4229-56-5Relevant academic research and scientific papers
SYNTHETIC METHOD FOR NMN DERIVATIVE AND MEDICAL APPLICATIONS OF NMN AND ITS DERIVATIVE
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Page/Page column 16, (2021/05/29)
It relates to use of nicotinamide mononucleotide, in particular, relates to use of nicotinamide mononucleotide for the preparation of a medicament for preventing or alleviating liver injury or liver fibrosis in a subject, and a method for preventing liver injury or liver fibrosis in a subject. It also relates to a method of producing dihydronicotinamide mononucleotide (NMNH) and uses of NMNH.
Reduced nicotinamide mononucleotide is a new and potent nad+ precursor in mammalian cells and mice
Zapata-Pérez, Rubén,Tammaro, Alessandra,Schomakers, Bauke V.,Scantlebery, Angelique M. L.,Denis, Simone,Elfrink, Hyung L.,Giroud-Gerbetant, Judith,Cantó, Carles,López-Leonardo, Carmen,McIntyre, Rebecca L.,van Weeghel, Michel,Sánchez-Ferrer, álvaro,Houtkooper, Riekelt H.
, p. 1 - 17 (2021/03/22)
Nicotinamide adenine dinucleotide (NAD+) homeostasis is constantly compromised due to degradation by NAD+-dependent enzymes. NAD+ replenishment by sup-plementation with the NAD+ precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) can alleviate this imbalance. However, NMN and NR are limited by their mild effect on the cellular NAD+ pool and the need of high doses. Here, we report a synthesis method of a reduced form of NMN (NMNH), and identify this molecule as a new NAD+ precursor for the first time. We show that NMNH increases NAD+ levels to a much higher extent and faster than NMN or NR, and that it is metabolized through a different, NRK and NAMPT-independent, pathway. We also demonstrate that NMNH reduces damage and accelerates repair in renal tubular epithelial cells upon hypoxia/reoxygenation injury. Finally, we find that NMNH administration in mice causes a rapid and sustained NAD+ surge in whole blood, which is accompanied by increased NAD+ levels in liver, kidney, muscle, brain, brown adipose tissue, and heart, but not in white adipose tissue. Together, our data highlight NMNH as a new NAD+ precursor with therapeutic potential for acute kidney injury, confirm the existence of a novel pathway for the recycling of reduced NAD+ precursors and establish NMNH as a member of the new family of reduced NAD+ precursors.
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 (2017/01/28)
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.
