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  • 1. Ertan-Bolelli, Tugba
    et al.
    Bolelli, Kayhan
    Musdal, Yaman
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Yildiz, Ilkay
    Aki-Yalcin, Esin
    Mannervik, Bengt
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Yalcin, Ismail
    Design and synthesis of 2-substituted-5-(4-trifluoromethylphenyl-sulphonamido)benzoxazole derivatives as human GST P1-1 inhibitors2018In: Artificial Cells, Nanomedicine, and Biotechnology, ISSN 2169-1401, Vol. 46, no 3, p. 510-517Article in journal (Refereed)
    Abstract [en]

    The glutathione transferases (GSTs) are a family of widely distributed Phase II detoxification enzymes. GST P1-1 is frequently overexpressed in rat and human tumours. It is suggested that overexpression of hGST P1-1 by human tumor cells may play a role in resistance to cancer chemotherapy. Hence, hGST P1-1 can be a promising target for cancer treatment. In this study, new hGST P1-1 inhibitors, 2-(4-substitutedphenyl/benzyl)-5-(4-trifluoromethylphenylsulphonamido) benzoxazole derivatives (Va-Vk) have been designed and synthesized. Surprisingly, in vitro hGST P1-1 enzyme inhibition studies demonstrated that all of the tested compounds except Vj had better activity than the reference drug EA and it is also correlated with the docking results. Additionally we compared the interactions with hGST P1-1 enzyme of newly synthesized compound Vh (bearing CF3 group) and previously synthesized compound 5f (bearing NO2 group). According to the docking results, compound Vh bound to the hGST P1-1 enzyme with a higher affinity compared to 5f. Therefore, we can consider that these data make a sense and can explain its higher activity. The compounds that obtained from this research could be used as scaffolds in design of new potent hGST P1-1 inhibitors useful in the treatment of the resistance of cancer chemotherapy.

  • 2.
    Hegazy, Usama M.
    et al.
    National Research Centre (NRC), Egypt.
    Musdal, Yaman
    Hacettepe University, Turkey.
    Mannervik, Bengt
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Hidden Allostery in Human Glutathione Transferase P1-1 Unveiled by Unnatural Amino Acid Substitutions and Inhibition Studies2013In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 425, no 9, p. 1509-1514Article in journal (Refereed)
    Abstract [en]

    Conventional steady-state kinetic studies of the dimeric human glutathione transferase (GST) P1-1 do not reveal obvious deviations from Michaelis-Menten behavior. By contrast, engineering of the key residue Y50 of the lock-and-key motif in the subunit interface reveals allosteric properties of the enzyme. The low-activity mutant Y50C, characterized by 150-fold decreased kat and 300-fold increased K-M(GSH) values, displays an apparent Hill coefficient of 0.82 +/- 0.22. Chemical alkylation of the sulfhydryl group of Y50C by unnatural n-butyl or n-pentyl substitutions enhances the catalytic efficiency k(cat)/K-M(GSH) to near the wild-type value but still yields Hill coefficients of 0.61 +/- 0.08 and 0.86 +/- 0.1, respectively. Thus, allosteric kinetic behavior is not dependent on low activity of the enzyme. On the other hand, S-cyclobutylmethyl-substituted Y50C, which also displays high catalytic efficiency, has a Hill coefficient of 0.99 +/- 0.11, showing that subtle differences in structure at the subunit interface influence the complex kinetic behavior. Furthermore, inhibition studies of native GST P1-1 using ethacrynic acid demonstrate that a ligand bound noncovalently to the wild-type enzyme also can elicit allosteric kinetic behavior. Thus, we conclude that the GST P1-1 structure has intrinsic allostery that becomes overt under some, but not all, ambient conditions.

  • 3.
    Lindström, Helena
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mazari, Aslam M. A.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Musdal, Yaman
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mannervik, Bengt
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Inhibition characteristics of equine steroid isomerase EcaGST A3-3Manuscript (preprint) (Other academic)
    Abstract [en]

    Equine glutathione transferase A3-3 (EcaGST A3-3) belongs to the superfamily of detoxifying enzymes found in all organisms. However it is also the most efficient steroid double-bond isomerase known in mammals. In contrast to the rodents, Equus ferus caballus shares the steroidogenic pathway with Homo sapiens, which makes it a more suitable model for human steroidogenesis than the murine one. Inhibition of EcaGST A3-3 might help treat reproductive and neurodegenerative disorders. We screened an FDA-approved library of 1040 compounds for the ability as novel inhibitors of EcaGST A3-3. Our results revealed anthralin, sennoside A, tannic acid and ethacrynic acid as the most potent, submicromolar-range inhibitors of EcaGST A3-3 with the natural substrate Δ5-androstene-3,17-dione.

  • 4.
    Musdal, Yaman
    et al.
    Hacettepe University, Turkey.
    Ertan-Bolelli, Tugba
    Bolelli, Kayhan
    Yilmaz, Serap
    Ceyhan, Deniz
    Hegazy, Usama
    Mannervik, Bengt
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Aksoy, Yasemin
    Inhibition of human glutathione transferase P1-1 by novel benzazole derivatives2012In: Türk Biyokimya Dergisi, ISSN 0250-4685, E-ISSN 1303-829X, Vol. 37, no 4, p. 431-436Article in journal (Refereed)
    Abstract [en]

    Objective: Glutathione transferases (GST) are multifunctional enzymes involved in detoxication, drug resistance, cell signaling and apoptosis. The inhibitory effects of novel benzazole derivatives were tested on human GST P1-1 to find new agents for overcoming drug resistance in cancer cells. Methods: GST P1-1 was heterogously expressed in E. coli strain XL-1 Blue and purified using S-hexylglutathione-Sepharose 6B affinity chromatography. The effect of 33 potential inhibitors on enzymatic activity was assayed spectrophotometrically with 1-chloro-2,4-dinitrobenzene (CDNB) as well as with the alternative substrate phenethyl isothiocyanate (PEITC). Results: Compound-18(N-[2-(4-chloro-benzyl)-benzooxazol-5-yl]-4-nitro-benzenesulfonamide) was the most potent inhibitor found with an IC50 value of approximately 10 mu M with respect to CDNB and a somewhat less strong inhibitor (45 % inhibition at 40 mu M) with PEITC as substrate. Compound-18 showed mixed inhibition with GSH and uncompetitive inhibition with CDNB with the K-i values 6.3 +/- 0.7 mu M and 11.8 +/- 3.4 mu M, respectively. Conclusion: Compound-18 is a potent inhibitor of GST P1-1. It may serve as a lead for further chemical modifications for increased potency. Additional studies will elucidate the effects of the inhibitor on cancer cells.

  • 5.
    Musdal, Yaman
    et al.
    Uppsala University, Sweden; Hacettepe University, Turkey.
    Hegazy, Usama M.
    Aksoy, Yasemin
    Mannervik, Bengt
    Stockholm University, Faculty of Science, Department of Neurochemistry. Uppsala University, Sweden.
    FDA-approved drugs and other compounds tested as inhibitors of human glutathione transferase P1-12013In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 205, no 1, p. 53-62Article in journal (Refereed)
    Abstract [en]

    Objective: Glutathione transferase P1-1 (GST P1-1) is often overexpressed in tumor cells and is regarded as a contributor to their drug resistance. Inhibitors of GST P1-1 are expected to counteract drug resistance and may therefore serve as adjuvants in the chemotherapy of cancer by increasing the efficacy of cytostatic drugs. Finding useful inhibitors among compounds used for other indications would be a shortcut to clinical applications and a search for GST P1-1 inhibitors among approved drugs and other compounds was therefore conducted. Methods: We tested 1040 FDA-approved compounds as inhibitors of the catalytic activity of purified human GST P1-1 in vitro. Results: We identified chlorophyllide, merbromine, hexachlorophene, and ethacrynic acid as the most effective GST P1-1 inhibitors with IC50 values in the low micromolar range. For comparison, these compounds were even more potent in the inhibition of human GST A3-3, an enzyme implicated in steroid hormone biosynthesis. In distinction from the other inhibitors, which showed conventional inhibition patterns, the competitive inhibitor ethacrynic acid elicited strong kinetic cooperativity in the glutathione saturation of GST P1-1. Apparently, ethacrynic acid serves as an allosteric inhibitor of the enzyme. Conclusion and practical implications: In their own right, the compounds investigated are less potent than desired for adjuvants in cancer chemotherapy, but the structures of the most potent inhibitors could serve as leads for the synthesis of more efficient adjuvants.

  • 6.
    Musdal, Yaman
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Mannervik, Bengt
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Substrate specificities of two tau class glutathione transferases inducible by 2,4,6-trinitrotoluene in poplar2015In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1850, no 9, p. 1877-1883Article in journal (Refereed)
    Abstract [en]

    Background: The genome of poplar (Populus trichocarpa) encodes 81 glutathione transferases (GSTs) annotated in eight distinct classes. The tau class is considered the most versatile in the biotransformation of xenobiotics and is composed of 58 GSTs. Two of the enzymes, GSTU16 and GSTU45, have particular interest since their expression is induced by exposure of poplar tissues to 2,4,6-trinitrotoluene (TNT) and could potentially be involved in the metabolism of this toxic environmental contaminant.

    Results: DNA encoding these GSTs was synthesized and the proteins were heterologously expressed in Escherichia coli and the purified enzymes were characterized.

    Major conclusions: GSTU16 assayed with a number of conventional GST substrates showed the highest specific activity (60 mu mol min(-1) mg(-1)) with phenethyl isothiocyanate, 150-fold higher than that with CDNB. By contrast, GSTU45 showed CDNB as the most active substrate (3.3 mu mol min(-1) mg(-1)) whereas all of the 16 alternative substrates tested yielded significantly lower activities. Homology modeling suggested that the aromatic residues Phe10 and Tyr107 in the active site of GSTU16 are promoting the high activity with PEITC and other substrates with aromatic side-chains. Nonetheless, TNT was a poor substrate for GSTU16 as well as for GSTU45 with a specific activity of 0.05 nmol min(-1) mg(-1) for both enzymes. General significance: GSTU16 and GSTU45 do not play a major role in the degradation of TNT in poplar.

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