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991.
《FEBS letters》2014,588(23):4287-4296
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Tatiana S. Cherkesova Tatiana Y. Hargrove M. Cristina Vanrell Igor Ges Sergey A. Usanov Patricia S. Romano Galina I. Lepesheva 《FEBS letters》2014
CYP51 (sterol 14α-demethylase) is an efficient target for clinical and agricultural antifungals and an emerging target for treatment of Chagas disease, the infection that is caused by multiple strains of a protozoan pathogen Trypanosoma cruzi. Here, we analyze CYP51A from the Y strain T. cruzi. In this protein, proline 355, a residue highly conserved across the CYP51 family, is replaced with serine. The purified enzyme retains its catalytic activity, yet has been found less susceptible to inhibition. These biochemical data are consistent with cellular experiments, both in insect and human stages of the pathogen. Comparative structural analysis of CYP51 complexes with VNI and two derivatives suggests that broad-spectrum CYP51 inhibitors are likely to be preferable as antichagasic drug candidates. 相似文献
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Amornrat Naranuntarat Jensen Worathad Chindaudomsate Kanate Thitiananpakorn Skorn Mongkolsuk Laran T. Jensen 《FEBS letters》2014
Lysine deacetylases (KDACs) inhibitors may have therapeutic value in anti-malarial combination therapies with artemisinin. To evaluate connections between KDACs and artemisinin, Saccharomyces cerevisiae deletion mutants in KDAC genes were assayed. Deletion of RPD3, but not other KDAC genes, resulted in strong sensitivity to artemisinin, which was also observed in sit4Δ mutants with impaired endoplasmic reticulum (ER) to Golgi protein trafficking. Decreased accumulation of the transporters Pdr5p, Fur4p, and Tat2p was observed in rpd3Δ and sit4Δ cells. The unfolded protein response is induced in rpd3Δ cells consistent with retention of proteins in the ER. Disruption of protein trafficking appears to sensitize cells to artemisinin and targeting these pathways may be useful as part of artemisinin based anti-malarial therapy. 相似文献
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The effects of experimental conditions of fluorescence quenching on the binding parameters of apigenin to bovine serum albumin by response surface methods 下载免费PDF全文
A fluorescence quenching technique is often used to study interactions between small molecules and serum albumin. However, the results are quite different by using spectroscopic techniques on the same drug‐protein interaction research and they may be affected by different conditions (e.g. working solution of pH and ionic strength). In this research, using apigenin as an example, the effect of experimental conditions of fluorescence quenching on the binding parameters of drug to bovine serum albumin was investigated using a response surface method (RSM). The effect of pH, the concentration of NaCl and the concentration Mg2+ on the quenching constant (KSV), the apparent association constant (Ka) and the number of binding sites (n) was studied by single‐factor experiments with pH, [NaCl] and [Mg2+] as independent variables and KSV, Ka and n as response values. Prediction models were fit to a quadratic polynomial regression equation and the results showed that both KSV and n displayed a second‐order model, whereas Ka displayed linear relation dependence on pH, [NaCl] and [Mg2+]. Under these experimental conditions, [NaCl] was the most significant (p < 0.05) impact factor on KSV and Ka, whereas n was most affected by pH (p < 0.05). Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
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DNA damage response (DDR) to double strand breaks is coordinated by 3 phosphatidylinositol 3-kinase-related kinase (PIKK) family members: the ataxia-telangiectasia mutated kinase (ATM), the ATM and Rad3-related (ATR) kinase and the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs). ATM and ATR are central players in activating cell cycle checkpoints and function as an active barrier against genome instability and tumorigenesis in replicating cells. Loss of ATM function is frequently reported in various types of tumors, thus placing more reliance on ATR for checkpoint arrest and cell survival following DNA damage. To investigate the role of ATR in the G2/M checkpoint regulation in response to ionizing radiation (IR), particularly when ATM is deficient, cell lines deficient of ATM, ATR, or both were generated using a doxycycline-inducible lentiviral system. Our data suggests that while depletion of ATR or ATM alone in wild-type human mammary epithelial cell cultures (HME-CCs) has little effect on radiosensitivity or IR-induced G2/M checkpoint arrest, depletion of ATR in ATM-deficient cells causes synthetic lethality following IR, which correlates with severe G2/M checkpoint attenuation. ATR depletion also inhibits IR-induced autophagy, regardless of the ATM status, and enhances IR-induced apoptosis particularly when ATM is deficient. Collectively, our results clearly demonstrate that ATR function is required for the IR-induced G2/M checkpoint activation and subsequent survival of cells with ATM deficiency. The synthetic lethal interaction between ATM and ATR in response to IR supports ATR as a therapeutic target for improved anti-cancer regimens, especially in tumors with a dysfunctional ATM pathway. 相似文献
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Regulation of chromatin structure is an essential component of the DNA damage response (DDR), which effectively preserves the integrity of DNA by a network of multiple DNA repair and associated signaling pathways. Within the DDR, chromatin is modified and remodeled to facilitate efficient DNA access, to control the activity of repair proteins and to mediate signaling. The mammalian ISWI family has recently emerged as one of the major ATP-dependent chromatin remodeling complex families that function in the DDR, as it is implicated in at least 3 major DNA repair pathways: homologous recombination, non-homologous end-joining and nucleotide excision repair. In this review, we discuss the various manners through which different ISWI complexes regulate DNA repair and how they are targeted to chromatin containing damaged DNA. 相似文献
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