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911.
Reena Gyanda Jayati Banerjee Yi‐Pin Chang Angela M. Phillips Lawrence Toll Christopher J. Armishaw 《Journal of peptide science》2013,19(1):16-24
α‐Conotoxins are peptide neurotoxins that selectively inhibit various subtypes of nicotinic acetylcholine receptors. They are important research tools for studying numerous pharmacological disorders, with profound potential for developing drug leads for treating pain, tobacco addiction, and other conditions. They are characterized by the presence of two disulfide bonds connected in a globular arrangement, which stabilizes a bioactive helical conformation. Despite extensive structure–activity relationship studies that have produced α‐conotoxin analogs with increased potency and selectivity towards specific nicotinic acetylcholine receptor subtypes, the efficient production of diversity‐oriented α‐conotoxin combinatorial libraries has been limited by inefficient folding and purification procedures. We have investigated the optimized conditions for the reliable folding of α‐conotoxins using simplified oxidation procedures for use in the accelerated production of synthetic combinatorial libraries of α‐conotoxins. To this end, the effect of co‐solvent, redox reagents, pH, and temperature on the proportion of disulfide bond isomers was determined for α‐conotoxins exhibiting commonly known Cys loop spacing frameworks. In addition, we have developed high‐throughput ‘semi‐purification’ methods for the quick and efficient parallel preparation of α‐conotoxin libraries for use in accelerated structure–activity relationship studies. Our simplified procedures represent an effective strategy for the preparation of large arrays of correctly folded α‐conotoxin analogs and permit the rapid identification of active hits directly from high‐throughput pharmacological screening assays. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
912.
The oxygenation of polyunsaturated fatty acids such as arachidonic and linoleic acid through lipoxygenases (LOXs) and cyclooxygenases (COXs) leads to the production of bioactive lipids that are important both in the induction of acute inflammation and its resolution. Amongst the several isoforms of LOX that are expressed in mammals, 15‐LOX‐1 was shown to be important both in the context of inflammation, being expressed in cells of the immune system, and in epithelial cells where the enzyme has been shown to crosstalk with a number of important signalling pathways. This review looks into the latest developments in understanding the role of 15‐LOX‐1 in different disease states with emphasis on the emerging role of the enzyme in the tumour microenvironment as well as a newly re‐discovered form of cell death called ferroptosis. We also discuss future perspectives on the feasibility of use of this protein as a target for therapeutic interventions. 相似文献
913.
Vibeke Strand Evo Alemao Thomas Lehman Alyssa Johnsen Subhashis Banerjee Harris A. Ahmad Philip J. Mease 《Arthritis research & therapy》2018,20(1):269
Background
To explore the effect of abatacept treatment on patient-reported outcomes (PROs) in psoriatic arthritis (PsA).Methods
Patients with PsA were randomised (1:1) to subcutaneous abatacept 125?mg weekly/placebo for 24?weeks with early escape (EE) to open-label abatacept (week 16). Adjusted mean changes from baseline to weeks 16 (all patients) and 24 (non-EE responders) in Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form-36 (SF-36; physical and mental component summary and domains), Dermatology Life Quality Index and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated. Subpopulations were analysed by baseline C-reactive protein (CRP) level (> vs?≤?upper limit of normal [ULN]) and prior tumour necrosis factor inhibitor (TNFi) exposure. Proportions of patients reporting improvements ≥ minimal clinically important differences (MCIDs) and?≥?normative values (NVs) in HAQ-DI, SF-36 and FACIT-F (week 16 before EE) were analysed.Results
In total population, numerically higher improvements in most PROs were reported with abatacept (n?=?213) versus placebo (n?=?211) at both time points (P?>?0.05). Higher proportions of abatacept versus placebo patients reported PRO improvements ≥ MCID and?≥?NV at week 16. At week 16, all PRO improvements were numerically greater (P?>?0.05) in patients with baseline CRP?>?ULN versus CRP?≤?ULN (all significant [95% confidence interval] for abatacept vs placebo); improvements in SF-36 component summaries and FACIT-F were greater in TNFi-naïve versus TNFi-exposed patients (abatacept > placebo). Week 24 subgroup data were difficult to interpret due to low patient numbers.Conclusions
Abatacept treatment improved PROs in patients with PsA versus placebo, with better results in elevated baseline CRP and TNFi-naïve subpopulations.Trial registration
ClinicalTrials.gov number, NCT01860976 (funded by Bristol-Myers Squibb); date of registration: 23 May 2013.914.
Struther Arnott R. Chandrasekaran A. K. Banerjee Rungen He J. K. Walker 《Journal of biomolecular structure & dynamics》2013,31(2):437-452
Abstract Most fibrous polynucleotides of general sequence exhibit secondary structures that are described adequately by regular helices with a repeated motif of only one nucleotide. Such helices exploit the fact that A:T, T:A, G:C, and C:G pairs are essentially isomorphous and have dyadically-related glycosylic bonds. Polynucleotides with regularly repeated base-sequences sometimes assume secondary structures with larger repeated motifs which reflect these base-sequences. The dinucleotide units of the Z-like forms of poly d(As4T):poly d(As4T), poly d(AC):poly d(GT) and poly d(GC):poly d(GC) are dramatic instances of this phenomenon. The wrinkled B and D forms of poly d(GC):poly d(GC) and poly d(AT):poly d(AT) are just as significant but more subtle examples. It is possible also to trap more exotic secondary structures in which the molecular asymmetric unit is even larger. There is, for example, a tetragonal form of poly d(AT):poly d(AT) which has unit cell dimensions a = b = 1.71nm, c= 7.40nm, γ = 90°. The C dimension corresponds to the pitch of a molecular helix which accommodates 24 successive nucleotide pairs arranged as a 43 helix of hexanucleotide duplexes. The great variety of nucleotide conformations which occur in these large asymmetric units has prompted us to describe them as pleiomeric, a term used in botany to describe whorls having more than the usual number of structures. Pleiomeric DNAs need not contain nucleotide conformations that are very different from one another. On the other hand, DNAs carrying nucleotides of very different conformation must be pleiomeric. This is because 4 nucleotides of different conformation are needed to join patches of secondary structure which are as different as A or B or Z. Differences in nucleotide structures may occur also between chains rather than within chains. In poly d(A):poly d(T), the purine nucleotides all contain Ci'-endo furanose rings and the pyrimidine nucleotides C2 '-endo rings. Analogous heteronomous structures may exist in DNA-RNA hybrids although these duplexes are also found to have symmetrical A-type conformations. 相似文献
915.
The kinetic mechanism of the reaction catalyzed by cobalamin-dependent methionine synthase from Escherichia coli K12 has been investigated by both steady-state and pre-steady-state kinetic analyses. The reaction catalyzed by methionine synthase involves the transfer of a methyl group from methyltetrahydrofolate to homocysteine to generate tetrahydrofolate and methionine. The postulated reaction mechanism invokes an initial transfer of the methyl group to the enzyme to generate enzyme-bound methylcobalamin and tetrahydrofolate. Enzyme-bound methylcobalamin then donates its methyl group to homocysteine to generate methionine and cob(I)alamin. The key questions that were addressed in this study were the following: (1) Does the reaction involve a sequential or ping-pong mechanism? (2) Is enzyme-bound cob(I)alamin a kinetically competent intermediate? (3) If the reaction does involve a sequential mechanism, what is the nature of the "free" enzyme to which the substrates bind; i.e., is the prosthetic group in the cob(I)alamin or methylcobalamin state? Both the steady-state and rapid reaction studies were conducted at 25 degrees C under anaerobic conditions. Initial velocity analysis under steady-state conditions revealed a family of parallel lines suggesting either a ping-pong mechanism or an ordered sequential mechanism. Steady-state product inhibition studies provided evidence for an ordered sequential mechanism in which the first substrate to bind is methyltetrahydrofolate and the last product to be released is tetrahydrofolate. Pre-steady-state kinetic studies were then conducted to determine the rate constants for the various reactions. Enzyme-bound cob(I)alamin was shown to react very rapidly with methyltetrahydrofolate (with an observed rate constant of 250 s-1 versus a turnover number under maximal velocity conditions of 19 s-1).(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
916.
Khandelwal P Bhatnagar R Choudhury D Banerjee N 《Biochemical and biophysical research communications》2004,314(4):943-949
Xenorhabdus nematophila is an insect pathogenic bacterium, known to produce protein toxins that kill the larval host. We have described a cytotoxic pilin subunit of X. nematophila, which is expressed on the cell surface and also secreted in the extracellular medium associated with outer membrane vesicles. A 17kDa pilin subunit was isolated and purified from X. nematophila cell surface. The protein showed cytotoxicity to larval hemocytes of Helicoverpa armigera in an in vitro assay, causing agglutination of the cells, and releasing cytoplasmic enzyme lactate dehydrogenase in the medium. The pilin protein was able to bind to the surface of larval hemocytes. The binding and cytotoxicity of the purified 17kDa protein to hemocytes was inhibited by antiserum raised against the pilin protein. The study demonstrates for the first time a cytotoxic structural subunit of pilin from an entomopathogenic bacterium X. nematophila that is excreted in the extracellular medium with outer membrane vesicles. 相似文献
917.
Role of inflammatory cytokine-induced cyclooxygenase 2 in the ocular immunopathologic disease herpetic stromal keratitis 总被引:2,自引:0,他引:2 下载免费PDF全文
Ocular infection with herpes simplex virus (HSV) results in a blinding immunoinflammatory stromal keratitis (SK) lesion. Early preclinical events include polymorphonuclear neutrophil (PMN) infiltration and neovascularization in the corneal stroma. We demonstrate here that HSV infection of the cornea results in the upregulation of the cyclooxygenase 2 (COX-2) enzyme. Early after infection, COX-2 was produced from uninfected stromal fibroblasts as an indirect effect of virus infection. Subsequently, COX-2 may also be produced from other inflammatory cells that infiltrate the cornea. The induction of COX-2 is a critical event, since inhibition of COX-2 with a selective inhibitor was shown to reduce corneal angiogenesis and SK severity. The administration of a COX-2 inhibitor resulted in compromised PMN infiltration into the cornea, as well as diminished corneal vascular endothelial growth factor levels, likely accounting for the reduced angiogenic response. COX-2 stimulation by HSV infection represents a critical early event accessible for therapy and the control of SK severity. 相似文献
918.
Sumathra Manokaran Jayati Banerjee Sanku Mallik D.K. Srivastava 《Biochimica et Biophysica Acta - Proteins and Proteomics》2010,1804(10):1965-1973
We synthesized a fluorogenic dansylamide derivative (JB2-48), which fills the entire (15 Å deep) active site pocket of human carbonic anhydrase I, and investigated the contributions of sulfonamide and hydrophobic regions of the ligand structure on the spectral, kinetic, and thermodynamic properties of the enzyme–ligand complex. The steady-state and fluorescence lifetime data revealed that the deprotonation of the sulfonamide moiety of the enzyme bound ligand increases the fluorescence emission intensity as well as the lifetime of the fluorophores. This is manifested via the electrostatic interaction between the active site resident Zn2+ cofactor and the negatively charged sulfonamide group of the ligand, and such interaction contributes to about 2.2 kcal/mol (ΔΔG°) and 0.89 kcal/mol (ΔΔG‡) energy in stabilizing the ground and the putative transition states, respectively. We provide evidence that the anionic and neutral forms of JB2-48 are stabilized by the complementary microscopic/conformational states of the enzyme. The implication of the mechanistic studies presented herein in rationale design of carbonic anhydrase inhibitors is discussed. 相似文献
919.
S Banerjee 《Cancer biochemistry biophysics》1988,10(2):165-173
920.
Geotrichum candidum is well known for the reduction of prochiral ketones to chiral alcohol with high yield and excellent enantioselectivity. Carbonyl reductase from G. candidum was purified by ammonium sulphate precipitation, anion exchange and hydrophobic interaction chromatographies. Gel filtration chromatography together with SDS-PAGE revealed this protein to be a dimer of 60 kDa subunits. Maximum enzyme activity was found in acetate buffer at pH 5.4 with t1/2 of 7.13 h at 30 °C and t1/2 of 2.8 h at 65 °C. The enzyme was inhibited by p-hydroxymercuribenzoate and hydroxylamine indicating the involvement of thiol and carbonyl groups in the reduction reaction catalyzed by the enzyme. Chelating agents also reduced the enzyme activity indicating the requirement of metal ions as cofactors. The purified carbonyl reductase was found to be highly selective for ketones containing naphthyl ring, whereas aryl or hetero-aryl ketones showed very less or no activity at all. 相似文献