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71.
Evan Q. Comeaux Selma M. Cuya Kyoko Kojima Nauzanene Jafari Keith C. Wanzeck James A. Mobley Mary-Ann Bjornsti Robert C. A. M. van Waardenburg 《The Journal of biological chemistry》2015,290(10):6203-6214
Tyrosyl-DNA phosphodiesterase I (Tdp1) catalyzes the repair of 3′-DNA adducts, such as the 3′-phosphotyrosyl linkage of DNA topoisomerase I to DNA. Tdp1 contains two conserved catalytic histidines: a nucleophilic His (Hisnuc) that attacks DNA adducts to form a covalent 3′-phosphohistidyl intermediate and a general acid/base His (Hisgab), which resolves the Tdp1-DNA linkage. A Hisnuc to Ala mutant protein is reportedly inactive, whereas the autosomal recessive neurodegenerative disease SCAN1 has been attributed to the enhanced stability of the Tdp1-DNA intermediate induced by mutation of Hisgab to Arg. However, here we report that expression of the yeast HisnucAla (H182A) mutant actually induced topoisomerase I-dependent cytotoxicity and further enhanced the cytotoxicity of Tdp1 Hisgab mutants, including H432N and the SCAN1-related H432R. Moreover, the HisnucAla mutant was catalytically active in vitro, albeit at levels 85-fold less than that observed with wild type Tdp1. In contrast, the HisnucPhe mutant was catalytically inactive and suppressed Hisgab mutant-induced toxicity. These data suggest that the activity of another nucleophile when Hisnuc is replaced with residues containing a small side chain (Ala, Asn, and Gln), but not with a bulky side chain. Indeed, genetic, biochemical, and mass spectrometry analyses show that a highly conserved His, immediately N-terminal to Hisnuc, can act as a nucleophile to catalyze the formation of a covalent Tdp1-DNA intermediate. These findings suggest that the flexibility of Tdp1 active site residues may impair the resolution of mutant Tdp1 covalent phosphohistidyl intermediates and provide the rationale for developing chemotherapeutics that stabilize the covalent Tdp1-DNA intermediate. 相似文献
72.
《Journal of morphology》2017,278(6):865-876
Amphinomid species are since long known to cause urtication upon contact with the human skin. Since it has been reported that amphinomid chaetae are hollow, it has repeatedly been suggested that poison is injected upon epidermal contact. To test predictions for the structural correlate of such a stinging device we studied the structure and formation of chaetae in the fireworm Eurythoe complanata (Amphinomida). Neither the structure of the chaetae nor their formation and their position within the parapodium provide evidence for their function as hollow needles to inject poison. The chaetae even turned out to be not hollow, but containing calcareous depositions. The latter most likely cause artificial ruptures of delicate chitin lamellae in the inner of the chaeta when treated with acidic fixatives. Inorganic calcium compounds harden the chaetae and make them brittle so that they break easily. Additional information on the structure of the chaetal sac, the site of formation and the acicula do not contradict the position of the Amphinomida within Annelida as revealed by phylogenomic studies. 相似文献
73.
The protein KRAS has for decades been considered a holy grail of cancer drug discovery. For most of that time, it has also been considered undruggable. Since 2018, five compounds have entered the clinic targeting a single mutant form of KRAS, G12C. Here, we review each of these compounds along with additional approaches to targeting this and other mutants. Remaining challenges include expanding the identification of inhibitors to a broader range of known mutants and to conformations of the protein more likely to avoid development of resistance. 相似文献
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76.
An irreversible inhibitor of peptidyl-prolyl cis/trans isomerase Pin1 and evaluation of cytotoxicity
Naoya Ieda Kaoru Itoh Yasumichi Inoue Yusuke Izumiya Mitusyasu Kawaguchi Naoki Miyata Hidehiko Nakagawa 《Bioorganic & medicinal chemistry letters》2019,29(3):353-356
Pin1 (protein interacting with never in mitosis A-1) is a member of the peptidyl prolyl isomerase (PPIase) family, and catalyzes cis-trans isomerization of pThr/Ser-Pro amide bonds. Because Pin1 is overexpressed in various cancer cell lines and promotes cell growth, it is considered a target for anticancer agents. Here, we designed and synthesized a covalently binding Pin1 inhibitor (S)-2 to target Pin1’s active site. This compound inhibited Pin1 in protease-coupled assay, and formed a covalent bond with Cys113 of Pin1, as determined by ESI-MS. The acetoxymethyl ester of (S)-2, i.e., 6, suppressed cyclin D1 expression in human prostate cancer PC-3 cells, and exhibited cytotoxicity. Pin1-knockdown experiments indicated that a target for the cytotoxicity of 6 is Pin1. 相似文献
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78.
Carlos Díaz Blanco María Díaz Gonzlez Jos María Dag Monmany Tzanko Tzanov 《Enzyme and microbial technology》2009,44(6-7):380-385
Oxidation of colourless dye precursors with laccase enzyme provided simultaneous “in situ” generation and fixation of a pigment on amino groups pre-functionalized cotton fabric. Aromatic amine moieties of 2,5-diaminobenzenesulfonic acid introduced onto tosylated cotton were coupled and copolymerised with a phenolic compound catechol into coloured product covalently fixed on the fabric upon oxidation with laccase. The controlled amination of cellulose in a first step and subsequent colouration allowed for up to 95% pigment fixation on the fabric. Electrochemical studies were performed to elucidate the mechanism of the pigment formation. The pigment was further isolated from the acid hydrolysate of the dyed cellulose fabric to confirm the covalent fixation and to further elucidate the pigment structure by means of FTIR, MS, 1H and 13C NMR analysis. An oligomeric pigment has been identified composed by up to six phenolic units. 相似文献
79.
Michelle Oppenheimer Joshua A. Crawford Richard F. Helm 《Archives of biochemistry and biophysics》2010,496(2):123-131
Tetrahydrofuran monooxygenase (Thm) catalyzes the NADH-and oxygen-dependent hydroxylation of tetrahydrofuran to 2-hydroxytetrahydrofuran. Thm is composed of a hydroxylase enzyme, a regulatory subunit, and an oxidoreductase named ThmD. ThmD was expressed in Escherichia coli as a fusion to maltose-binding protein (MBP) and isolated to homogeneity after removal of the MBP. Purified ThmD contains covalently bound FAD, [2Fe-2S] center, and was shown to use ferricyanide, cytochrome c, 2,6-dichloroindophenol, and to a lesser extent, oxygen as surrogate electron acceptors. ThmD displays 160-fold preference for NADH over NADPH and functions as a monomer. The flavin-binding domain of ThmD (ThmD-FD) was purified and characterized. ThmD-FD displayed similar activity as the full-length ThmD and showed a unique flavin spectrum with a major peak at 463 nm and a small peak at 396 nm. Computational modeling and mutagenesis analyses suggest a novel three-dimensional fold or covalent flavin attachment in ThmD. 相似文献
80.
Kristofor J. Webb Cecilia I. Zurita-Lopez Qais Al-Hadid Arthur Laganowsky Brian D. Young Rebecca S. Lipson Puneet Souda Kym F. Faull Julian P. Whitelegge Steven G. Clarke 《The Journal of biological chemistry》2010,285(48):37598-37606
We have shown that Rpl3, a protein of the large ribosomal subunit from baker''s yeast (Saccharomyces cerevisiae), is stoichiometrically monomethylated at position 243, producing a 3-methylhistidine residue. This conclusion is supported by top-down and bottom-up mass spectrometry of Rpl3, as well as by biochemical analysis of Rpl3 radiolabeled in vivo with S-adenosyl-l-[methyl-3H]methionine. The results show that a +14-Da modification occurs within the GTKKLPRKTHRGLRKVAC sequence of Rpl3. Using high-resolution cation-exchange chromatography and thin layer chromatography, we demonstrate that neither lysine nor arginine residues are methylated and that a 3-methylhistidine residue is present. Analysis of 37 deletion strains of known and putative methyltransferases revealed that only the deletion of the YIL110W gene, encoding a seven β-strand methyltransferase, results in the loss of the +14-Da modification of Rpl3. We suggest that YIL110W encodes a protein histidine methyltransferase responsible for the modification of Rpl3 and potentially other yeast proteins, and now designate it Hpm1 (Histidine protein methyltransferase 1). Deletion of the YIL110W/HPM1 gene results in numerous phenotypes including some that may result from abnormal interactions between Rpl3 and the 25 S ribosomal RNA. This is the first report of a methylated histidine residue in yeast cells, and the first example of a gene required for protein histidine methylation in nature. 相似文献