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  • 1
    Online Resource
    Online Resource
    The Pleiotropic Function of Human Sirtuins as Modulators of Metabolic Pathways and Viral Infections
    MDPI AG ; 2021
    In:  Cells Vol. 10, No. 2 ( 2021-02-21), p. 460-
    Details
    In: Cells, MDPI AG, Vol. 10, No. 2 ( 2021-02-21), p. 460-
    Abstract: Sirtuins (SIRTs) are nicotinamide adenine dinucleotide-dependent histone deacetylases that incorporate complex functions in the mechanisms of cell physiology. Mammals have seven distinct members of the SIRT family (SIRT1-7), which play an important role in a well-maintained network of metabolic pathways that control and adapt the cell to the environment, energy availability and cellular stress. Until recently, very few studies investigated the role of SIRTs in modulating viral infection and progeny. Recent studies have demonstrated that SIRT1 and SIRT2 are promising antiviral targets because of their specific connection to numerous metabolic and regulatory processes affected during infection. In the present review, we summarize some of the recent progress in SIRTs biochemistry and their emerging function as antiviral targets. We also discuss the potential of natural polyphenol-based SIRT modulators to control their functional roles in several diseases including viral infections.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells10020460
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2661518-6
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  • 2
    Online Resource
    Online Resource
    The Interaction of Human Glutathione Transferase GSTA1-1 with Reactive Dyes
    MDPI AG ; 2021
    In:  Molecules Vol. 26, No. 8 ( 2021-04-20), p. 2399-
    Details
    In: Molecules, MDPI AG, Vol. 26, No. 8 ( 2021-04-20), p. 2399-
    Abstract: Human glutathione transferase A1-1 (hGSTA1-1) contributes to developing resistance to anticancer drugs and, therefore, is promising in terms of drug-design targets for coping with this phenomenon. In the present study, the interaction of anthraquinone and diazo dichlorotriazine dyes (DCTD) with hGSTA1-1 was investigated. The anthraquinone dye Procion blue MX-R (PBMX-R) appeared to interact with higher affinity and was selected for further study. The enzyme was specifically and irreversibly inactivated by PBMX-R, following a biphasic pseudo-first-order saturation kinetics, with approximately 1 mol of inhibitor per mol of the dimeric enzyme being incorporated. Molecular modeling and protein chemistry data suggested that the modified residue is the Cys112, which is located at the entrance of the solvent channel at the subunits interface. The results suggest that negative cooperativity exists upon PBMX-R binding, indicating a structural communication between the two subunits. Kinetic inhibition analysis showed that the dye is a competitive inhibitor towards glutathione (GSH) and mixed-type inhibitor towards 1-chloro-2,4-dinitrobenzene (CDNB). The present study results suggest that PBMX-R is a useful probe suitable for assessing by kinetic means the drugability of the enzyme in future drug-design efforts.
    Type of Medium: Online Resource
    ISSN: 1420-3049
    URL: Article
    DOI: 10.3390/molecules26082399
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2008644-1
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  • 3
    Online Resource
    Online Resource
    Copper-induced oxidative cleavage of glutathione transferase F1-1 from Zea mays
    Elsevier BV ; 2019
    In:  International Journal of Biological Macromolecules Vol. 128 ( 2019-05), p. 493-498
    Details
    In: International Journal of Biological Macromolecules, Elsevier BV, Vol. 128 ( 2019-05), p. 493-498
    Type of Medium: Online Resource
    ISSN: 0141-8130
    URL: Article
    DOI: 10.1016/j.ijbiomac.2019.01.128
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 1483284-7
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    The Interaction of the Flavonoid Fisetin with Human Glutathione Transferase A1-1
    MDPI AG ; 2021
    In:  Metabolites Vol. 11, No. 3 ( 2021-03-23), p. 190-
    Details
    In: Metabolites, MDPI AG, Vol. 11, No. 3 ( 2021-03-23), p. 190-
    Abstract: Glutathione transferases (GSTs) are a family of Phase II detoxification enzymes that are involved in the development of the multidrug resistance (MDR) mechanism in cancer cells and therefore affect the clinical outcome of cancer chemotherapy. The discovery of nontoxic natural compounds as inhibitors for GSTs is a promising approach for chemosensitizing and reversing MDR. Fisetin (7,3′,4′-flavon-3-ol) is a plant flavonol present in many plants and fruits. In the present work, the interaction of fisetin with human glutathione transferase A1-1 (hGSTA1-1) was investigated. Kinetic analysis revealed that fisetin is a reversible inhibitor for hGSTA1-1 with IC50 1.2 ± 0.1 μΜ. It functions as a mixed-type inhibitor toward glutathione (GSH) and as a noncompetitive inhibitor toward the electrophile substrate 1-chloro-2,4-dinitrobenzene (CDNB). In silico molecular modeling and docking predicted that fisetin binds at a distinct location, in the solvent channel of the enzyme, and occupies the entrance of the substrate-binding sites. Treatment of proliferating human epithelial colorectal adenocarcinoma cells (CaCo-2) with fisetin causes a reduction in the expression of hGSTA1-1 at the mRNA and protein levels. In addition, fisetin inhibits GST activity in CaCo-2 cell crude extract with an IC50 (2.5 ± 0.1 μΜ), comparable to that measured using purified recombinant hGSTA1-1. These actions of fisetin can provide a synergistic role toward the suppression and chemosensitization of cancer cells. The results of the present study provide insights into the development of safe and effective GST-targeted cancer chemosensitizers.
    Type of Medium: Online Resource
    ISSN: 2218-1989
    URL: Article
    DOI: 10.3390/metabo11030190
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662251-8
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  • 5
    Online Resource
    Online Resource
    Myricetin as a Potential Adjuvant in Chemotherapy: Studies on the Inhibition of Human Glutathione Transferase A1–1
    MDPI AG ; 2022
    In:  Biomolecules Vol. 12, No. 10 ( 2022-09-24), p. 1364-
    Details
    In: Biomolecules, MDPI AG, Vol. 12, No. 10 ( 2022-09-24), p. 1364-
    Abstract: Glutathione transferases (GSTs) are a family of Phase II detoxification enzymes that are involved in the development of multi-drug resistance (MDR) phenomena toward chemotherapeutic agents. GST inhibitors are considered candidate compounds able to chemomodulate and reverse MDR. The natural flavonoid myricetin (MYR) has been shown to exhibit a wide range of pharmacological functions, including antitumor activity. In the present work, the interaction of MYR with human glutathione transferase A1–1 (hGSTA1–1) was investigated by kinetics inhibition analysis and molecular modeling studies. The results showed that MYR binds with high affinity to hGSTA1–1 (IC50 2.1 ± 0.2 μΜ). It functions as a non-competitive inhibitor towards the electrophile substrate 1-chloro−2,4-dinitrobenzene (CDNB) and as a competitive inhibitor towards glutathione (GSH). Chemical modification studies with the irreversible inhibitor phenethyl isothiocyanate (PEITC), in combination with in silico molecular docking studies allowed the prediction of the MYR binding site. MYR appears to bind at a distinct location, partially overlapping the GSH binding site (G-site). The results of the present study show that MYR is a potent inhibitor of hGSTA1–1 that can be further exploited towards the development of natural, safe, and effective GST-targeted cancer chemosensitizers.
    Type of Medium: Online Resource
    ISSN: 2218-273X
    URL: Article
    DOI: 10.3390/biom12101364
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2701262-1
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  • 6
    Online Resource
    Online Resource
    Ligand-induced glutathione transferase degradation as a therapeutic modality: Investigation of a new metal-mediated affinity cleavage strategy for human GSTP1-1
    Elsevier BV ; 2018
    In:  International Journal of Biological Macromolecules Vol. 116 ( 2018-09), p. 84-90
    Details
    In: International Journal of Biological Macromolecules, Elsevier BV, Vol. 116 ( 2018-09), p. 84-90
    Type of Medium: Online Resource
    ISSN: 0141-8130
    URL: Article
    DOI: 10.1016/j.ijbiomac.2018.04.187
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2018
    detail.hit.zdb_id: 1483284-7
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Probing the Role of the Conserved Arg174 in Formate Dehydrogenase by Chemical Modification and Site-Directed Mutagenesis
    MDPI AG ; 2021
    In:  Molecules Vol. 26, No. 5 ( 2021-02-25), p. 1222-
    Details
    In: Molecules, MDPI AG, Vol. 26, No. 5 ( 2021-02-25), p. 1222-
    Abstract: The reactive adenosine derivative, adenosine 5′-O-[S-(4-hydroxy-2,3-dioxobutyl)]-thiophosphate (AMPS-HDB), contains a dicarbonyl group linked to the purine nucleotide at a position equivalent to the pyrophosphate region of NAD+. AMPS-HDB was used as a chemical label towards Candida boidinii formate dehydrogenase (CbFDH). AMPS-HDB reacts covalently with CbFDH, leading to complete inactivation of the enzyme activity. The inactivation kinetics of CbFDH fit the Kitz and Wilson model for time-dependent, irreversible inhibition (KD = 0.66 ± 0.15 mM, first order maximum rate constant k3 = 0.198 ± 0.06 min−1). NAD+ and NADH protects CbFDH from inactivation by AMPS-HDB, showing the specificity of the reaction. Molecular modelling studies revealed Arg174 as a candidate residue able to be modified by the dicarbonyl group of AMPS-HDB. Arg174 is a strictly conserved residue among FDHs and is located at the Rossmann fold, the common mononucleotide-binding motif of dehydrogenases. Arg174 was replaced by Asn, using site-directed mutagenesis. The mutant enzyme CbFDHArg174Asn was showed to be resistant to inactivation by AMPS-HDB, confirming that the guanidinium group of Arg174 is the target for AMPS-HDB. The CbFDHArg174Asn mutant enzyme exhibited substantial reduced affinity for NAD+ and lower thermostability. The results of the study underline the pivotal and multifunctional role of Arg174 in catalysis, coenzyme binding and structural stability of CbFDH.
    Type of Medium: Online Resource
    ISSN: 1420-3049
    URL: Article
    DOI: 10.3390/molecules26051222
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2008644-1
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  • 8
    Online Resource
    Online Resource
    Development of Staphylococcus Enzybiotics: The Ph28 Gene of Staphylococcus epidermidis Phage PH15 Is a Two-Domain Endolysin
    MDPI AG ; 2020
    In:  Antibiotics Vol. 9, No. 4 ( 2020-03-30), p. 148-
    Details
    In: Antibiotics, MDPI AG, Vol. 9, No. 4 ( 2020-03-30), p. 148-
    Abstract: Given the worldwide increase in antibiotic resistant bacteria, bacteriophage derived endolysins represent a very promising new alternative class of antibacterials in the fight against infectious diseases. Endolysins are able to degrade the prokaryotic cell wall, and therefore have potential to be exploited for biotechnological and medical purposes. Staphylococcus epidermidis is a Gram-positive multidrug-resistant (MDR) bacterium of human skin. It is a health concern as it is involved in nosocomial infections. Genome-based screening approach of the complete genome of Staphylococcus virus PH15 allowed the identification of an endolysin gene (Ph28; NCBI accession number: YP_950690). Bioinformatics analysis of the Ph28 protein predicted that it is a two-domain enzyme composed by a CHAP (22-112) and MurNAc-LAA (171-349) domain. Phylogenetic analysis and molecular modelling studies revealed the structural and evolutionary features of both domains. The MurNAc-LAA domain was cloned, and expressed in E. coli BL21 (DE3). In turbidity reduction assays, the recombinant enzyme can lyse more efficiently untreated S. epidermidis cells, compared to other Staphylococcus strains, suggesting enhanced specificity for S. epidermidis. These results suggest that the MurNAc-LAA domain from Ph28 endolysin may represent a promising new enzybiotic.
    Type of Medium: Online Resource
    ISSN: 2079-6382
    URL: Article
    DOI: 10.3390/antibiotics9040148
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2681345-2
    SSG: 15,3
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