Novel human D-amino acid oxidase inhibitors stabilize an active-site lid-open conformation.
Ryan T. Terry-Lorenzo,Lawrence Chun,Scott P. Brown,Michelle L. R. Heffernan,Q. K. Fang,M. A. Orsini,Loredano Pollegioni,Larry W. Hardy,Kerry L. Spear,Thomas H. Large +9 more
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TLDR
The results confirm previous hypotheses regarding active-site lid flexibility of mammalian D-amino acid oxidases and could assist in the design of the next generation of hDAAO inhibitors.Abstract:
The NMDAR (N-methyl-D-aspartate receptor) is a central regulator of synaptic plasticity and learning and memory. hDAAO (human D-amino acid oxidase) indirectly reduces NMDAR activity by degrading the NMDAR co-agonist D-serine. Since NMDAR hypofunction is thought to be a foundational defect in schizophrenia, hDAAO inhibitors have potential as treatments for schizophrenia and other nervous system disorders. Here, we sought to identify novel chemicals that inhibit hDAAO activity. We used computational tools to design a focused, purchasable library of compounds. After screening this library for hDAAO inhibition, we identified the structurally novel compound, ‘compound 2’ [3-(7-hydroxy-2-oxo-4-phenyl-2H-chromen-6-yl)propanoic acid], which displayed low nM hDAAO inhibitory potency (Ki=7 nM). Although the library was expected to enrich for compounds that were competitive for both D-serine and FAD, compound 2 actually was FAD uncompetitive, much like canonical hDAAO inhibitors such as benzoic acid. Compound 2 and an analog were independently co-crystalized with hDAAO. These compounds stabilized a novel conformation of hDAAO in which the active-site lid was in an open position. These results confirm previous hypotheses regarding active-site lid flexibility of mammalian D-amino acid oxidases and could assist in the design of the next generation of hDAAO inhibitors.read more
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Journal ArticleDOI
Human D-Amino Acid Oxidase: Structure, Function, and Regulation
TL;DR: The known properties of human DAAO suggest that its activity must be finely tuned to fulfill a main physiological function such as the control of D-serine levels in the brain as well as the role of post-translational modifications on its main biochemical properties at the cellular level.
Journal ArticleDOI
Gut Microbiota-Based Pharmacokinetics and the Antidepressant Mechanism of Paeoniflorin.
Jin-Bo Yu,Jin-Bo Yu,Zhen-Xiong Zhao,Ran Peng,Li-Bin Pan,Jie Fu,Shu-Rong Ma,Pei Han,Lin Cong,Zheng-Wei Zhang,Li-Xin Sun,Jian-Dong Jiang,Yan Wang +12 more
TL;DR: Paeoniflorin can be metabolized into benzoic acid via gut microbiota enzymes, which might exert antidepressant effects through the blood–brain barrier into the brain, and the metabolism effect of gut microbiota may be one of the main reasons for the low oral bioavailability of paeonIFlorin.
Journal ArticleDOI
Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity
Silvia Sacchi,Vito de Novellis,Giovanna Paolone,Tommaso Nuzzo,Monica Iannotta,Carmela Belardo,Marta Squillace,Paolo Bolognesi,Elena Rosini,Zoraide Motta,Martina Frassineti,Alessandro Bertolino,Loredano Pollegioni,Michele Morari,Sabatino Maione,Francesco Errico,Alessandro Usiello +16 more
TL;DR: Results suggest that the second-generation antipsychotic olanzapine, through the inhibition of DDO activity, increases L-glutamate release in the PFC of treated mice.
Journal ArticleDOI
6-Hydroxy-1,2,4-triazine-3,5(2H,4H)-dione Derivatives as Novel D-Amino Acid Oxidase Inhibitors.
Niyada Hin,Bridget Duvall,Dana Ferraris,Jesse Alt,Ajit G. Thomas,Rana Rais,Camilo Rojas,Ying Wu,Krystyna M. Wozniak,Barbara S. Slusher,Takashi Tsukamoto +10 more
TL;DR: 6-hydroxy-2-(naphthalen-1-ylmethyl)-1,2,4-triazine-3,5(2H,4H)-dione 11h was found to be selective over a number of targets and orally available in mice, demonstrating its ability to serve as a pharmacoenhancer of d-serine.
Journal ArticleDOI
Expression of D-Amino Acid Oxidase (DAO/DAAO) and D-Amino Acid Oxidase Activator (DAOA/G72) during Development and Aging in the Human Post-mortem Brain.
TL;DR: DAO and DAOA expression in the human brain are both age and brain region dependent and post-transcriptional regulation at the transcriptional level is suggested.
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