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41.
Abbas H. K. Al Temimi Dr. Michael Martin Dr. Qingxi Meng Danny C. Lenstra Dr. Ping Qian Prof. Dr. Hong Guo Prof. Dr. Elmar Weinhold Prof. Dr. Jasmin Mecinović 《Chembiochem : a European journal of chemical biology》2020,21(3):392-400
Biomedicinally important histone lysine methyltransferases (KMTs) catalyze the transfer of a methyl group from S-adenosylmethionine (AdoMet) cosubstrate to lysine residues in histones and other proteins. Herein, experimental and computational investigations on human KMT-catalyzed ethylation of histone peptides by using S-adenosylethionine (AdoEth) and Se-adenosylselenoethionine (AdoSeEth) cosubstrates are reported. MALDI-TOF MS experiments reveal that, unlike monomethyltransferases SETD7 and SETD8, methyltransferases G9a and G9a-like protein (GLP) do have the capacity to ethylate lysine residues in histone peptides, and that cosubstrates follow the efficiency trend AdoMet>AdoSeEth>AdoEth. G9a and GLP can also catalyze AdoSeEth-mediated ethylation of ornithine and produce histone peptides bearing lysine residues with different alkyl groups, such as H3K9meet and H3K9me2et. Molecular dynamics and free energy simulations based on quantum mechanics/molecular mechanics potential supported the experimental findings by providing an insight into the geometry and energetics of the enzymatic methyl/ethyl transfer process. 相似文献
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Cover Feature: Biochemical Characterization of β‐Amino Acid Incorporation in Fluvirucin B2 Biosynthesis (ChemBioChem 13/2018) 下载免费PDF全文
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Charlotte Olagnon Dr. Julia Monjaras Feria Clemens Grünwald-Gruber Dr. Markus Blaukopf Prof. Dr. Miguel A. Valvano Prof. Dr. Paul Kosma 《Chembiochem : a European journal of chemical biology》2019,20(23):2936-2948
4-Amino-4-deoxy-l -arabinopyranose (Ara4N) residues have been linked to antibiotic resistance due to reduction of the negative charge in the lipid A and core regions of the bacterial lipopolysaccharide (LPS). To study the enzymatic transfer of Ara4N onto lipid A, which is catalysed by the ArnT transferase, we chemically synthesised a series of anomeric phosphodiester-linked lipid Ara4N derivatives containing linear aliphatic chains as well as E- and Z-configured monoterpene units. Coupling reactions were based on sugar-derived H-phosphonates, followed by oxidation and global deprotection. The enzymatic Ara4N transfer was performed in vitro with crude membranes from a deep-rough mutant from Escherichia coli as acceptor. Product formation was detected by TLC and LC-ESI-QTOF mass spectrometry. Out of seven analogues tested, only the α-neryl derivative was accepted by the Burkholderia cenocepacia ArnT protein, leading to substitution of the Kdo2-lipid A acceptor and thus affording evidence that ArnT is an inverting glycosyl transferase that requires the Z-configured double bond next to the anomeric phosphate moiety. This approach provides an easily accessible donor substrate for biochemical studies relating to modifications of bacterial LPS that modulate antibiotic resistance and immune recognition. 相似文献
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José Carlos Martins Alexandre Campos Hugo Osório Rute da Fonseca Vítor Vasconcelos 《International journal of molecular sciences》2014,15(2):1887-1900
Suspension-feeding bivalves are considered efficient toxin vectors with a relative insensitivity to toxicants compared to other aquatic organisms. This fact highlights the potential role of detoxification enzymes, such as glutathione transferases (GSTs), in this bivalve resistance. Nevertheless, the GST system has not been extensively described in these organisms. In the present study, cytosolic GSTs isoforms (cGST) were surveyed in three bivalves with different habitats and life strategies: Corbicula fluminea, Anodonta cygnea and Mytilus galloprovincialis. GSTs were purified by glutathione-agarose affinity chromatography, and the collection of expressed cGST classes of each bivalve were identified using a proteomic approach. All the purified extracts were also characterized kinetically. Results reveal variations in cGST subunits collection (diversity and properties) between the three tested bivalves. Using proteomics, four pi-class and two sigma-class GST subunits were identified in M. galloprovincialis. C. fluminea also yielded four pi-class and one sigma-class GST subunits. For A. cygnea, two mu-class and one pi-class GST subunits were identified, these being the first record of GSTs from these freshwater mussels. The affinity purified extracts also show differences regarding enzymatic behavior among species. The variations found in cGST collection and kinetics might justify diverse selective advantages for each bivalve organism. 相似文献
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Selective Inhibitors of Glutathione Transferase P1 with Trioxane Structure as Anticancer Agents 下载免费PDF全文
Maria Bräutigam Prof. Dr. Nicole Teusch Tobias Schenk Miriam Sheikh Rocky Z. Aricioglu Swantje H. Borowski Dr. Jörg‐Martin Neudörfl Prof. Dr. Ulrich Baumann Prof. Dr. Axel G. Griesbeck Dr. Markus Pietsch 《ChemMedChem》2015,10(4):629-639
The response to chemotherapy in cancer patients is frequently compromised by drug resistance. Although chemoresistance is a multifactorial phenomenon, many studies have demonstrated that altered drug metabolism through the expression of phase II conjugating enzymes, including glutathione transferases (GSTs), in tumor cells can be directly correlated with resistance against a wide range of marketed anticancer drugs. In particular, overexpression of glutathione transferase P1 (GSTP1) appears to be a factor for poor prognosis during cancer therapy. Former and ongoing clinical trials have confirmed GSTP1 inhibition as a principle for antitumor therapy. A new series of 1,2,4‐trioxane GSTP1 inhibitors were designed via a type II photooxygenation route of allylic alcohols followed by acid‐catalyzed peroxyacetalization with aldehydes. A set of novel inhibitors exhibit low micromolar to high nanomolar inhibition of GSTP1, revealing preliminary SAR for further lead optimization. Importantly, high selectivity over another two human GST classes (GSTA1 and GSTM2) has been achieved. The trioxane GSTP1 inhibitors may therefore serve as a basis for the development of novel drug candidates in overcoming chemoresistance. 相似文献
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Kinetic Analysis of PRMT1 Reveals Multifactorial Processivity and a Sequential Ordered Mechanism 下载免费PDF全文
Jennifer I. Brown Dr. Timo Koopmans Jolinde van Strien Dr. Nathaniel I. Martin Dr. Adam Frankel 《Chembiochem : a European journal of chemical biology》2018,19(1):85-99
Arginine methylation is a prevalent post‐translational modification in eukaryotic cells. Two significant debates exist within the field: do these enzymes dimethylate their substrates in a processive or distributive manner, and do these enzymes operate using a random or sequential method of bisubstrate binding? We revealed that human protein arginine N‐methyltransferase 1 (PRMT1) enzyme kinetics are dependent on substrate sequence. Further, peptides containing an Nη‐hydroxyarginine generally demonstrated substrate inhibition and had improved KM values, which evoked a possible role in inhibitor design. We also revealed that the perceived degree of enzyme processivity is a function of both cofactor and enzyme concentration, suggesting that previous conclusions about PRMT sequential methyl transfer mechanisms require reassessment. Finally, we demonstrated a sequential ordered Bi–Bi kinetic mechanism for PRMT1, based on steady‐state kinetic analysis. Together, our data indicate a PRMT1 mechanism of action and processivity that might also extend to other functionally and structurally conserved PRMTs. 相似文献
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Sami Ahmad 《Journal of chemical ecology》1986,12(2):533-560
A variety of oxidases, reductases, esterases, epoxide hydrolases, and group transferases in herbivorous insects and mites detoxify and facilitate the excretion of toxic phytochemicals (allelochemicals). Current theory indicates that the cytochrome P-450-dependent mixed-function oxidases (MFOs) are by far the most important enzymes because they have many attributes that are essential for an effective detoxification system. Data presented here on the midgut microsomal MFO activity of larvae of the gypsy moth,Lymantria dispar, are discussed in the light of previous work and support the theory. In the gypsy moth, the MFO levels exhibit a parallel trend with changes in specific feeding rates, and changes in the specific activity of the enzyme appear to be regulated ontogenetically and by inductive effect of chemicals in the diet. The specific activity of the MFOs rises more sharply on leaves of a highly preferred type-1 plant, the pin oak, than on an artificial wheat germ diet; the increase from mid-second instar to mid-fifth is 4.5- and 1.8-fold, respectively. The relationship of food consumption rate to increase in body mass (W) was slightly in excess of a 11 ratio for both pin oak and the artificial diet, indicating that the feeding rate surpasses the increase in W (a rare phenomenon in insects). Moreover, the surface-to-volume ratios are fairly constant for combined data of gut lumen and epithelium in second to fifth instars, because the volume occupied by the epithelial cells is much larger than in older ones. Thus, it is concluded that greater specific activity of the MFO is necessary with larval advancement to higher instars in order that they may process dietary allelochemicals with an efficiency comparable to younger larvae. Additional data suggest that MFO level increases reflect further adaptation to: (1) normal, seasonal changes in plants' allelochemical composition and concentration; (2) increase in allelochemical concentration in response to leaf damage; and (3) the risk faced by dispersing larvae of encountering a greater amount and variety of allelochemicals on suboptimal/ less suitable plants. Evidence also has emerged recently for MFO-catalyzed metabolism/deactivation of numerous plant allelochemicals, including compounds that induce the enzyme. MFOs are further adapted for participation in the biogenesis of substances physiologically important to insects. Moreover, the catalytic center of the MFO system, cytochrome P-450, occurs in multiple forms; the significance of this important feature is discussed.Paper presented at the Symposium Bioorganic Chemistry of Communication Systems, at the NERM-15 ACS meeting, SUNY College at New Paltz, New York, June 1985. 相似文献
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Pljevaljcić G Schmidt F Weinhold E 《Chembiochem : a European journal of chemical biology》2004,5(3):265-269
A new concept for sequence-specific labeling of DNA by using chemically modified cofactors for DNA methyltransferases is presented. Replacement of the amino acid side chain of the natural cofactor S-adenosyl-L-methionine with an aziridine group leads to a cofactor suitable for DNA methyltransferase-catalyzed sequence-specific coupling with DNA. Sequence-specifically fluorescently labeled plasmid DNA was obtained by using the DNA methyltransferase from Thermus aquaticus (M.TaqI) as catalyst and attaching a fluorophore to the aziridine cofactor. First results suggest that all classes of DNA methyltransferases with different recognition sequences can be used. In addition, this novel method for DNA labeling should be applicable to a wide variety of reporter groups. 相似文献
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Porntip Rojruthai Jitladda Tangpakdee Sakdapipanich Seiji Takahashi Lee Hyegin Motoyoshi Noike Tanetoshi Koyama Yasuyuki Tanaka 《Journal of Bioscience and Bioengineering》2010,109(2):107-114
Hevea brasiliensis is one of few higher plants producing the commercial natural rubber used in many significant applications. The biosynthesis of high molecular weight rubber molecules by the higher plants has not been clarified yet. Here, the in vitro rubber biosynthesis was performed by using enzymatically active small rubber particles (SRP) from Hevea. The mechanism of the in vitro rubber synthesis was investigated by the molecular weight distribution (MWD). The highly purified SRP prepared by gel filtration and centrifugation in the presence of Triton® X-100 showed the low isopentenyl diphosphate (IPP) incorporation for the chain extension mechanism of pre-existing rubber. The MWD of in vitro rubber elongated from the pre-existing rubber chains in SRP was analyzed for the first time in the case of H. brasiliensis by incubating without the addition of any initiator. The rubber transferase activity of 70% incorporation of the added IPP (w/w) was obtained when farnesyl diphosphate was present as the allylic diphosphate initiator. The in vitro synthesized rubber showed a typical bimodal MWD of high and low molecular weight fractions in GPC analysis, which was similar to that of the in vivo rubber with peaks at around 106 and 105 Da or lower. The reaction time independence and dependence of molecular weight of high and low molecular weight fractions, respectively, indicated that the high molecular weight rubber was synthesized from the chain extension of pre-existing rubber molecules whereas the lower one was from the chain elongation of rubber molecules newly synthesized from the added allylic substrates. 相似文献