Docking of 4-oxalocrotonate tautomerase substrates: Implications for the catalytic mechanism

Soares, Thereza A.; Goodsell, David S.; Briggs, James M.; Ferreira, Ricardo; Olson, Arthur J.

doi:10.1002/(sici)1097-0282(199909)50:3<319::aid-bip7>3.0.co;2-8

Cited by 31 publications

(27 citation statements)

References 32 publications

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“…This anion stabilizing group is probably Arg39, as has already been proposed on the basis of both mutagenesis [7] and calculations. [8] Our goal was to convert 4-OT from an acid/base tautomerase into an enzyme that utilizes an imine (Schiff base) mechanism, since such enzymes have been engineered to catalyze synthetically useful transformations such as the aldol and retroaldol reaction. [9,10] Understanding the catalytic role played by the secondary amine group of Pro1 in the wild-type enzyme (wt4-OT) was crucial for this rational design.…”

Section: Introductionmentioning

confidence: 99%

Mutants of 4-Oxalocrotonate Tautomerase Catalyze the Decarboxylation of Oxaloacetate through an Imine Mechanism

et al. 2002

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Section: Introductionmentioning

confidence: 99%

Mutants of 4-Oxalocrotonate Tautomerase Catalyze the Decarboxylation of Oxaloacetate through an Imine Mechanism

et al. 2002

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“…10 6 sampled conformations. 47,52,53,56 Ideally, the lowest energy conformers should also belong to the most populated conformational cluster. This was the case for Amox based on an RMSD of 1.0 Å.…”

Section: Molecular Docking Calculationsmentioning

confidence: 99%

“…[46][47][48] A more detailed description of the methodology employed has been previously presented. 52,53 Coordinates and trajectories were visualized with the software VMD version 1.9.1. 54 The atomic coordinates for Amox and Gen were built and the geometry optimized with the software MarvinSketch 5.3.1.…”

Section: Computational Detailsmentioning

confidence: 99%

See 1 more Smart Citation

Metal Organic Frameworks for Selective Degradation of Amoxicillin in Biomedical Wastes

Paula

Barros

Wanderley

et al. 2018

J. Braz. Chem. Soc.

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The accumulation of antibiotics in wastewater has led to the development and spreading of antibiotic resistance in the environment. Amoxicillin (Amox), a beta-lactamic antibiotic, is one of the most frequently consumed antibiotics in the world. We have applied two metal-organic frameworks (MOFs) containing zinc(II) as platforms to degrade Amox. We have predicted the adsorption of this antibiotic via molecular docking calculations which have been further corroborated by means of Fourier transform infrared and UV-Vis spectroscopies, thermogravimetric analysis, X-ray diffraction and scanning microscopy measurements. We have subsequently performed mass spectrometry analysis of Amox@zeolitic imidazolate framework-8 (ZIF-8) and Amox@Zn(1,4-benzenedicarboxylate) (ZnBDC) to demonstrate the degradation of Amox upon contact with the Zn-containing frameworks. We propose a possible pathway for the degradation of Amox involving the cleavage of the four-membered β-lactam ring. These Zn-containing frameworks provide a biocompatible platform for the degradation in solution of Amox, which should also be suitable to degrade other β-lactam antibiotics.Keywords: β-lactamase activity, gentamicin, β-lactam catalysis, penicilloic and penilloic acids, biocompatible frameworks IntroductionIn the last decade, antibiotics have emerged as novel environmental pollutants. The widespread use of antibiotics in human and veterinary medicine, animal husbandry, plant production and aquaculture has led to high consumption and the gradual accumulation of antibiotics in the environment (e.g., wastewater, landfills, industrial and hospital effluents). [1][2][3][4][5][6] From 100,000 to 200,000 t of antibiotics are consumed per year in hospitals, homes, veterinary use and aquaculture throughout the world. On average, high-income countries generate ca. 0.5 kg of hazardous waste per bed per day whereas low-income countries generate ca. 0.2 kg. Furthermore, low-income countries do not separate hospital waste into hazardous or non-hazardous wastes, making the real quantity of hazardous waste much higher, as reported by the World Health Organization (WHO).Environmental accumulation of antibiotics has raised serious concerns about the induction of antibiotic resistance. [8][9][10] The exposure of bacteria to the subinhibitory antibiotic concentrations found in many natural environments such as sewage water and sludge, rivers, lakes and even drinking water is a crucial aspect of the current antibiotic resistance crisis.11-14 Furthermore, the incomplete absorption or metabolism of antibiotics in target organisms may lead to excretion rates from 5 to 90% of the dose in the form of metabolites or as parent compounds. 15,16 The chemical structure of antibiotics often contains cyclic moieties such as benzene rings, piperazine units, hexahydropyrimidines, sulfonamides, quinolone, and morpholine groups.5 Upon metabolic processing in humans and animals, these meta-stable compounds yield activated metabolites, which are continuously released in Metal Organic Framewor...

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“…A more detailed description of the methodology employed here can be found elsewhere. 46,47 Setup and molecular dynamics simulations MD simulations were performed for glutathione S-transferase isoforms AgGSTE5 and AgGSTE2 from Anopheles gambiae ( Table 1). High-resolution crystallographic structures of AgGSTE2 from A. gambiae were used as initial coordinates for simulations of the apo (PDB ID 2IL3) and the holoenzyme (PDB ID 2IMI) forms.…”

Section: Molecular Docking Of Ddt To Aggste Variantsmentioning

confidence: 99%

The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance inAnopheles gambiae

Pontes¹,

Maia²,

Lima³

et al. 2016

Journal of the Brazilian Chemical Society

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Glutathione S-transferases (GSTs) are enzymes capable of metabolizing cytotoxic compounds. The enzyme AgGSTE2, member of epsilon class GSTs (GSTE), is the most important GST conferring resistance to dichloro-diphenyl-trichloroethane (DDT) in Anopheles gambiae. We have investigated the conformational dynamics of three GSTE variants (GSTE2, GSTE2-I114T/F120L, GSTE5) from A. gambiae. Large-scale motions of helices H2 and H4 and conformational transition of the C-terminal governs the opening of the G-site and is expected to affect substrate binding and product release. This structural rearrangement places Glu116 (Glu120 in GSTE5) close of the thiol group of the tripeptide glutathione (GSH) cofactor, making this residue a candidate to act as a base in the activation of DDT. The structural rearrangement is noticeable for AgGSTE2-F120L, which has been shown to confer increased DDT-resistance. The other variants exhibit a more subtle rearrangement. These findings corroborate the hypothesis that the increase of the conformational dynamics of GST Epsilon class isoforms from A. gambiae promotes higher DDTase activity.Keywords: molecular dynamics simulation, evolutional constraint, positive and negative selection, metabolic resistance, malaria vector IntroductionGlutathione transferases (EC 2.5.1.18) are highly promiscuous proteins where broad functional promiscuity co-exists with highly conserved structural fold. Glutathione S-transferases (GSTs) constitute a large family of cytosolic and membrane-bound proteins that catalyze the nucleophilic addition of the tripeptide glutathione (GSH) to a variety of electrophilic toxins and drugs (xenobiotics), leading to their excretion. 1,2 Lately, several other activities have also been associated with GSTs, including steroid and leukotriene biosynthesis, peroxide degradation, doublebond cis-trans isomerization, dehydroascorbate reduction, Michael addition, and noncatalytic ligand binding and transport activity. 3 These polymorphic enzymes belong to supergene families whose members are generated by punctual mutations, gene duplication and alternative splicing. 4 The GST family is subdivided into several classes accordingly to its occurrence in different taxa.The number of isoforms per class varies widely, ranging from one to forty. 4 A single GST isoform is capable of conjugating glutathione to several hydrophobic substrates. Such promiscuity when coupled with the large number of isozymes generates a large range of potential substrates.Insects exhibit at least six classes of GSTs (Sigma, Omega, Theta, Zeta, Delta and Epsilon) with the first four classes present in almost all living organisms. 4,5 The Epsilon and Delta classes are arthropod specific and some members of these classes have been associated to insecticide resistance in culicid vectors. 5,6 The metabolism of toxic compounds in insects is conducted by a series of enzymes from different phases and GSTs act in phase II. GSTs metabolize these compounds in two ways: one has been cited above (through GSH conjugation) and the oth...

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Docking of 4-oxalocrotonate tautomerase substrates: Implications for the catalytic mechanism

Cited by 31 publications

References 32 publications

Mutants of 4-Oxalocrotonate Tautomerase Catalyze the Decarboxylation of Oxaloacetate through an Imine Mechanism

Mutants of 4-Oxalocrotonate Tautomerase Catalyze the Decarboxylation of Oxaloacetate through an Imine Mechanism

Metal Organic Frameworks for Selective Degradation of Amoxicillin in Biomedical Wastes

The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance inAnopheles gambiae

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