Cyclopropane derivatives as potential human serine racemase inhibitors: unveiling novel insights into a difficult target

Beato, Claudia; Pecchini, Chiara; Cocconcelli, C; Campanini, Barbara; Marchetti, Marialaura; Pieroni, Marco; Mozzarelli, Andrea; Costantino, Gabriele

doi:10.3109/14756366.2015.1057720

Cited by 12 publications

(11 citation statements)

References 45 publications

(60 reference statements)

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“…43 In all these studies, the inhibitory effects of the compounds were counteracted by application of D-serine and were opposed to the enzymatic degradation of D-serine by applied DAAO, just apparently warranting the use of the SR inhibitors. 86,87 The same caution should be applied to compounds inhibiting DAAO. Of course, these mentioned studies proposed a significant role of the NMDAR co-agonist despite that the actual real specificity of these compounds remains totally unknown since they were identified as prototype inhibitors of SR only from in silico and in vitro screening assays.…”

Section: Off-target Effects Of Some Genetic and Pharmacological Toomentioning

confidence: 99%

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Investigating brain d‐serine: Advocacy for good practices

et al. 2019

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The last two decades have witnessed remarkable advance in our understanding the role of D-amino acids in the mammalian nervous system: from the unknown, to known molecules with unknown functions, to potential central players in health and disease. D-Amino acids have emerged as an important class of signaling molecules. In particular, the exploration of the roles of D-serine in brain physiopathology is a vibrant field that is growing at an accelerating pace. However, disentangling the functions of a chiral molecule in a complex chemical matrice as the brain requires specific measurement and detection methods but is also a challenging task as many molecular tools and models investigators are using can lead to confounded observations. Thus, study of D-amino acids demands accurate methodologies and specific controls, and these have often been lacking. Here we outline best practices for D-amino acid research, with a special emphasis on D-serine. We hope these concepts help move the field to greater rigor and reproducibility, allowing the field to advance. K E Y W O R D Sanalytical methods, D-Serine, glia, immunostainings, neurons, NMDA receptors, rescue experiments, serine racemase inhibitors

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Section: Off-target Effects Of Some Genetic and Pharmacological Toomentioning

confidence: 99%

“…Clearly, there is a need for the development of more specific SR inhibitors. 86,87 The same caution should be applied to compounds inhibiting DAAO. We encourage investigators to test their efficacity in DAAO −/− mice before going further in their studies.…”

Section: Some Genetic and Pharmacological Tools To Explore The Functimentioning

confidence: 99%

Investigating brain d‐serine: Advocacy for good practices

et al. 2019

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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%

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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“…SR can also catabolize D- and L-serine through an α,β-elimination reaction to give pyruvate (Foltyn et al, 2005 ). From a cellular point of view, SR is a “complex” enzyme since its activity is modulated by energy level (ATP), metal ions, post-translational modifications, and protein interactors; for details, see (Pollegioni and Sacchi, 2010 ; Conti et al, 2011 ; Dellafiora et al, 2015 ; Beato et al, 2016 ). Once released by neurons, D-serine is rapidly taken up and stored in astrocytes (Wolosker, 2011 ; Wolosker and Radzishevsky, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Human D-Amino Acid Oxidase: Structure, Function, and Regulation

Pollegioni

Sacchi

Murtas

2018

Front. Mol. Biosci.

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D-Amino acid oxidase (DAAO) is an FAD-containing flavoenzyme that catalyzes with absolute stereoselectivity the oxidative deamination of all natural D-amino acids, the only exception being the acidic ones. This flavoenzyme plays different roles during evolution and in different tissues in humans. Its three-dimensional structure is well conserved during evolution: minute changes are responsible for the functional differences between enzymes from microorganism sources and those from humans. In recent years several investigations focused on human DAAO, mainly because of its role in degrading the neuromodulator D-serine in the central nervous system. D-Serine is the main coagonist of N-methyl D-aspartate receptors, i.e., excitatory amino acid receptors critically involved in main brain functions and pathologic conditions. Human DAAO possesses a weak interaction with the FAD cofactor; thus, in vivo it should be largely present in the inactive, apoprotein form. Binding of active-site ligands and the substrate stabilizes flavin binding, thus pushing the acquisition of catalytic competence. Interestingly, the kinetic efficiency of the enzyme on D-serine is very low. Human DAAO interacts with various proteins, in this way modulating its activity, targeting, and cell stability. 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. At present, studies are focusing on the epigenetic modulation of human DAAO expression and the role of post-translational modifications on its main biochemical properties at the cellular level.

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Cyclopropane derivatives as potential human serine racemase inhibitors: unveiling novel insights into a difficult target

Cited by 12 publications

References 45 publications

Investigating brain d‐serine: Advocacy for good practices

Investigating brain d‐serine: Advocacy for good practices

Conformational flexibility within the small domain of human serine racemase

Human D-Amino Acid Oxidase: Structure, Function, and Regulation

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