17750-23-1Relevant articles and documents
Human serine racemase is allosterically modulated by NADH and reduced nicotinamide derivatives
Bruno, Stefano,Marchesani, Francesco,Dellafiora, Luca,Margiotta, Marilena,Faggiano, Serena,Campanini, Barbara,Mozzarelli, Andrea
, p. 3505 - 3516 (2016)
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 adenosine triphosphate (ATP), which increases its activity around 7-fold through a cooperative binding mechanism. Serine racemase has been proposed as a drug target for the treatment of several neuropathologies but, so far, the search has been directed only toward the active site, with the identification of a few, low-Affinity inhibitors. Following the recent observation that nicotinamide adenine dinucleotide (reduced form) (NADH) inhibits serine racemase, here we show that the inhibition is partial, with an IC50 of 246 ± 63 μM, several-fold higher than NADH intracellular concentrations. At saturating concentrations of NADH, ATP binds with a 2-fold lower affinity and without co-operativity, suggesting ligand competition. NADH also reduces the weak activity of human serine racemase in the absence of ATP, indicating an additional ATP-independent inhibition mechanism. By dissecting the NADH molecule, we discovered that the inhibitory determinant is the Nsubstituted 1,4-dihydronicotinamide ring. Particularly, the NADH precursor 1,4-dihydronicotinamide mononucleotide exhibited a partial mixed-Type inhibition, with a KI of 18 ± 7 μM. Docking simulations suggested that all 1,4-dihydronicotinamide derivatives bind at the interdimeric interface, with the ring positioned in an unoccupied site next to the ATPbinding site. This newly recognized allosteric site might be exploited for the design of high-Affinity serine racemase effectors to finely modulate D-serine homeostasis.
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Hutton,Westheimer
, p. 73,74 (1958)
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Photoswitchable hydride transfer from iridium to 1-methylnicotinamide rationalized by thermochemical cycles
Barrett, Seth M.,Pitman, Catherine L.,Walden, Andrew G.,Miller, Alexander J. M.
supporting information, p. 14718 - 14721 (2014/12/11)
Visible light-triggered hydride transfer from [CpIr(bpy)(H)]+ (1) to organic acids and 1-methylnicotinamide (MNA+) is reported (Cp = pentamethylcyclopentadienyl; bpy = 2,2′-bipyridine). A new thermochemical cycle for determining excited-state hydride donor ability (hydricity) predicted that 1 would be an incredibly potent photohydride in acetonitrile. Phototriggered H2 release was indeed observed from 1 in the presence of various organic acids, providing experimental evidence for an increase in hydricity of at least 18 kcal/mol in the excited state. The rate and product selectivity of hydride transfer to MNA+ are photoswitchable: 1,4-dihydro-1-methylnicotinamide forms slowly in the dark but rapidly under illumination, and photolysis can also produce doubly reduced 1,4,5,6-tetrahydro-1-methylnicotinamide.
Direct observation of NADH radical cation generated in reactions with one-electron oxidants
Zielonka, Jacek,Marcinek, Andrzej,Adamus, Jan,Gebicki, Jerzy
, p. 9860 - 9864 (2007/10/03)
The formation of NADH radical cation in reactions with one-electron oxidants was observed for the first time. Transient products involving two tautomeric (keto and enol) forms of radical cation and neutral radical were spectroscopically characterized by means of pulse radiolysis. The kinetics of the decay of keto radical cation and neutral radical was investigated. The pKa value of the enol form of NADH radical cation was determined. The simple analogues of NADH and NAD+, namely, 1-methyl-1,4-dihydronicotinamide and it oxidized form, were studied for comparison.
