Modulating D-amino acid oxidase (DAAO) substrate specificity through facilitated solvent access

Subramanian, Kalyanasundaram; Góra, Artur; Spruijt, Ruud B.; Mitusińska, Karolina; Suárez-Diez, María; Schaap, Peter J.

doi:10.1371/journal.pone.0198990

Cited by 18 publications

(16 citation statements)

References 64 publications

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“…As a consequence of the mutation, the Leu158 will be replaced by Ala160, and Lys159 by Lys161. Luckily, the deleted Lys159 should be replaced by Lys161, and thus its role can be preserved (a similar replacement of the key amino acid was observed, for example, in D-amino acid oxidase, where Tyr314 repossesses the function of the Tyr55, eliminated by the Tyr55Ala mutation and modifies the enzyme-substrate specificity) [ 12 ]. Since the second one replaces the crucial lysine, one could expect that the precursor Z binding can still occur; however, the protein–ligand affinity can be already modified.…”

Section: Discussionmentioning

confidence: 99%

Proteins Structure Models in the Evaluation of Novel Variant (C.472_477del) in the MOCS2 Gene

Jezela‐Stanek¹,

Blaz²,

Góra

et al. 2020

Diagnostics

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(1) Background: Molybdenum cofactor deficiency type B (MOCODB, #252160) is a rare autosomal recessive metabolic disorder characterized by intractable seizures of neonatal-onset, muscular spasticity, accompanying with hypouricemia, elevated urinary sulfite levels and craniofacial dysmorphism. Thirty-five patients were reported to date. (2) Methods: Our paper aimed to delineate the disease genotype by presenting another patient, in whom a novel, in-frame variant within the MOCS2 gene was identified. (3) Results: Exome sequencing led to the identification of a novel variant in the MOSC2 gene-c.472_477del of unknown significance (VUS). (4) Conclusions: To prove the clinical significance of the mentioned variant, analysis of the possible mutation consequences on molecular level with the use of the available crystal structure of the human molybdopterin synthase complex was of great importance. Moreover, a potential pathomechanism resulting from a molecular defect was presented, giving original insight into the current knowledge on this rare disease, including treatment options.

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Section: Discussionmentioning

confidence: 99%

Proteins Structure Models in the Evaluation of Novel Variant (C.472_477del) in the MOCS2 Gene

Jezela‐Stanek¹,

Blaz²,

Góra

et al. 2020

Diagnostics

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“…On the other hand, modification of the enzyme’s selectivity targets the binding site cavity or the residues composing or controlling the access pathways [1,49,50]. Recent examples show that substrate specificity regulation can be achieved by subtle changes, at a distance from the active site, which modify water or solvent accessibility [51,52,53]. Also, an entropy contribution to both binding affinity and catalysis is greatly affected by internal water positioning and dynamics, therefore mutations of residues positioning water can modify enzyme properties significantly [54,55,56].…”

Section: Discussionmentioning

confidence: 99%

Exploring Solanum tuberosum Epoxide Hydrolase Internal Architecture by Water Molecules Tracking

et al. 2018

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Several different approaches are used to describe the role of protein compartments and residues in catalysis and to identify key residues suitable for the modification of the activity or selectivity of the desired enzyme. In our research, we applied a combination of molecular dynamics simulations and a water tracking approach to describe the water accessible volume of Solanum tuberosum epoxide hydrolase. Using water as a molecular probe, we were able to identify small cavities linked with the active site: (i) one made up of conserved amino acids and indispensable for the proper positioning of catalytic water and (ii) two others in which modification can potentially contribute to enzyme selectivity and activity. Additionally, we identified regions suitable for de novo tunnel design that could also modify the catalytic properties of the enzyme. The identified hot-spots extend the list of the previously targeted residues used for modification of the regioselectivity of the enzyme. Finally, we have provided an example of a simple and elegant process for the detailed description of the network of cavities and tunnels, which can be used in the planning of enzyme modifications and can be easily adapted to the study of any other protein.

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“…To delve into the structure-function relationships in mammalian DAAOs, alanine-scanning analysis of first and second shell residues of the enzyme from pig prompted the focus on active-site lid residues (region 221–225) and on the positions 55 and 56 in hDAAO (Subramanian et al, 2018 ). Molecular dynamics simulations identified a narrow tunnel that could provide access to the active site of hDAAO, named tunnel T1.…”

Section: Modulation Of Hdaao Activitymentioning

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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Modulating D-amino acid oxidase (DAAO) substrate specificity through facilitated solvent access

Cited by 18 publications

References 64 publications

Proteins Structure Models in the Evaluation of Novel Variant (C.472_477del) in the MOCS2 Gene

Proteins Structure Models in the Evaluation of Novel Variant (C.472_477del) in the MOCS2 Gene

Exploring Solanum tuberosum Epoxide Hydrolase Internal Architecture by Water Molecules Tracking

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

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