On the catalytic role of the active site residue E121 of E. coli l-aspartate oxidase

Tedeschi, Gioacchino; Nonnis, Simona; Strumbo, Bice; Cruciani, Gabriele; Carosati, Emanuele; Negri, Armando

doi:10.1016/j.biochi.2010.06.015

Cited by 14 publications

(18 citation statements)

References 33 publications

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“…The catalytic characteristics of the PpLASPO active site mutants support the general findings of mutational studies on LASPOs typified by EcLASPO performed previously [14,15] with additional data on residues Q242 and T259 suggesting significant roles that are supported by the structural data on the E. coli enzyme. However, the higher activity of PpLASPO, and its promiscuous recognition of both l-asparagine and l-glutamate as substrates, if with low activity, identify PpLASPO as a preferred candidate enzyme for directed evolution studies towards AAOs of altered substrate specificity for biotechnological applications.…”

Section: Resultssupporting

confidence: 80%

“…The binding of succinate to the structure of the E. coli LASPO allowed site-directed mutagenesis studies to be performed on that enzyme, with roles in substrate binding and catalysis attributed to the side chains [14,15]. The results of those studies can be compared with the data from the PpLASPO enzyme herein.…”

Section: Discussionmentioning

confidence: 99%

“…Crystallisation of an inactive mutant, R386L, resulted in a further structure [13], this time complexed with FAD and the ligand succinate, in which it was revealed that a rotation of the capping domain on FAD binding resulted in the completion of the active site in a cleft between the capping and flavin binding domains. Mutational analyses of the enzyme [14,15], coupled with the succinate-complex structure, suggested roles in substrate binding and catalysis for many active site residues (vide infra).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cloning, expression, characterisation and mutational analysis of l-aspartate oxidase from Pseudomonas putida

Leese¹,

Fotheringham²,

Escalettes³

et al. 2013

Journal of Molecular Catalysis B: Enzymatic

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Section: Resultssupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cloning, expression, characterisation and mutational analysis of l-aspartate oxidase from Pseudomonas putida

Leese¹,

Fotheringham²,

Escalettes³

et al. 2013

Journal of Molecular Catalysis B: Enzymatic

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“…We consider that AspC-mediated aspartate metabolism functions as a coordinating mechanism of the E. coli cell cycle, as it is an important metabolic pathway connecting sugar,amino acid and fatty acid synthesis. It is known that L-aspartate is involved in the biosynthesis of multifarious substances including amino acids, mDAP (meso-diaminopimelate), purine and pyrimidine nucleotides, NAD+, and pantothenic acid [43]–[48]. CoA, an important coenzyme derived from pantothenic acid, is responsible for amino acid metabolism, tricarboxylic acid cycle (TCA cycle) and fatty acid synthesis [49].…”

Section: Discussionmentioning

confidence: 99%

AspC-Mediated Aspartate Metabolism Coordinates the Escherichia coli Cell Cycle

Liu

Qimuge²,

Hao³

et al. 2014

PLoS ONE

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BackgroundThe fast-growing bacterial cell cycle consists of at least two independent cycles of chromosome replication and cell division. To ensure proper cell cycles and viability, chromosome replication and cell division must be coordinated. It has been suggested that metabolism could affect the Escherichia coli cell cycle, but the idea is still lacking solid evidences.Methodology/Principle FindingsWe found that absence of AspC, an aminotransferase that catalyzes synthesis of aspartate, led to generation of small cells with less origins and slow growth. In contrast, excess AspC was found to exert the opposite effect. Further analysis showed that AspC-mediated aspartate metabolism had a specific effect in the cell cycle, as only extra aspartate of the 20 amino acids triggered production of bigger cells with more origins per cell and faster growth. The amount of DnaA protein per cell was found to be changed in response to the availability of AspC. Depletion of (p)ppGpp by ΔrelAΔspoT led to a slight delay in initiation of replication, but did not change the replication pattern found in the ΔaspC mutant.Conclusion/SignificancesThe results suggest that AspC-mediated metabolism of aspartate coordinates the E. coli cell cycle through altering the amount of the initiator protein DnaA per cell and the division signal UDP-glucose. Furthermore, AspC sequence conservation suggests similar functions in other organisms.

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“…In particular, the latter allow the analysis of structurally diverse data series. GRID MIFs [13] have been applied to many areas of computational drug discovery, including 3D-QSAR [14], docking [15], high-throughput virtual screening [16], ADME profiling, kinetic [17, 18] and metabolism prediction [19] of early drug candidates. In this manuscript we explore the capability of the GRIND approach to derive predictive 3D-QSAR models for a set of diastereomeric benzopyrano[3,4b][1,4]oxazines.…”

Section: Introductionmentioning

confidence: 99%

2D- and 3D-QSAR studies of a series of benzopyranes and benzopyrano[3,4b][1,4]-oxazines as inhibitors of the multidrug transporter P-glycoprotein

Jabeen

Wetwitayaklung

Chiba

et al. 2013

J Comput Aided Mol Des

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The ATP-binding cassette efflux transporter P-glycoprotein (P-gp) is notorious for contributing to multidrug resistance in antitumor therapy. Due to its expression in many blood-organ barriers, it also influences the pharmacokinetics of drugs and drug candidates and is involved in drug/drug- and drug/nutrient interactions. However, due to lack of structural information the molecular basis of ligand/transporter interaction still needs to be elucidated. Towards this goal, a series of Benzopyranes and Benzopyrano[3,4b][1,4]oxazines have been synthesized and pharmacologically tested for their ability to inhibit P-gp mediated daunomycin efflux. Both quantitative structure–activity relationship (QSAR) models using simple physicochemical and novel GRID-independent molecular descriptors (GRIND) were established to shed light on the structural requirements for high P-gp inhibitory activity. The results from 2D-QSAR showed a linear correlation of vdW surface area (Å2) of hydrophobic atoms with the pharmacological activity. GRIND (3D-QSAR) studies allowed to identify important mutual distances between pharmacophoric features, which include one H-bond donor, two H-bond acceptors and two hydrophobic groups as well as their distances from different steric hot spots of the molecules. Activity of the compounds particularly increases with increase of the distance of an H-bond donor or a hydrophobic feature from a particular steric hot spot of the benzopyrane analogs.Electronic supplementary materialThe online version of this article (doi:10.1007/s10822-013-9635-9) contains supplementary material, which is available to authorized users.

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On the catalytic role of the active site residue E121 of E. coli l-aspartate oxidase

Cited by 14 publications

References 33 publications

Cloning, expression, characterisation and mutational analysis of l-aspartate oxidase from Pseudomonas putida

Cloning, expression, characterisation and mutational analysis of l-aspartate oxidase from Pseudomonas putida

AspC-Mediated Aspartate Metabolism Coordinates the Escherichia coli Cell Cycle

2D- and 3D-QSAR studies of a series of benzopyranes and benzopyrano[3,4b][1,4]-oxazines as inhibitors of the multidrug transporter P-glycoprotein

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