A novel serine racemase inhibitor suppresses neuronal over-activation in vivo

Mori, Hisashi; Wada, Ryogo; Takahara, Satoyuki; Horino, Yoshikazu; Izumi, Hironori; Ishimoto, Tetsuya; Yoshida, Tomoyuki; Mizuguchi, Mineyuki; Obita, Takayuki; Gouda, Hiroaki; Hirono, Shuichi; Toyooka, Naoki

doi:10.1016/j.bmc.2017.05.011

Cited by 15 publications

(14 citation statements)

References 32 publications

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“…Almost all endogenous d-serine is produced by SR, as demonstrated by the observation that SR-knockout mice have an 80-90% reduction in d-serine levels (Balu et al, 2013). Several groups have tried to identify new SR inhibitors that are potent, selective and structurally distinct from the many well described amino-acid analogues, but overall there has been relatively little progress (Jirá sková -Vaníčková et al, 2011;Beato et al, 2015;Vorlová et al, 2015;Watanabe et al, 2016;Mori et al, 2017). One of the more promising approaches identified a series of dipeptidelike inhibitors with a clear structural motif and slow-binding kinetics (Dixon et al, 2006), which later provided the query molecule for an in silico screen (Mori et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…One of the more promising approaches identified a series of dipeptidelike inhibitors with a clear structural motif and slow-binding kinetics (Dixon et al, 2006), which later provided the query molecule for an in silico screen (Mori et al, 2014). The resulting amide inhibitors and halogen-substituted derivatives showed improved inhibitory activity (compared with classical SR inhibitors), binding affinity and ligand efficiency, but limited potency, with reported IC 50 values of 0.28, 0.27 and 0.14 mM for the best compounds (Mori et al, 2017). Overall, there are a negligible number of drug-like SR inhibitors and none that have been confirmed by crystallography.…”

Section: Introductionmentioning

confidence: 99%

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Conformational flexibility within the small domain of human serine racemase

et al. 2020

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Serine racemase (SR) is a pyridoxal 5′‐phosphate (PLP)‐containing enzyme that converts l‐serine to d‐serine, an endogenous co‐agonist for the N‐methyl‐d‐aspartate receptor (NMDAR) subtype of glutamate ion channels. SR regulates d‐serine levels by the reversible racemization of l‐serine to d‐serine, as well as the catabolism of serine by α,β‐elimination to produce pyruvate. The modulation of SR activity is therefore an attractive therapeutic approach to disorders associated with abnormal glutamatergic signalling since it allows an indirect modulation of NMDAR function. In the present study, a 1.89 Å resolution crystal structure of the human SR holoenzyme (including the PLP cofactor) with four subunits in the asymmetric unit is described. Comparison of this new structure with the crystal structure of human SR with malonate (PDB entry 3l6b) shows an interdomain cleft that is open in the holo structure but which disappears when the inhibitor malonate binds and is enclosed. This is owing to a shift of the small domain (residues 78–155) in human SR similar to that previously described for the rat enzyme. This domain movement is accompanied by changes within the twist of the central four‐stranded β‐sheet of the small domain, including changes in the ϕ–ψ angles of all three residues in the C‐terminal β‐strand (residues 149–151). In the malonate‐bound structure, Ser84 (a catalytic residue) points its side chain at the malonate and is preceded by a six‐residue β‐strand (residues 78–83), but in the holoenzyme the β‐strand is only four residues (78–81) and His82 has ϕ–ψ values in the α‐helical region of the Ramachandran plot. These data therefore represent a crystallographic platform that enables the structure‐guided design of small‐molecule modulators for this important but to date undrugged target.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Conformational flexibility within the small domain of human serine racemase

et al. 2020

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“…2a, d, g). Holoenzyme hSR structures (5×2L, 6SLH) share a common ‘open’ (inactive) conformation for the small domain 32,38 that is not observed in the spSR holoenzyme structures (1V71 and 1WTC) 36 . In one of the ‘open’ yeast structures (1WTC) the ATP analogue AMPPCP was soaked into holo crystals and was found to bind at the dimer interface.…”

Section: Introductionmentioning

confidence: 94%

“…Careful optimisation of malonate-based inhibitors 47 using the hSR structure with malonate 30 produced more polar compounds, none of which were much more potent than malonate (IC 50 67 μM). A 2017 paper published an inhibitor of mouse SR, 13J, that could suppress neuronal overactivation in vivo 38 and produced better IC 50 values (140 μM) than malonate (770 μM). In 2020, a novel plant derivative SR inhibitor, madecassoside (IC 50 26 μM), was reported and described as a far better inhibitor than malonate (IC 50 449 μM) 48 .…”

Section: Introductionmentioning

confidence: 99%

Tyrosine 121 moves revealing a druggable pocket that couples catalysis to ATP-binding in serine racemase

et al. 2021

Preprint

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Human serine racemase (hSR) catalyses racemisation of L-serine to D-serine, the latter of which is a co-agonist of the NMDA subtype of glutamate receptors that are important in synaptic plasticity, learning and memory. In a closed hSR structure containing the allosteric activator ATP, the inhibitor malonate is enclosed between the large and small domains while ATP is distal to the active site, residing at the dimer interface with the Tyr121 hydroxyl group contacting the ATP alpha-phosphate. In contrast, in open hSR structures, Tyr121 sits in the core of the small domain with its hydroxyl contacting the key catalytic residue Ser84. The ability to regulate SR activity by flipping Tyr121 from the core of the small domain to the dimer interface appears to have evolved in animals with a CNS. Multiple X-ray crystallographic enzyme-fragment structures show that Tyr121 is flipped out of its pocket, suggesting that this pocket is druggable.

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“…By a combination of in silico screening and de novo synthesis, compound 2 was identified (Mori et al, 2014), and further optimized to generate compound 3 , which showed an IC 50 in vitro of 14 μM for mSR, a calculated K i of about 4 μM (Table 3) and an in vivo activity on a mouse model, suppressing neuronal over-activation (Mori et al, 2017). An inhibitor with an IC 50 of 1 mM ( compound 4 ) was identified and optimized by structure-based drug design starting from hSR, leading to compound 5 , with an IC 50 of 0.84 mM (Takahara et al, 2018) and a calculated K i of 0.207 mM (Table 3).…”

Section: Sr Inhibitorsmentioning

confidence: 99%

The Energy Landscape of Human Serine Racemase

Raboni

Marchetti

Faggiano

et al. 2019

Front. Mol. Biosci.

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Human serine racemase is a pyridoxal 5′-phosphate (PLP)-dependent dimeric enzyme that catalyzes the reversible racemization of L-serine and D-serine and their dehydration to pyruvate and ammonia. As D-serine is the co-agonist of the N-methyl-D-aspartate receptors for glutamate, the most abundant excitatory neurotransmitter in the brain, the structure, dynamics, function, regulation and cellular localization of serine racemase have been investigated in detail. Serine racemase belongs to the fold-type II of the PLP-dependent enzyme family and structural models from several orthologs are available. The comparison of structures of serine racemase co-crystallized with or without ligands indicates the presence of at least one open and one closed conformation, suggesting that conformational flexibility plays a relevant role in enzyme regulation. ATP, Mg2+, Ca2+, anions, NADH and protein interactors, as well as the post-translational modifications nitrosylation and phosphorylation, finely tune the racemase and dehydratase activities and their relative reaction rates. Further information on serine racemase structure and dynamics resulted from the search for inhibitors with potential therapeutic applications. The cumulative knowledge on human serine racemase allowed obtaining insights into its conformational landscape and into the mechanisms of cross-talk between the effector binding sites and the active site.

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A novel serine racemase inhibitor suppresses neuronal over-activation in vivo

Cited by 15 publications

References 32 publications

Conformational flexibility within the small domain of human serine racemase

Conformational flexibility within the small domain of human serine racemase

Tyrosine 121 moves revealing a druggable pocket that couples catalysis to ATP-binding in serine racemase

The Energy Landscape of Human Serine Racemase

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