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1.
《Bioorganic & medicinal chemistry》2020,28(20):115698
A series of allosteric kidney-type glutaminase (GLS) inhibitors possessing a mercaptoethyl (SCH2CH2) linker were synthesized in an effort to further expand the structural diversity of chemotypes derived from bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a prototype allosteric inhibitor of GLS. BPTES analog 3a with a mercaptoethyl linker between the two thiadiazole rings was found to potently inhibit GLS with an IC50 value of 50 nM. Interestingly, the corresponding derivative with an n-propyl (CH2CH2CH2) linker showed substantially lower inhibitory potency (IC50 = 2.3 μM) while the derivative with a dimethylsulfide (CH2SCH2) linker showed no inhibitory activity at concentrations up to 100 μM, underscoring the critical role played by the mercaptoethyl linker in the high affinity binding to the allosteric site of GLS. Additional mercaptoethyl-linked compounds were synthesized and tested as GLS inhibitors to further explore SAR within this scaffold including derivatives possessing a pyridazine as a replacement for one of the two thiadiazole moiety. 相似文献
2.
《Biochimica et Biophysica Acta - Proteins and Proteomics》2023,1871(3):140887
The short peptidoglycan recognition protein (PGRP-S) of the innate immune system recognizes the invading microbes through binding to their cell wall molecules. In order to understand the mode of binding of PGRP-S to bacterial cell wall molecules, the structure of the complex of camel PGRP-S (CPGRP-S) with hexanoic acid has been determined at 2.07 Å resolution. Previously, we had reported the structures of CPGRP-S in the native unbound state as well as in the complexed forms with the components of various bacterial cell wall molecules such as peptidoglycan (PGN), lipopolysaccharide (LPS), lipoteichoic acid (LTA), mycolic acid (MA) and other fatty acids. These structures revealed that CPGRP-S formed two homodimers which were designated as A-B and CD dimers. It also showed that the fatty acids bind to CPGRP-S in the binding site at the A-B dimer while the non-fatty acids were shown to bind at the interfaces of both A-B and CD dimers. The present structure of the complex of CPGRP-S with hexanoic acid (HA) showed that HA binds to CPGRP-S at the interface of CD dimer. HA was located in the same groove at the CD interface which was occupied by non-fatty acids such as PGN, LPS and LTA and interacts with residues from both C and D molecules. HA is firmly held in the groove with several hydrogen bonds and a number of van der Waals contacts. This is the first structure which reports the binding of a fatty acid in the cleft at the interface of CD dimer. 相似文献
3.
Sulfoxide synthases are non-heme iron enzymes that catalyze oxidative carbonsulfur bond formation in the biosynthesis of thiohistidines such as ergothioneine and ovothiol. The catalytic mechanism of these enzymes has been studied by protein crystallography, steady-state kinetics, non-natural amino acid incorporation and computational modeling. This review discusses the current status of this research and also highlights similarities between the CS bond forming activity of sulfoxide synthases with that of synthetic coordination compounds. 相似文献
4.
Bioactivity exhibited by nanoparticles has been interesting for researchers globally. The phytogenic synthesis of zinc oxide nanoparticles (ZnO-NPs) has been an eco-friendly approach due to its low toxicity and biological potential. In this pretext, the present study has been conducted. The bacterial inhibition by ZnO-NPs could be attributed to its high specific surface charge and reactive oxygen species generation. The present study states the phyto-fabrication of ZnO-NPs employing aqueous leaf extract of Canthium dicoccum (L.). The synthesized nanoparticles (NPs) displayed characteristic excitation at 293 nm. The dynamic light scattering (DLS) analysis revealed an average 33 nm size of ZnO-NPs. The FT-IR functional groups CH stretch, CH bend, aromatic CN stretch, and CO stretch were observed in phyto-fabricated ZnO-NPs. Results obtained from antibacterial activities inferred that ZnO-NPs were most effective against Bacillus subtilis, least sensitive to Staphylococcus aureus. The minimum inhibitory concentration (MIC) was observed in the range 78.12 to 625 μg mL−1 which was further confirmed by bacterial cell viability test. The Anti-TB activity by Alamar Blue Dye test revealed phyto-fabricated ZnO-NPs inhibited M. tuberculosis at 25 μg mL−1. The result of the antioxidant activity of the DPPH method was dose-dependent. The application of ZnO-NPs as potential antibacterial applications could be envisioned. 相似文献
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6.
《Bioorganic & medicinal chemistry letters》2020,30(22):127526
This study reports a preparation of silver nanoparticles (SNPs) using Microsorum pteropus methanol extract, as a new approach in the development of therapeutic strategies against diseases caused by oxidative stress, reactive oxygen, and nitrogen species. During the effort of extraction and isolation from M. pteropus, X-ray single-crystal structural analysis of sucrose was succeeded. 1,1-Diphenyl-2-picrylhydrazyl (DPPH) and hydrogen peroxide scavenging assay were used to confirm the antioxidant potential. Preparation of SNPs was confirmed by ultraviolet–visible (UV–Vis) spectra with peaks between 431 and 436 nm. Infrared (IR) analysis showed OH, NH functional groups of alcohol, phenol, amine, and aliphatic CH stretching vibrations of hydrocarbon chains of the synthesized nanoparticles. The antioxidant properties of the SNPs significantly showed DPPH reduction with an IC₅₀ value of 47.0 µg/mL and hydrogen peroxide scavenging activity with an IC₅₀ value of 35.8 µg/mL, and hence, indicating their capability to eliminate potentially damaging oxidants involved in oxidative stress and their related diseases. 相似文献
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8.
《Bio Systems》2008,91(3):792-801
We have investigated the roles played by CH⋯OC interactions in RNA binding proteins. There was an average of 78 CH⋯OC interactions per protein and also there was an average of one significant CH⋯OC interaction for every 6 residues in the 59 RNA binding proteins studied. Main chain–Main chain (MM) CH⋯OC interactions are the predominant type of interactions in RNA binding proteins. The donor atom contribution to CH⋯OC interactions was mainly from aliphatic residues. The acceptor atom contribution for MM CH⋯OC interactions was mainly from Val, Phe, Leu, Ile, Arg and Ala. The secondary structure preference analysis of CH⋯OC interacting residues showed that, Arg, Gln, Glu and Tyr preferred to be in helix, while Ala, Asp, Cys, Gly, Ile, Leu, Lys, Met, Phe, Trp and Val preferred to be in strand conformation. Most of the CH⋯OC interacting polar amino acid residues were solvent exposed while, majority of the CH⋯OC interacting non polar residues were excluded from the solvent. Long and medium-range CH⋯OC interactions are the predominant type of interactions in RNA binding proteins. More than 50% of CH⋯OC interacting residues had a higher conservation score. Significant percentage of CH⋯OC interacting residues had one or more stabilization centers. Sixty-six percent of the theoretically predicted stabilizing residues were also involved in CH⋯OC interactions and hence these residues may also contribute additional stability to RNA binding proteins. 相似文献
9.
《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2023,1870(1):119367
Studies suggested that the pathogenesis of inflammatory breast cancer (IBC) is related to inflammatory manifestations accompanied by specific cellular and molecular mechanisms in the IBC tumor microenvironment (TME). IBC is characterized by significantly higher infiltration of tumor-associated macrophages (TAMs) that contribute to its metastatic process via secreting many cytokines such as TNF, IL-6, IL-8, and IL-10 that enhance invasion and angiogenesis. Thus, there is a need to first understand how IBC-TME modulates the polarization of TAMs to better understand the role of TAMs in IBC. Herein, we used gene expression signature and Synchrotron Fourier-Transform Infrared Microspectroscopy (SR-μFTIR) to study the molecular and biochemical changes, respectively of in vitro polarized TAMs stimulated by the secretome of IBC and non-IBC cells. The gene expression signature showed significant differences in the macrophage's polarization-related genes between stimulated TAMs. FTIR spectra showed absorption bands in the region of 1700–1500 cm?1 attributed to the amide I ν(C=O), & νAS (CN), δ (NH), and amide II ν(CN), δ (NH) proteins bands. Moreover, three peaks of different intensities and areas were detected in the lipid region of the νCH2 and νCH3 stretching modes positioned within the 3000–2800 cm?1 range. The PCA analysis for the second derivative spectra of the amide regions discriminates between stimulated IBC and non-IBC TAMs. This study showed that IBC and non-IBC TMEs differentially modulate the polarization of TAMs and SR-μFTIR can determine these biochemical changes which will help to better understand the potential role of TAMs in IBC. 相似文献
10.
《Biochimica et Biophysica Acta (BBA)/General Subjects》2020,1864(11):129696
BackgroundIt has been reported that the genes coding for NADP-dependent glutamate dehydrogenases (NADP-GDHs) showed a cause-effect relationship with Yeast-Hypha (YH) reversible transition in a zygomycete Benjaminiella poitrasii. As YH transition is significant in human pathogenic fungi for their survival and proliferation in the host, the NADP-GDHs can be explored as antifungal drug targets.MethodsThe yeast-form specific BpNADPGDH I and hyphal-form specific BpNADPGDH II of B. poitrasii were purified by heterologous expression in E. coli BL-21 cells and characterized. The structural analogs of L-glutamate, dimethyl esters of isophthalic acid (DMIP) and its derivatives were designed, synthesized and screened for inhibition of NADP-GDH activity as well as YH transition in B. poitrasii, and also in human pathogenic Candida albicans strains.ResultsThe BpNADPGDH I and BpNADPGDH II were found to be homo-hexameric proteins with native molecular mass of 282 kDa and 298 kDa, respectively and subunit molecular weights of 47 kDa and 49 kDa, respectively. Besides the distinct kinetic properties, BpNADPGDH I and BpNADPGDH II were found to be regulated by cAMP-dependent- and Calmodulin (CaM) dependent- protein kinases, respectively. The DMIP compounds showed a more pronounced effect on H-form specific BpNADPGDH II and inhibited YH transition as well as growth in B. poitrasii and C. albicans strains.ConclusionThe present study will be useful to design and develop antifungal drugs against dimorphic human pathogens using glutamate dehydrogenase as a target.SignificanceGlutamate dehydrogenases can be explored as a target against human pathogenic fungi. 相似文献
11.
Adaptive management of estuarine resource utilization and wetland conservation (ERU&WC) have both socioeconomic and ecological implications because estuaries involve plentiful navigation, aquaculture, wetland, and land-reclamation resources but are featured with complexity and vulnerability of hydrodynamics, morphodynamics, and ecological processes. To achieve positive synergistic effects and prevent disasters by optimizing the allocation of estuarine space to various activities and biological habitats, there is a need to track the estuarine evolutionary trajectories and demarcate the spatial function subareas. However, estuarine field data acquisition is time-consuming, spatially limited, expensive, and there are some areas not accessible due to shallowness or moving sand bars. This paper presents an exact estuarine morphodynamics acquisition and evolution analysis based on multi-temporal remote sensing images, with Minjiang Estuary, China as a case study. The imageries with high tide level (1995, 2017) and low tide level (1995, 2002, 2010, and 2017) were chosen to track the changes of coastline, tidal flat, channel, sand bar, sand island, wetland vegetation, and the spatial heterogeneity of Minjiang Estuary, and the results show visually the section of shoreline change, the pattern of TCSS change and the part of tidal flat vegetation change, which are the fundamental data for demarcating the spatial function subareas. Also, the adaptive management rule was explored, and the schematic diagram of the estuarine morphodynamic evolution process and the framework of ERU&WC adaptive management were outlined. The research result will provide technical support and theoretical guidance for the management of other estuarine environments. 相似文献
12.
《BBA》2020,1861(5-6):148173
Infrared absorption bands associated with the neutral state of quinones in the A1 binding site in photosystem I (PSI) have been difficult to identify in the past. This problem is addressed here, where time-resolved step-scan FTIR difference spectroscopy at 77 K has been used to study PSI with six different quinones incorporated into the A1 binding site. (P700+A1− – P700A1) and (A1− – A1) FTIR difference spectra (DS) were obtained for PSI with the different quinones incorporated, and several double-difference spectra (DDS) were constructed from the DS. From analysis of the DS and DDS, in combination with density functional theory based vibrational frequency calculations of the quinones, the neutral state bands of the incorporated quinones are identified and assigned. For neutral PhQ in the A1 binding site, infrared absorption bands were identified near 1665 and 1635 cm−1, that are due to the C1O and C4O stretching vibrations of the incorporated PhQ, respectively. These assignments indicate a 30 cm−1 separation between the C1O and C4O modes, considerably less than the ~80 cm−1 found for similar modes of PhQ−. The C4O mode downshifts due to hydrogen bonding, so the suggestion is that hydrogen bonding is weaker for the neutral state compared to the anion state, indicating radical-induced proton dynamics associated with the quinone in the A1 binding site in PSI. 相似文献
13.
《Saudi Journal of Biological Sciences》2020,27(11):2980-2986
This study was aimed to analyze the anti-cancer activity of silver nanoparticles (AgNPs) synthesized using aqueous plant extracts from the rhizome of Curcuma longa and Zingiber officinale. Synergistic aqueous extract of rhizome of C. longa and Z. officinale was used to green synthesis of AgNPs. Characterization of AgNPs was performed using UV–visible spectroscopy, FTIR, X-ray diffraction, TEM, and SEM analyses. Anti-cancer activity of AgNPs against human colon carcinoma (HT-29) cells was tested using MTT assay. UV–Visible spectroscopy analysis indicated the surface plasmon resonance (SPR) sharp peak at 350–430 nm wavelength that corresponds to the production of AgNPs. FTIR analysis reveals that existence of carboxyl (CO) and amine (NH) functional groups in the AgNPs. The X-ray diffraction analysis confirms four spectral peaks at 111, 200, 220, and 311. SEM analysis showed that AgNPs are in a spherical shape with a size of 42–61 nm and TEM analysis showed particle size are ranged between 20–51 nm. Anti-cancer study reveals that AgNPs had shown cytotoxicity against HT-29 cells at the concentrations ranged from 25 to 500 μg/mL and IC50 at 150.8 µg/mL. This study concludes that AgNPs synthesized using rhizome of Z. officinale and C. longa possesses potential anti-cancer activity. 相似文献
14.
《Bioorganic & medicinal chemistry》2020,28(1):115187
In a search for potent antileishmanial drug candidates, eighteen rhodacyanine analogues bearing fluorine or perfluoroalkyl substituents at various positions were synthesized. These compounds were tested for their inhibitory activities against Leishmania martiniquensis and L. orientalis. This ‘fluorine-walk’ analysis revealed that the introduction of fluorine atom at C-5, 6, 5′, or 6′ on the benzothiazole units led to significant enhancement of the activity, correlating with the less negative reduction potentials of the fluorinated analogues confirmed by the electrochemical study. On the other hand, CF3 and OCF3 groups were found to have detrimental effects, which agreed with the poor aqueous solubility predicted by the in silico ADMET analysis. In addition, some of the analogues including the difluorinated species showed exceptional potency against the promastigote and axenic amastigote stages (IC50 = 40–85 nM), with the activities surpassing both amphotericin B and miltefosine. 相似文献
15.
《Peptides》2013
Peptide de13a was previously purified from the venom of the worm-hunting cone snail Conus delessertii from the Yucatán Channel, México. This peptide has eight cysteine (Cys) residues in the unique arrangement CCCCCCCC, which defines the cysteine framework XIII (“” represents one or more non-Cys residues). Remarkably, δ-hydroxy-lysine residues have been found only in conotoxin de13a, which also contains an unusually high proportion of hydroxylated amino acid residues. Here, we report the cDNA cloning of the complete precursor De13.1 of a related peptide, de13b, which has the same Cys framework and inter-Cys spacings as peptide de13a, and shares high protein/nucleic acid sequence identity (87%/90%) with de13a, suggesting that both peptides belong to the same conotoxin gene superfamily. Analysis of the signal peptide of precursor De13.1 reveals that this precursor belongs to a novel conotoxin gene superfamily that we chose to name gene superfamily G. Thus far superfamily G only includes two peptides, each of which contains the same, distinctive Cys framework and a high proportion of amino acid residues with hydroxylated side chains. 相似文献
16.
A series of eleven 1-methyl, 5-phenyl substituted thiosemicarbazones (MT1–MT11) with the phenyl ring substitutions were prepared and investigated for their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). [4-(dimethylamino) phenyl]methylidene}-N-methylhydrazine-1-carbothioamide (MT5) inhibited MAO-B potently with an IC50 of 8.77 μM. Potencies for MAO-B increased in the order N(CH3)2 in MT5 > OCH3 in MT3 > Br in MT9. Most of the 11 compounds weakly inhibited AChE by <30% at 10 μM. MT5 competitively inhibited MAO-B and Ki value was 6.58 ± 0.064 μM. Reversibility experiments showed MT5 also reversibly inhibited MAO-B. MTT assays revealed that MT5 and MT3 were non-toxic to normal VERO cell lines with IC50 values of 191.96 and 187.04 μg/mL, respectively. From the molecular docking, MT5 binding was found to be stabilized by hydrogen bonding to the non-bonding electron of the terminal N-methyl group with Cys172 (binding energy = −7.01 kcal/mol) of MAO-B. The molecular dynamics further predicted that MT5 had a major π–π hydrophobic interaction with Tyr326 of MAO-B, suggesting that it plays an important role in the stabilization of protein-ligand interaction.These results documents that MT5 is a moderately selective, reversible, and competitive inhibitor of MAO-B with low cytotoxic profile. 相似文献
17.
Raman microscopy has been used to deduce information about the distributions of endogenous biomolecules without exogenous labeling. Several functional groups, such as alkynes (CC), nitriles (CN), and carbon-deuterium (C–D) bonds, have been employed in recent years as Raman tags to detect target molecules in cells. In this article, we review some recent advances in applications using deuterated fatty acids for lipid analysis, such as investigation of tumor-selective cytotoxicity of γ-linolenic acid (GLA), simultaneous two-color imaging of stearate and oleate using deuterated and protonated alkynes, Raman hyperspectral imaging, and analyses of the physical properties of lipids through spectral unmixing of the C–D vibrational frequencies. In addition, we review some advanced methods for observing intracellular metabolic activities, such as de novo lipogenesis from deuterium-labeled precursors. 相似文献
18.
《Saudi Journal of Biological Sciences》2020,27(3):894-898
This study investigated the in vitro antioxidant, proapoptotic and anti-proliferative activity of phycocyanin extracted from Ulva lactuca (Chlorophyta) algae extract loaded on albumin nanoparticle (ULANP). The characterization of ULANP profile was done by using FTIR and its cytotoxicity was investigated by using MTT assay against HepG2 and MCF7 cell lines. The proapoptotic markers caspase 8 & 9 were measured. Analysis of ULANP by FTIR showed the characteristic band (2100 cm−1 ~3700 cm−1) that is indicated primarily by COO, CO and conjugated double bond. These bonds showed the spectral band at peaks of 2985 cm−1 and 2860 cm−1, 2986 cm−1 respectively. The antioxidant potential and radical scavenging property of ULANP was also appreciable as compared to the vitamin C and gallic acid. The antiproliferative assay carried out by WST-1 suggests that ULANP was effective against both HepG2 (93.17%) and MCF7 (91.3%). Caspase-8 and −9 were significantly elevated (p < 0.001) in both the cell lines of breast and liver cancer. It was concluded that ULANP induced anti-proliferative and pro-apoptotic activities on liver and breast cancer. It is promising as a novel antitumor activity for further investigation the mechanistic pathways mediated this action. 相似文献
19.
Jorge J. Wenz 《生物化学与生物物理学报:生物膜》2021,1863(4):183553
The covalent OH bonds of water vibrate and absorb radiation in the near infrared (NIR) region at wavelengths that vary according to the strength of the bonds which, at the same time, are sensitive to the number and/or strength of hydrogen bonds. By means of multivariate analytical tools, such spectral shift was exploited to study the effect of temperature, 25-hydroxycholesterol and progesterone on the H-bonded network of water in DMPA membranes. Temperature was found as the dominating factor altering the NIR spectra of water and then the H-bonds. Increasing temperatures disrupt the H-bonds network, strengthening the OH covalent bonds. The disruption of the H-bonds along the 13–58 °C range was noticeably greater than that caused by lipids or steroids at 500 μM. The H-bonded network of the interfacial water in DMPA membranes was disrupted by the presence of 25-hydroxycholesterol, but no significant disruption was observed in the presence of progesterone. The reduction of the H-bonds entails a reduction in the aggregation of the interfacial water by a reduction in the number of H-bonded molecules. It is proposed that the number of water molecules bonded with two H-bonds diminishes and the number of molecules with no H-bond increases roughly at similar proportions, with a constant population of molecules with one H-bond. The opposed effects of steroids are discussed in the context of their opposed effects on the phase state of membranes, the membrane water content and the steroid molecular structure. 相似文献
20.
《Bioorganic & medicinal chemistry》2014,22(20):5697-5704
The direct conversion of aliphatic CH bonds into CN bonds provides an attractive approach to the introduction of nitrogen-containing functionalities in organic molecules. Following the recent discovery that cytochrome P450 enzymes can catalyze the cyclization of arylsulfonyl azide compounds via an intramolecular C(sp3)H amination reaction, we have explored here the CH amination reactivity of other hemoproteins. Various heme-containing proteins, and in particular myoglobin and horseradish peroxidase, were found to be capable of catalyzing this transformation. Based on this finding, a series of engineered and artificial myoglobin variants containing active site mutations and non-native Mn- and Co-protoporphyrin IX cofactors, respectively, were prepared to investigate the effect of these structural changes on the catalytic activity and selectivity of these catalysts. Our studies showed that metallo-substituted myoglobins constitute viable CH amination catalysts, revealing a distinctive reactivity trend as compared to synthetic metalloporphyrin counterparts. On the other hand, amino acid substitutions at the level of the heme pocket were found to be beneficial toward improving the stereo- and enantioselectivity of these Mb-catalyzed reactions. Mechanistic studies involving kinetic isotope effect experiments indicate that CH bond cleavage is implicated in the rate-limiting step of myoglobin-catalyzed amination of arylsulfonyl azides. Altogether, these studies indicate that myoglobin constitutes a promising scaffold for the design and development of CH amination catalysts. 相似文献