Literature summary for 5.1.1.18 extracted from

Bruno, S.; Marchesani, F.; Dellafiora, L.; Margiotta, M.; Faggiano, S.; Campanini, B.; Mozzarelli, A.
Human serine racemase is allosterically modulated by NADH and reduced nicotinamide derivatives (2016), Biochem. J., 473, 3505-3516 .

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Activating Compound

Activating Compound	Comment	Organism	Structure
ATP	the enzyme is allosterically controlled by ATP, which increases its activity around 7fold through a cooperative binding mechanism	Homo sapiens

Cloned(Commentary)

Cloned (Comment)	Organism
recombinant expression of His-tagged wild-type enzyme in Escherichia coli strain BL21 CodonPlus (DE3)-RIL	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
1,4-dihydronicotinamide mononucleotide	the NADH precursor exhibits a partial mixed-type inhibition. Docking simulations suggest that all 1,4-dihydronicotinamide derivatives bind at the interdimeric interface, with the ring positioned in an unoccupied site next to the ATP binding site	Homo sapiens
2,2-dichloromalonate	as malonate, it binds in a small pocket of the active site	Homo sapiens
beta-NADH	reduced NADH inhibits the serine racemase, the inhibition is partial, the IC50 value is several-fold higher than the intracellular NADH concentrations. At saturating concentrations of NADH, ATP binds with a 2fold lower affinity and without co-operativity, suggesting ligand competition. But NADH also reduces the weak activity of human serine racemase in the absence of ATP, indicating an additional ATP-independent inhibition mechanism. The inhibitory determinant is the N-substituted 1,4-dihydronicotinamide ring. NAD+ does not seem to compete at all with NADH. Identification of the NADH-binding site, overview	Homo sapiens
beta-NADPH	-	Homo sapiens
additional information	design of high-affinity serine racemase effectors to finely modulate D-serine homeostasis; no enzyme inhibition by ADP and the oxidized forms NAD+ and NADP+. Molecular modeling. The NADH/NAD+ fragments 1-methyl-1,4-dihydronicotinamide (MNA-red), 1,4-dihydronicotinamide mononucleotide (NMN-red), their oxidized forms 1-methylnicotinamide (MNA-ox) and beta-nicotinamide monucleotide (NMN-ox), the fully reduced form of MNA-ox-1-methyl 3-piperidinecarboxamide (MPCA), ADP and diphosphate are screened at 2 mM concentration using the beta-elimination (EC 4.3.1.17) assay to identify the inhibitory determinant of NADH, inhibition mechanism, overview	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
L-serine	Homo sapiens	-	D-serine	-	r

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	Q9GZT4	-	-

Purification (Commentary)

Purification (Comment)	Organism
recombinant His-tagged wild-type enzyme from Escherichia coli strain BL21 CodonPlus (DE3)-RIL by nickel affinity chromatography	Homo sapiens

Source Tissue

Source Tissue	Comment	Organism	Textmining
brain	-	Homo sapiens	-
neuron	-	Homo sapiens	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
L-serine	-	Homo sapiens	D-serine	-	r

Synonyms

Synonyms	Comment	Organism
hSR	-	Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
37	-	assay at	Homo sapiens

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
8	-	assay at	Homo sapiens

Cofactor

Cofactor	Comment	Organism	Structure
pyridoxal 5'-phosphate	-	Homo sapiens

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism	Structure
0.018	-	1,4-dihydronicotinamide mononucleotide	pH 8.0, 37°C	Homo sapiens
0.019	-	2,2-dichloromalonate	pH 8.0, 37°C	Homo sapiens

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor	Structure
0.243	-	pH 8.0, 37°C	Homo sapiens	beta-NADH

General Information

General Information	Comment	Organism
physiological function	human 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 ATP, which increases its activity around 7fold through a cooperative binding mechanism. Serine racemase is allosterically inhibited by NADH and reduced nicotinamide derivatives suggesting a physiological regulation of hSR activity by the glycolytic flux in neurons. NADH binding counteracts ATP activation of the enzyme with a complete loss of cooperativity	Homo sapiens

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Release 2023.1 (January 2023)