New Insights Into the Mechanisms and Biological Roles of D-Amino Acids in Complex Eco-Systems

Aliashkevich, Alena; Álvarez, Laura; Cava, Felipe

doi:10.3389/fmicb.2018.00683

Cited by 145 publications

(129 citation statements)

References 135 publications

(161 reference statements)

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“…[1][2][3] In mammals, d-serine (d-Ser) and d-aspartate (d-Asp) have attracted interest owing to their involvement in important physiological processes and pathological states. [1][2][3] In mammals, d-serine (d-Ser) and d-aspartate (d-Asp) have attracted interest owing to their involvement in important physiological processes and pathological states.…”

Section: Introductionmentioning

confidence: 99%

“…In recent years, a number of studies focused on the physiological role of the "wrong" enantiomer of amino acids, namely, the d-amino acids, starting from simple bacteria up to humans. [1][2][3] In mammals, d-serine (d-Ser) and d-aspartate (d-Asp) have attracted interest owing to their involvement in important physiological processes and pathological states. [4][5][6] The metabolism of d-Ser in mammalian brain has been established, 7,8 providing deep insight into the molecular mechanisms underlying relevant physiological processes (such as N-methyl-d-aspartate receptor (NMDAR)-mediated neurotransmission and brain functions such as learning and memory) and generating the opportunity to develop novel therapeutic approaches.…”

Section: Introductionmentioning

confidence: 99%

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Structure and kinetic properties of humand‐aspartate oxidase, the enzyme‐controllingd‐aspartate levels in brain

et al. 2019

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Savinelli equally contributed to this study.Abbreviations: 5-An, 5-aminonicotinic acid; AMPA, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate; CBIO, 6-chloro-1,2-benzisoxazol-3(2H)-one; DAAO, d-amino acid oxidase; DASPO or DDO, d-aspartate oxidase; DPPD, pyrido[2,3-b]pyrazine-2,3(1H,4H)-dione; EMTN, enzyme monitored turnover; hDAAO, human d-amino acid oxidase; hDASPO, human d-aspartate oxidase; IAsp, iminoaspartate; MT, meso-tartrate; NMDAR, N-methyl-d-aspartate receptor; OA, oxaloacetate; RgDAAO, d-amino acid oxidase from Rhodotorula gracilis. Abstract d-Amino acids are the "wrong" enantiomers of amino acids as they are not used in proteins synthesis but evolved in selected functions. On this side, d-aspartate (d-Asp) plays several significant roles in mammals, especially as an agonist of N-methyl-daspartate receptors (NMDAR), and is involved in relevant diseases, such as schizophrenia and Alzheimer's disease. In vivo modulation of d-Asp levels represents an intriguing task to cope with such pathological states. As little is known about d-Asp synthesis, the only option for modulating the levels is via degradation, which is due to the flavoenzyme d-aspartate oxidase (DASPO). Here we present the first threedimensional structure of a DASPO enzyme (from human) which belongs to the damino acid oxidase family. Notably, human DASPO differs from human d-amino acid oxidase (attributed to d-serine degradation, the main coagonist of NMDAR)showing peculiar structural features (a specific active site charge distribution), oligomeric state and kinetic mechanism, and a higher FAD affinity and activity. These results provide useful insights into the structure-function relationships of human DASPO: modulating its activity represents now a feasible novel therapeutic target. K E Y W O R D Sd-aspartate, d-aspartate oxidase, flavoprotein, NMDA receptor, structure-function relationships

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure and kinetic properties of humand‐aspartate oxidase, the enzyme‐controllingd‐aspartate levels in brain

et al. 2019

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“…D and E) similarly to PenP. Finally, numerous soil and gut residing bacterial species produce d ‐amino acids (Aliashkevich et al ., ), indicating a potential role of these small molecules as environmental ques for the production of β‐lactamases production. Indeed, B. pumilus and B. simplex environmental isolates (Supporting Information Fig.…”

Section: Resultsmentioning

confidence: 99%

An active β‐lactamase is a part of an orchestrated cell wall stress resistance network of Bacillus subtilis and related rhizosphere species

Bucher

Keren-Paz

Hausser

et al. 2019

Environmental Microbiology

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Summary A hallmark of the Gram‐positive bacteria, such as the soil‐dwelling bacterium Bacillus subtilis, is their cell wall. Here, we report that d‐leucine and flavomycin, biofilm inhibitors targeting the cell wall, activate the β‐lactamase PenP. This β‐lactamase contributes to ampicillin resistance in B. subtilis under all conditions tested. In contrast, both Spo0A, a master regulator of nutritional stress, and the general cell wall stress response, differentially contribute to β‐lactam resistance under different conditions. To test whether β‐lactam resistance and β‐lactamase genes are widespread in other Bacilli, we isolated Bacillus species from undisturbed soils, and found that their genomes can encode up to five β‐lactamases with differentiated activity spectra. Surprisingly, the activity of environmental β‐lactamases and PenP, as well as the general stress response, resulted in a similarly reduced lag phase of the culture in the presence of β‐lactam antibiotics, with little or no impact on the logarithmic growth rate. The length of the lag phase may determine the outcome of the competition between β‐lactams and β‐lactamases producers. Overall, our work suggests that antibiotic resistance genes in B. subtilis and related species are ancient and widespread, and could be selected by interspecies competition in undisturbed soils.

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“…All test strains in this study were able to use L-aspartate and L-malate, while the ΔphbC1C2 mutant showed enhanced ability to use D-aspartate and D-malate. Although less abundant in nature than L-amino acids, D-amino acids, including D-aspartate, have been detected and play diverse roles in plants, bacteria, and animals (36,37). Transport and oxidization of D-malate into pyruvate by E. coli have been demonstrated (38).…”

Section: Discussionmentioning

confidence: 99%

Coordinated Regulation of the Size and Number of Polyhydroxybutyrate Granules by Core and Accessory Phasins in the Facultative Microsymbiont Sinorhizobium fredii NGR234

Sun

et al. 2019

Appl Environ Microbiol

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The exact roles of various granule-associated proteins (GAPs) of polyhydroxybutyrate (PHB) are poorly investigated, particularly for bacteria associated with plants. In this study, four structural GAPs, named phasins PhaP1 to PhaP4, were identified and demonstrated as true phasins colocalized with PHB granules in Sinorhizobium fredii NGR234, a facultative microsymbiont of Vigna unguiculata and many other legumes. The conserved PhaP2 dominated in regulation of granule size under both free-living and symbiotic conditions. PhaP1, another conserved phasin, made a higher contribution than accessory phasins PhaP4 and PhaP3 to PHB biosynthesis at stationary phase. PhaP3, with limited phyletic distribution on the symbiosis plasmid of Sinorhizobium, was more important than PhaP1 in regulating PHB biosynthesis in V. unguiculata nodules. Under the test conditions, no significant symbiotic defects were observed for mutants lacking individual or multiple phaP genes. The mutant lacking two PHB synthases showed impaired symbiotic performance, while mutations in individual PHB synthases or a PHB depolymerase yielded no symbiotic defects. This phenomenon is not related to either the number or size of PHB granules in test mutants within nodules. Distinct metabolic profiles and cocktail pools of GAPs of different phaP mutants imply that core and accessory phasins can be differentially involved in regulating other cellular processes in the facultative microsymbiont S. fredii NGR234. IMPORTANCE Polyhydroxybutyrate (PHB) granules are a store of carbon and energy in bacteria and archaea and play an important role in stress adaptation. Recent studies have highlighted distinct roles of several granule-associated proteins (GAPs) in regulating the size, number, and localization of PHB granules in free-living bacteria, though our knowledge of the role of GAPs in bacteria associated with plants is still limited. Here we report distinct roles of core and accessory phasins associated with PHB granules of Sinorhizobium fredii NGR234, a broad-host-range microsymbiont of diverse legumes. Core phasins PhaP2 and PhaP1 are conserved major phasins in free-living cells. PhaP2 and accessory phasin PhaP3, encoded by an auxiliary gene on the symbiosis plasmid, are major phasins in nitrogen-fixing bacteroids in cowpea nodules. GAPs and metabolic profiles can vary in different phaP mutants. Contrasting symbiotic performances between mutants lacking PHB synthases, depolymerase, or phasins were revealed.

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New Insights Into the Mechanisms and Biological Roles of D-Amino Acids in Complex Eco-Systems

Cited by 145 publications

References 135 publications

Structure and kinetic properties of humand‐aspartate oxidase, the enzyme‐controllingd‐aspartate levels in brain

Structure and kinetic properties of humand‐aspartate oxidase, the enzyme‐controllingd‐aspartate levels in brain

An active β‐lactamase is a part of an orchestrated cell wall stress resistance network of Bacillus subtilis and related rhizosphere species

Coordinated Regulation of the Size and Number of Polyhydroxybutyrate Granules by Core and Accessory Phasins in the Facultative Microsymbiont Sinorhizobium fredii NGR234

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