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  • Aslam, Muhammad, et al. (författare)
  • Transgenic Overexpression of Glutathione Transferase E7 in Drosophila Attenuates Toxicity of Organic Isothiocyanates Affecting Survival and Oviposition
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Organic isothiocyanates (ITCs) are allelochemicals produced by plants in order to combat insects and other herbivores. The compounds are toxic electrophiles that can be inactivated and conjugated with intracellular glutathione in reactions catalyzed by glutathione transferases (GSTs). The Drosophila melanogaster GSTE7 was heterologously expressed in Escherichia coli and purified for functional studies. The enzyme showed high catalytic activity with various isothiocyanates including phenethyl isothiocyanate (PEITC) and allyl isothiocyanate (AITC), which in millimolar dietary concentrations conferred toxicity to adult D. melanogaster leading to death or a shortened life-span of the flies. In situ hybridization revealed a maternal contribution of GSTE7 transcripts to embryos, and strongest zygotic expression in the digestive tract.  Transgenesis involving the GSTE7 gene controlled by an actin promoter produced viable flies expressing the GSTE7 transcript ubiquitously. Transgenic females show a significant extension in life-span when subjected to the same PEITC treatment as the wild-type flies. By contrast, transgenic male flies showed no significant effect in the first few days, and subsequently showed a somewhat lower survival rate. At 1 mM AITC concentration, no toxicity was noted. However, the oviposition activity was dramatically enhanced from a very low level in wild-type flies reared in the presence of 1 mM AITC to values an order of magnitude higher for the transgenic flies. The results demonstrate a clear protective effect of GSTE7 against exposure to ITC allelochemicals which can affect both life-span and fecundity of female flies.
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  • Lindström, Helena, et al. (författare)
  • Inhibition characteristics of equine steroid isomerase EcaGST A3-3
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • 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.
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  • Peer, Shawna M., et al. (författare)
  • Conservation of glutathione transferase mRNA and protein sequences similar to human GST Alpha 3 across diverse mammalian species
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Recently, the glutathione transferase A3-3 (GST A3-3) enzyme was identified as the most efficient enzyme that catalyzes isomerization of the precursors of testosterone, estradiol, and progesterone in the gonads of humans and horses. However, the presence of GST A3-3 orthologs with equally high isomerase activity has not been verified in other mammalian species. Identifying GSTA3 genes is challenging because of multiple GSTA gene duplications, so few genomes have a corresponding GSTA3 gene annotated. To improve our understanding of GSTA3 gene products and their functions across diverse vertebrate species, we cloned homologs of the horse and human GSTA3 mRNAs from the testes of dogs, goats, and gray short-tailed opossums, whose current genomes lack verified GSTA3 gene annotations. These novel GSTA mRNA and inferred protein sequences had a high level of conservation with human GSTA3 mRNA and protein sequences (> 70% and > 63% identities, respectively). Sequence conservation was also apparent for the residues in the 222 amino acid protein that are known to interact with the steroid substrate. Our results help modeling the active sites of the newly cloned GST A3-3 enzymes and the cDNAs will allow protein expression for studies of the dog, goat, and opossum enzyme activities.
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  • Sun, Song, 1982-, et al. (författare)
  • Evolution of increased ß-lactam resistance in an engineered Metallo-ß-lactamase
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • The extensive use and misuse of antibiotics during the last 60 years has led to the evolution and global spread of a variety of resistance mechanisms. Of high medical importance are ß-lactamases, a group of enzymes that can hydrolyze the ß-lactam ring present in all ß-lactam antibiotics. Metallo-ß-lactamases (MBLs) are particularly problematic due to their ability to hydrolyze virtually all classes of ß-lactam antibiotics. A novel MBL (evMBL9) with low-level resistance against ß-lactam antibiotics was designed and employed as the ancestral MBL during an experiment to examine how an enzyme evolved towards increased resistance. We designed and synthesized a mutant library in which the substrate binding profile was varied by randomizing six amino acid residues. Mutants with increased resistance against seven different ß-lactam antibiotics (penicillin G, ampicillin, cefalotin, cefaclor, cefuroxime, cefoperazone and cefotaxime) were isolated and characterized. For the majority of mutants, in spite of their significantly increased resistance, both mRNA and protein levels were reduced (up to >20 fold) relative to those of parental evMBL9, indicating that the catalytic activities of these mutant MBLs were highly increased. Multivariate analysis showed that the majority of mutant enzymes became generalists, conferring increased resistance against most of the examined ß-lactams. The increased resistance and decreased protein level suggest that the improved hydrolysis in these novel MBLs is associated with decreased protein stability.
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  • Resultat 1-9 av 9

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