Activating Compound | Comment | Organism | Structure |
---|---|---|---|
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 | Mus musculus | |
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 | Homo sapiens | |
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 | Mus musculus | |
additional information | Mg2+ and ATP modulate serine reacemase activity | Mus musculus | |
additional information | Mg2+ and ATP modulate serine reacemase activity | Homo sapiens |
Inhibitors | Comment | Organism | Structure |
---|---|---|---|
beta-haloalanine | reacts with pyridoxal 5'-phosphate to yield thiazolidine derivative | Mus musculus | |
cysteine | reacts with pyridoxal 5'-phosphate to yield thiazolidine derivative | Mus musculus | |
glycine | competitive inhibitor, the active site ligand glycine increases the enzyme's affinity for ATP by 22fold and abolishes cooperativity while ATP increases the noncooperative glycine binding 15fold. The in vivo concentration plays a role in D-serine synthesis (i.e., glycine concentration in astrocytes is in the 3-6 mM range) | Homo sapiens | |
glycine | competitive | Mus musculus | |
homocysteine | reacts with pyridoxal 5'-phosphate to yield thiazolidine derivative | Mus musculus | |
L-aspartate | competitive | Homo sapiens | |
L-aspartate | competitive | Mus musculus | |
L-erythro-3-hydroxyaspartate | competitive versus L-serine | Homo sapiens | |
additional information | EDTA impairs only the alpha,beta-elimination reaction, not the racemization. Several dicarboxylic acids are strong, competitive inhibitors of the enzyme | Homo sapiens | |
additional information | EDTA impairs only the alpha,beta-elimination reaction, not the racemization. Several dicarboxylic acids are strong, competitive inhibitors of the enzyme | Mus musculus |
Metals/Ions | Comment | Organism | Structure |
---|---|---|---|
Ca2+ | activates | Mus musculus | |
Ca2+ | activates | Homo sapiens | |
Mg2+ | activates the enzyme independently from ATP, the effect due to divalent ion and ATP is additive | Mus musculus | |
Mg2+ | activates the enzyme independently from ATP, the effect due to divalent ion and ATP is additive | Homo sapiens | |
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 | Mus musculus | |
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 | Homo sapiens |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
L-serine | Mus musculus | - |
D-serine | - |
r | |
L-serine | Homo sapiens | - |
D-serine | - |
r |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | Q9GZT4 | - |
- |
Mus musculus | Q9QZX7 | - |
- |
Reaction | Comment | Organism | Reaction ID |
---|---|---|---|
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 | Mus musculus | |
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 | Homo sapiens |
Source Tissue | Comment | Organism | Textmining |
---|---|---|---|
astrocyte | - |
Homo sapiens | - |
brain | the enzyme mainly localizes in brain areas containing high levels of endogenous D-serine (i.e., hippocampus and corpus callosum) with intermediate levels in substantia nigra and caudate and negligible levels in brainstem. During postnatal development in the brain, the enzyme is localized in glutamatergic neurons in the cerebral cortex and in the glutamatergic pyramidal neurons of the hippocampus, where it is mainly present at postsynaptic sites. In the adult cerebellum, levels of the enzyme expression are lower than those reported for the telencephalic regions, a weak enzyme expression is also apparent in GABAergic Purkinje cells | Homo sapiens | - |
heart | - |
Homo sapiens | - |
kidney | - |
Homo sapiens | - |
liver | - |
Homo sapiens | - |
neuron | - |
Mus musculus | - |
neuron | predominantly neuronal localization | Homo sapiens | - |
skeletal muscle | - |
Homo sapiens | - |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
L-serine | - |
Mus musculus | D-serine | - |
r | |
L-serine | - |
Homo sapiens | D-serine | - |
r | |
additional information | reactions catalyzed by serine racemase are racemization and alpha,beta-elimination, mechanisms, overview | Mus musculus | ? | - |
? | |
additional information | reactions catalyzed by serine racemase are racemization and alpha,beta-elimination, mechanisms, overview | Homo sapiens | ? | - |
? |
Subunits | Comment | Organism |
---|---|---|
homodimer | 2 * 42000, native enzyme from brain, SDS-PAGE, 2 * 39000, recombinnat enzyme from HEK-293 cells, SDS-PAGE | Homo sapiens |
homodimer | dimeric structure, overview | Mus musculus |
More | dimeric structure analysis, overview | Homo sapiens |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
pyridoxal 5'-phosphate | - |
Mus musculus | |
pyridoxal 5'-phosphate | - |
Homo sapiens |
Ki Value [mM] | Ki Value maximum [mM] | Inhibitor | Comment | Organism | Structure |
---|---|---|---|---|---|
0.049 | - |
L-erythro-3-hydroxyaspartate | pH and temperature not specified in the publication | Homo sapiens | |
0.15 | - |
glycine | pH and temperature not specified in the publication | Homo sapiens | |
1.9 | - |
L-aspartate | pH and temperature not specified in the publication | Homo sapiens |
Organism | Comment | Expression |
---|---|---|
Homo sapiens | the enzyme is downregulated in the early phase of neuronal apoptosis, but modulation of serine racemase expression by apoptosis is stimulus-dependent | down |
Homo sapiens | the enzyme accumulates in the late pase of apoptosis. The increased enzyme expression is not dependent on the increased transcription or increased stability of serine racemase mRNA | up |
General Information | Comment | Organism |
---|---|---|
physiological function | serine racemase is a key player in apoptosis and necrosis | Mus musculus |
physiological function | serine racemase is a key player in apoptosis and necrosis, physiological regulation of serine racemase, overview. NMDAR-mediated Ca2+ influx at postsynaptic neurons involves Ca2+/calmodulin-dependent activation of neuronal NO synthase. The NO produced here diffuses into adjacent astrocytes or neurons to nitrosylate and inhibit the serine racemase and activate D-amino acid oxidase (DAAO). Cys113, identified as the target residue of serine racemase nitrosylation, is in close proximity to the ATP-binding region and thus nitrosylation might displace ATP from its binding site and inactivate the enzyme. ATP and NO reciprocally activate and inhibit the enzyme by acting at the same protein site. Synthesis of both neuronal and astrocytic D-serine in the brain is dependent on 3-phosphoglycerate dehydrogenase, an enzyme that occurs mainly in astrocytes and which catalyzes the first step in L-serine biosynthesis: L-serine shuttles from astrocytes into neurons where it is transformed by neuronal SR to D-serine. Serine racemase D-serine-related pathway in neuronal apoptosis, D-serine and the enzyme are involved in controlling the extent of NMDAR activation and neurotoxic insults observed in many central nervous disorders, like Alzheimer's disease, amylothrophic lateral sclerosis (ALS), and epilepsy, and also stroke and ischemia, detailed overview | Homo sapiens |