chondrocytes
ganglion cells, bipolar cells, amacrine cells, horizontal cells and Müller cells of the retina
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
-
enzyme translocation to the membrane is blocked by a palmitoylation inhibitor, indicating that membrane binding is mediated by fatty acid acylation of the enzyme
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
no significant decreases in the intracellular D-Asp levels are observed in the SRR-KO cells, the intracellular concentration of D-Ser in the SRR-KO PC12 cells is visibly lower than that in the controls
physiological function
physiological function
additional information
physiological function
rat PC-12 cells rely on a non-SRR-based mechanism to produce the majority of its D-Asp
physiological function
serine racemase (SerR) is a pyridoxal 5'-phosphate-dependent enzyme catalyzing the racemization of L-Ser to D-Ser. In mammals, D-Ser is an endogenous coagonist required for the activation of N-methyl-D-aspartate receptors (NMDARs)
physiological function
-
inhibition of D-serine synthesis caused by translocation of the enzyme to the membrane provides a fail-safe mechanism to prevent NMDA receptor overactivation in vicinal cells or synapses
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
additional information
enzyme activity site structure, docking and modeling, overview
additional information
-
rat serine racemase lacks the C-terminal PDZrecognition sequence
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_RAT
333
0
35693
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
38000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
the enzyme does not possess any transmembrane region
additional information
-
the enzyme structures shows a fold typical of beta-family pyridoxal 5'-phosphate enzymes, with both a large domain and a flexible small domain associated into a symmetric dimer, and indicated a ligand-induced rearrangement of the small domain that organizes the active site for specific turnover of the substrate, ligand-induced shift of small and large domains of the racemase, structure analysis, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospholipoprotein
-
the enzyme is acylated in transfected neuroblastoma cells through the formation of an oxyester bond with serine or threonine residues using palmitate or octanoic acid as precursors. Phosphorylation of Thr227 is also required for steady-state binding of the enzyme to the membrane under basal, nonstimulated condition. No S-palmitoylation of the enzyme in SH-SY5Y neuroblastoma cells, but O-palmitoylation
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified recombinant mutant C2D/C6D by sitting drop vapor diffusion, 35 mg/ml protein, from 55% v/v Tacsimate, i.e. 1.8305 M malonic acid, 0.25 M ammonium citrate tribasic, 0.12 M succinic acid, 0.3 M DL-malic acid, 0.4 M sodium acetate trihydrate, 0.5 M sodium formate, and 0.16 M ammonium tartrate dibasic, pH 8.0, and 100 mM Bis-Tris propane, pH 7.8, 10 days, X-ray diffraction structure determination and analysis at 1.8-1.95 A resolution
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
SRR overexpression increases D-serine and pyruvate and decreases D-serine uptake and alanine-serine-cysteine transporter ASCT2 mRNA but does not affect D-amino acid oxidase. SRR knockdown does not alter any of the parameters
additional information
induction of mutation by CRISPR/Cas9 genome editing in Srr loci in PC-12 cells. Generation of SRR-KO PC-12 cells. Two independent SRR-KO PC12 cell clones, Nos. 16 and 21, are identified/selected as SRR-KO samples. Clone No. 16 contains a 1-bp insertion in exon 4 of both alleles, resulting in a frame-shift and premature termination of SRR translation to yield a severely truncated protein (69 amino acid residues). The No. 21 clone possesses an 8-bp and 1-bp deletion in each locus of SRR exon 4, and results in a frame-shift and truncation of the enzyme of the protein size by 66 amino acid residues. Both truncated proteins are predicted to lose the enzyme activity. No significant decreases in the intracellular D-Asp levels are observed in the SRR-KO cells
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged wild-type enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography and dialysis
recombinant His-tagged enzyme mutant from Escherichia coli strain Rosetta 2 (DE3) by affinity chromatography and gel filtration to over 98% purity
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene Srr, DNA and amino acid sequence determination and analysis, the single guide (sg) RNA target sequence in the exon 4 of Srr are annealed and subcloned into the BsbI site of pX362 to yield the pXSrre4T1, the circular pXSrre4T1 plasmid is transfected into PC-12 cells, recombinant expression of His-tagged wild-type enzyme in Escherichia coli strain BL21(DE3)
total RNA is isolated from rMC-1 cells reverse-transcribed into cDNA and subjected to PCR using rat-specific SR primers, expression analysis of the enzyme in retinal Mueller cells
expression of His-tagged enzyme mutant in Escherichia coli strain Rosetta 2 (DE3)
-
overexpression of HA-tagged enzyme in SH-SY5Y neuroblastoma cells and in HEK293 cells, coexpression with palmitic acid leads to acylation of the enzyme
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
L-serine or D-serine, but not D-proline, increase the expression of SRR in C6 cells when added to the cell culture medium
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
the enzyme and enzyme mutants may serve as targets for future docking studies and drug design
drug development
-
serine racemase is a promising target for the development of specific inhibitors in the treatment of disorders related to NMDAR dysfunction. Analysis of the molecular basis for rational drug design using the X-ray crystal structures of human and rat serine racemase
medicine
-
elevated levels of enzyme mRNA in Alzheimer´s disease hippocampus
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Wu, S.; Barger, S.W.; Sims, T.J.
Schwann cell and epineural fibroblast expression of serine racemase
Brain Res.
1020
161-166
2004
Rattus norvegicus
Wu, S.Z.; Bodles, A.M.; Porter, M.M.; Griffin, W.S.; Basile, A.S.; Barger, S.W.
Induction of serine racemase expression and D-serine release from microglia by amyloid beta-peptide
J. Neuroinflammation
1
2
2004
Rattus norvegicus
Dememes, D.; Mothet, J.P.; Nicolas, M.T.
Cellular distribution of d-serine, serine racemase and d-amino acid oxidase in the rat vestibular sensory epithelia
Neuroscience
137
991-997
2006
Rattus norvegicus
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
Wolosker, H.; Sheth, K.N.; Takahashi, M.; Mothet, J.P.; Brady, R.O., Jr.; Ferris, C.D.; Snyder, S.H.
Purification of serine racemase: biosynthesis of the neuromodulator D-serine
Proc. Natl. Acad. Sci. USA
96
721-725
1999
Rattus norvegicus
Wu, S.; Basile, A.S.; Barger, S.W.
Induction of serine racemase expression and D-serine release from microglia by secreted amyloid precursor protein (sAPP)
Curr. Alzheimer Res.
4
243-251
2007
Rattus norvegicus, Homo sapiens (Q9GZT4)
Takeyama, K.; Yoshikawa, M.; Oka, T.; Kawaguchi, M.; Suzuki, T.; Hashimoto, A.
Ketamine enhances the expression of serine racemase and D-amino acid oxidase mRNAs in rat brain
Eur. J. Pharmacol.
540
82-86
2006
Rattus norvegicus
Hashimoto, A.; Yoshikawa, M.; Andoh, H.; Yano, H.; Matsumoto, H.; Kawaguchi, M.; Oka, T.; Kobayashi, H.
Effects of MK-801 on the expression of serine racemase and D-amino acid oxidase mRNAs and on the D-serine levels in rat brain
Eur. J. Pharmacol.
555
17-22
2007
Rattus norvegicus
Dun, Y.; Mysona, B.; Itagaki, S.; Martin-Studdard, A.; Ganapathy, V.; Smith, S.B.
Functional and molecular analysis of D-serine transport in retinal Mueller cells
Exp. Eye Res.
84
191-199
2007
Rattus norvegicus (Q76EQ0)
Yoshikawa, M.; Shinomiya, T.; Takayasu, N.; Tsukamoto, H.; Kawaguchi, M.; Kobayashi, H.; Oka, T.; Hashimoto, A.
Long-term treatment with morphine increases the D-serine content in the rat brain by regulating the mRNA and protein expressions of serine racemase and D-amino acid oxidase
J. Pharmacol. Sci.
107
270-276
2008
Rattus norvegicus (Q76EQ0)
Takayasu, N.; Yoshikawa, M.; Watanabe, M.; Tsukamoto, H.; Suzuki, T.; Kobayashi, H.; Noda, S.
The serine racemase mRNA is expressed in both neurons and glial cells of the rat retina
Arch. Histol. Cytol.
71
123-129
2008
Rattus norvegicus (Q76EQ0)
Takarada, T.; Hinoi, E.; Takahata, Y.; Yoneda, Y.
Serine racemase suppresses chondrogenic differentiation in cartilage in a Sox9-dependent manner
J. Cell. Physiol.
215
320-328
2008
Rattus norvegicus
Smith, M.A.; Mack, V.; Ebneth, A.; Moraes, I.; Felicetti, B.; Wood, M.; Schonfeld, D.; Mather, O.; Cesura, A.; Barker, J.
The structure of mammalian serine racemase: evidence for conformational changes upon inhibitor binding
J. Biol. Chem.
285
12873-12881
2010
Rattus norvegicus, Homo sapiens (Q9GZT4), Homo sapiens
Sikka, P.; Walker, R.; Cockayne, R.; Wood, M.J.; Harrison, P.J.; Burnet, P.W.
D-Serine metabolism in C6 glioma cells: Involvement of alanine-serine-cysteine transporter (ASCT2) and serine racemase (SRR) but not D-amino acid oxidase (DAO)
J. Neurosci. Res.
88
1829-1840
2010
Rattus norvegicus (Q76EQ0)
Balan, L.; Foltyn, V.N.; Zehl, M.; Dumin, E.; Dikopoltsev, E.; Knoh, D.; Ohno, Y.; Kihara, A.; Jensen, O.N.; Radzishevsky, I.S.; Wolosker, H.
Feedback inactivation of D-serine synthesis by NMDA receptor-elicited translocation of serine racemase to the membrane
Proc. Natl. Acad. Sci. USA
106
7589-7594
2009
Rattus norvegicus
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
Nitoker, N.; Major, D.T.
Understanding the reaction mechanism and intermediate stabilization in mammalian serine racemase using multiscale quantum-classical simulations
Biochemistry
54
516-527
2015
Rattus norvegicus (Q76EQ0), Homo sapiens (Q9GZT4), Homo sapiens
EXTERNAL LINKS (specific for EC-Number 5.1.1.18)
Use of this online version of BRENDA is free under the CC BY 4.0 license. See terms of use for full details.
Release 2023.1 (January 2023)
Legal
Curated at
Member of
