The Effects of the Metal Ion Substitution into the Active Site of Metalloenzymes: A Theoretical Insight on Some Selected Cases

Prejanò, Mario; Alberto, Marta E.; Russo, Nino; Toscano, Marirosa; Marino, Tiziana

doi:10.3390/catal10091038

Cited by 45 publications

(22 citation statements)

References 144 publications

(315 reference statements)

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“…A single metal binding site identified in the crystal structure of Xyl-CE4 was correspondingly interpreted as Co 2+ without further corroboration ( Fig 3B ). Zn 2+ , the optimal ion for most CE4 enzymes [ 22 ], decreased the activity of Xyl-CE4 emphasizing the importance of identifying the optimal metal ions for each metalloenzyme.…”

Section: Resultsmentioning

confidence: 99%

Structural and biophysical characterization of the multidomain xylanase Xyl

2022

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The depletion of fossil fuels, associated pollution, and resulting health hazards are of concern worldwide. Woody biomass constitutes an alternative source of cleaner and renewable energy. The efficient use of woody biomass depends on xylan depolymerisation as the endo-β-1,4-xylopyranosyl homopolymer is the main component of hemicellulose, the second most abundant component of wood. Xylan depolymerisation is achieved by hemicellulolytic xylanases of glycoside hydrolase (GH) families 5, 8, 10, 11, 30 and 43 of the CAZY database. We analysed a multidomain xylanase (Xyl) from the hindgut metagenome of the snouted harvester termite Trinervitermes trinervoides that releases xylobiose and xylotriose from beech and birch xylan and wheat arabinoxylan. The four domains of Xyl include an N-terminal GH11 xylanase domain, two family 36-like carbohydrate-binding domains CBM36-1 and 2, and a C-terminal CE4 esterase domain. Previous analyses indicated that CBM36-1 deletion slightly increased GH11 catalysis at low pH whereas removal of both CBMs decreased xylanase activity at 60°C from 90 to 56%. Possible cooperativity between the domains suggested by these observations was explored. A crystal structure of the two-domain construct, GH11-CBM36-1, confirmed the structure of the GH11 domain whereas the CBM36-1 domain lacked electron density, possibly indicating a random orientation of the CBM36-1 domain around the GH11 domain. Isothermal titration calorimetry (ITC) experiments similarly did not indicate specific interactions between the individual domains of Xyl supporting a “beads-on-a-string” model for Xyl domains.

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Section: Resultsmentioning

confidence: 99%

Structural and biophysical characterization of the multidomain xylanase Xyl

2022

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“…We consider that for the proposal before mentioned and for our consolidated experience on the topic, the cluster model size represents an adequate combination of chemical and computational accuracy and efficiency to describe the chemical events underlying the inhibition. However, the cluster model is not without limitations − but able to discriminate among different mechanisms providing information to be exploited to generate new candidate LAT1 inhibitors …”

Section: Computational Methodsmentioning

confidence: 99%

Computational Study Reveals the Role of Water Molecules in the Inhibition Mechanism of LAT1 by 1,2,3-Dithiazoles

Prejanò

Romeo

Serra

et al. 2021

J. Chem. Inf. Model.

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The L-type amino acid transporter LAT1, involved in many biological processes including the overexpression of some tumors, is considered a potential pharmacological target. The 1,2,3-Dithiazole scaffold was predicted to inhibit LAT1 by the formation of an intermolecular disulfide bond with the thiolate group of cysteine(s). As a result of the identification of these irreversible covalent inhibitors, we decided to deeply investigate the recognition stage and the covalent interaction, characterizing the chemical structures of the selected ligands. With the aim to provide new insights into the access of the ligands to the binding pocket and to reveal the residues involved in the inhibition, we performed docking, molecular dynamics simulations, and density functional theory-based investigation of three 1,2,3-dithiazoles against LAT1. Our computational analysis further highlighted the crucial role played by water molecules in the inhibition mechanism. The results here presented are consistent with experimental observations and provide insights that can be helpful for the rational design of new-to-come LAT1’s inhibitors.

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“…ey are more distinct than nontransition metallic compounds due to their transition metals possessing unpaired electrons from partially filled d electrons and their variable oxidation states, which are involved in various biological processes [29,[64][65][66][67][68]. ese processes are electron transfer, catalysis, and structural functions, which are often associated with active sites of enzymes and proteins [69][70][71][72].…”

Section: Transition Metal Complexes (Coordination Compounds) As Antic...mentioning

confidence: 99%

Manganese Schiff Base Complexes, Crystallographic Studies, Anticancer Activities, and Molecular Docking

Odularu

2022

Journal of Chemistry

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Choice of ligands is significant to successful synthesis of metal complexes (coordination compounds). This study reports the use of Schiff base as the right ligand to control the poor bioavailability and neurodegenerative toxicity challenges of manganese ion. In line with this study, document analysis was used as the methodological approach to evaluate the significance of Schiff base ligands in easing these manganese’s challenges and aligning the resultant coordination compounds (manganese Schiff base complexes) as therapeutic agents in anticancer studies. Report also involves crystallographic studies where single crystal X-ray crystallography was used as a chemical characterization technique. In addition, molecular docking studies, MOE2008, and AutoDock software were used to reveal the mode of interaction between the Schiff base and the manganese(II) and (III) ions, as well as scrutinizing the biological efficacy of the manganese(II) and manganese(III) Schiff bases coordination compounds as anticancer agents against some anticancer cell lines. Conclusion drawn was that manganese(II) and manganese(III) Schiff bases coordination compounds gave more active and potent activities than the corresponding Schiff bases. As a result, challenges of neurodegenerative toxicity and poor bioavailability of manganese ion were overcome, and the chelation therapy was fulfilled. Results from single crystal X-ray crystallography confirmed the successful synthesis of manganese(II) and manganese(III) Schiff bases coordination compounds and revealed the mechanism of reaction, while the molecular docking buttressed the biological activities of the Schiff base ligand and manganese Schiff base coordination compounds by portraying the structure activity relationship (SAR) between either Schiff base or the manganese Schiff base coordination compounds and the virtual cancer cell line (receptor protein), where hits were obtained for lead optimizations.

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The Effects of the Metal Ion Substitution into the Active Site of Metalloenzymes: A Theoretical Insight on Some Selected Cases

Cited by 45 publications

References 144 publications

Structural and biophysical characterization of the multidomain xylanase Xyl

Structural and biophysical characterization of the multidomain xylanase Xyl

Computational Study Reveals the Role of Water Molecules in the Inhibition Mechanism of LAT1 by 1,2,3-Dithiazoles

Manganese Schiff Base Complexes, Crystallographic Studies, Anticancer Activities, and Molecular Docking

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