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731.
Uridine 5′-diphospho-glucuronosyltransferase-1A9 (UGT1A9) expressed in the liver, shows good sequence identity with UGT1A10, expressed in the intestine. Both uridine 5′-diphospho-glucuronosyltransferase (UGT) isoforms show comprehensive overlapping substrate selectivity but there are differences in stereoselectivity, regiospecificity and rate of glucuronidation of the substrates. Multiple sequence alignment analyses of UGT1A9 and UGT1A10 showed that 13% of the residues in N-terminal domain (NTD) are non-identical between them. Herein, authors attempted homology modelling of UGT1A9 and UGT1A10 and validation using software tools and reported mutagenic studies. A molecular docking study of the known substrates is performed on UGT1A9 and UGT1A10 homology models. The non-identical N-terminal residues ranging from 111 to 117 in UGT1A9 and UGT1A10 were identified to play a central role in the substrate selectivity. However, substrate binding is performed by Ser111, Gly115 and Leu117 in UGT1A10 and Gly111, Asp115 and Phe117 in UGT1A9. This study reports new residues in NTD, showing interaction with uridine 5′-diphospho-glucuronic acid which binds with C-terminal domain. Further, molecular dynamics simulations were carried out to study the role of non-identical residues in substrate identification. The study demonstrates the folding of the UGT enzyme, particularly, helix-loop-helix transition and movement of Nα3-2 helix, in response to substrate and co-substrate binding. 相似文献
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733.
Pavana M. Hegde Arijit Dutta Shiladitya Sengupta Joy Mitra Sanjay Adhikari Alan E. Tomkinson Guo-Min Li Istvan Boldogh Tapas K. Hazra Sankar Mitra Muralidhar L. Hegde 《The Journal of biological chemistry》2015,290(34):20919-20933
The human DNA glycosylase NEIL1 was recently demonstrated to initiate prereplicative base excision repair (BER) of oxidized bases in the replicating genome, thus preventing mutagenic replication. A significant fraction of NEIL1 in cells is present in large cellular complexes containing DNA replication and other repair proteins, as shown by gel filtration. However, how the interaction of NEIL1 affects its recruitment to the replication site for prereplicative repair was not investigated. Here, we show that NEIL1 binarily interacts with the proliferating cell nuclear antigen clamp loader replication factor C, DNA polymerase δ, and DNA ligase I in the absence of DNA via its non-conserved C-terminal domain (CTD); replication factor C interaction results in ∼8-fold stimulation of NEIL1 activity. Disruption of NEIL1 interactions within the BERosome complex, as observed for a NEIL1 deletion mutant (N311) lacking the CTD, not only inhibits complete BER in vitro but also prevents its chromatin association and reduced recruitment at replication foci in S phase cells. This suggests that the interaction of NEIL1 with replication and other BER proteins is required for efficient repair of the replicating genome. Consistently, the CTD polypeptide acts as a dominant negative inhibitor during in vitro repair, and its ectopic expression sensitizes human cells to reactive oxygen species. We conclude that multiple interactions among BER proteins lead to large complexes, which are critical for efficient BER in mammalian cells, and the CTD interaction could be targeted for enhancing drug/radiation sensitivity of tumor cells. 相似文献
734.
Ujjal Ghosh Shankhamala Bose Trinath Ghosh Tapas Kumar BandyopadhyayUtpal Basu 《Analytical biochemistry》2015
Commercially available reagents and published protocols are widely used for RNA isolation. However, genomic DNA contamination in isolated RNA is a potential problem. Here we describe a simple, inexpensive method for eliminating genomic DNA contamination beyond the level of PCR-based detection through reduction of the guanidine thiocyanate concentration (1.5 M) in a single monophasic solution based on Chomczynski–Sacchi reagents. The new method can be used to isolate small and large RNA species of high quality and can be completed within an hour. 相似文献
735.
Chaudhari A Mahfouz M Fialho AM Yamada T Granja AT Zhu Y Hashimoto W Schlarb-Ridley B Cho W Das Gupta TK Chakrabarty AM 《Biochemistry》2007,46(7):1799-1810
Azurin is a member of a family of metalloproteins called cupredoxins. Although previously thought to be involved in electron transfer, azurin has recently been shown to preferentially enter cancer cells than normal cells and induce apoptosis in such cells. Azurin also demonstrates structural similarity to a ligand known as ephrinB2, which binds its cognate receptor tyrosine kinase EphB2 to initiate cell signaling. Eph/ephrin signaling is known to be involved in cancer progression. We now demonstrate that azurin binds to the EphB2-Fc receptor with high affinity. We have localized a C-terminal domain of azurin (Azu 96-113) that exhibits structural similarity to ephrinB2 at the G-H loop region known to be involved in receptor binding. A synthetic peptide (Azu 96-113) as well as a GST fusion derivative GST-Azu 88-113 interferes with the growth of various human cancer cells. In a prostate cancer cell line DU145 lacking functional EphB2, azurin or its GST-fusion derivatives had little cytotoxic effect. However, in DU145 cells expressing functional EphB2, azurin and GST-Azu 88-113 demonstrated significant cytotoxicity, whereas ephrinB2 promoted cell growth. Azurin inhibited the ephrinB2-mediated autophosphorlyation of the EphB2 tyrosine residue, thus interfering in upstream cell signaling and contributing to cancer cell growth inhibition. 相似文献
736.
Bacterial proteins such as azurin and Laz have recently been shown to enter preferentially to cancer cells and kill them by multiple mechanisms. Historically, bacterial DNA, particularly the unmethylated CpG dinucleotides, have been shown to trigger activation of specific Toll-like receptors (TLRs) in immune cells, leading to various cytokine and chemokine production that allows cancer cell death and their regression. However, the enhanced release of specific protein or extrachromosomal DNA by bacteria in response to exposure to cancer cells has not been previously demonstrated. In this review, we discuss how an opportunistic, extracellular pathogenic bacterium, Pseudomonas aeruginosa, senses the presence of cancer cells and releases a specific protein or extrachromosomal DNA with antitumor activity for inhibition of cancer cell growth. 相似文献
737.
States of increased metabolic demand are associated with up-regulation of NPY and hyperphagia. However, we present some instances of hyperphagia in which NPY is not up-regulated. Ablation or functional disruption of specific sites in the hypothalamus, such as the ventromedial or paraventricular nuclei, or transection of inputs to the hypothalamus from the hindbrain results in hyperphagia and excess body weight gain. However, NPY expression and concentration in these experimental models is either decreased or unchanged. While there is no up-regulation of NPY in these models, there is increased sensitivity to the orexigenic effects of NPY. This enhanced responsiveness to NPY may more than compensate for the reduced levels of NPY and result in hyperphagia and excess body weight gain. The hyper-responsiveness may be due either to an increase in NPY receptors or to other changes in target cells and response pathways that may result from the treatments used in these models. 相似文献
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