Mol Biosyst [JOURNAL]
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200 papers
Structural modeling of the AhR:ARNT complex in the bHLH-PASA-PASB region elucidates the key determinants of dimerization.
Corrada D, Denison MS, Bonati L
Mol Biosyst · 2017 May · PMID 28393157 · Full text
Elucidation of the dimerization process of the aryl hydrocarbon receptor (AhR) with the AhR nuclear translocator (ARNT) is crucial for understanding the mechanisms underlying the functional activity of AhR, including med...
Elucidation of the dimerization process of the aryl hydrocarbon receptor (AhR) with the AhR nuclear translocator (ARNT) is crucial for understanding the mechanisms underlying the functional activity of AhR, including mediation of the toxicity of environmental contaminants. In this work, for the first time a structural model of the AhR:ARNT dimer encompassing the entire bHLH-PASA-PASB domain region is proposed. It is developed by using a template-based modeling approach, relying on the recently available crystallographic structures of two dimers of homologous systems in the bHLH-PAS family of proteins: the CLOCK:BMAL1 and the HIF2α:ARNT heterodimers. The structural and energetic characteristics of the modeled AhR:ARNT protein-protein interface are determined by evaluating the variations in solvent accessible surface area, the total binding free energy and the per-residue free energy contributions obtained by the MM-GBSA method and the Energy Decomposition Analysis. The analyses of the intricate network of inter-domain interactions at the dimerization interfaces provide insights into the key determinants of dimerization. These are confirmed by comparison of the computational findings with the available experimental mutagenesis and functional analysis data. The results presented here on the AhR:ARNT dimer structure and interactions provide a framework to start analyzing the mechanism of AhR transformation into its functional DNA binding form.
New insights into polyene macrolide biosynthesis in Couchioplanes caeruleus.
Sheehan J, Murphy CD, Caffrey P
Mol Biosyst · 2017 May · PMID 28383583 · Publisher ↗
Couchioplanes caeruleus DSM43634 synthesises 67-121C, an aromatic heptaene macrolide that contains a mannosyl-mycosaminyl disaccharide. An improved draft genome sequence was used to obtain the biosynthetic gene cluster f...
Couchioplanes caeruleus DSM43634 synthesises 67-121C, an aromatic heptaene macrolide that contains a mannosyl-mycosaminyl disaccharide. An improved draft genome sequence was used to obtain the biosynthetic gene cluster for this antifungal. Bioinformatic analysis of the polyketide synthase indicated that extension modules 7 and 8 contain A-type ketoreductase and dehydratase domains. These modules are therefore predicted to form cis double bonds. The deduced stereostructure of the 67-121C macrolactone is identical to that experimentally determined for the partricin subgroup of aromatic heptaenes. Some of these polyenes are N-methylated on the aminoacetophenone moiety. The C. caeruleus AceS protein was shown to methylate 4-aminoacetophenone and esters of 4-aminobenzoate, but not 4-aminobenzoate. This suggests that the substrate specificity of AceS prevents it from interfering with folate biosynthesis. The methyltransferase should be valuable for chemoenzymatic alkylation of compounds that contain aminobenzoyl moieties.
Aggregation behavior of novel heptamethine cyanine dyes upon their binding to native and fibrillar lysozyme.
Vus K, Tarabara U, Kurutos A … +5 more , Ryzhova O, Gorbenko G, Trusova V, Gadjev N, Deligeorgiev T
Mol Biosyst · 2017 May · PMID 28379242 · Publisher ↗
Two newly synthesized symmetrical heptamethine cyanine dyes, AK7-5 and AK7-6, absorbing in the region of low autofluorescence of biological samples, have been tested for their ability to detect proteins aggregated into a...
Two newly synthesized symmetrical heptamethine cyanine dyes, AK7-5 and AK7-6, absorbing in the region of low autofluorescence of biological samples, have been tested for their ability to detect proteins aggregated into amyloid fibrils. In aqueous solution these probes possess three absorption bands corresponding to the monomer, dimer and H-aggregate species. The association of the dye with fibrillar lysozyme was followed by the enhancement of the monomer band and the reduction of the H-band. The absorption spectra measured at various fibril concentrations were analyzed in terms of the model allowing for the shift of equilibria between various dye species due to the binding of monomers and dimers of AK7-5 and AK7-6 to amyloid fibrils. The association constants and stoichiometries of the dye-fibril complexation have been evaluated. In contrast to fibrillar lysozyme, the native protein brought about strong J-aggregate formation accompanied by a marked drop in the absorbance of the dye monomer species. Quantum chemical calculations and simple docking studies showed that AK7-5 and AK7-6 monomers can bind to the grooves, running parallel to the fibril axis. Due to their ability to distinguish between the native and fibrillar protein states, the novel cyanines are recommended as complementary to existing amyloid markers.
A systematic reconstruction and constraint-based analysis of Leishmania donovani metabolic network: identification of potential antileishmanial drug targets.
Sharma M, Shaikh N, Yadav S … +2 more , Singh S, Garg P
Mol Biosyst · 2017 May · PMID 28367572 · Publisher ↗
Visceral leishmaniasis, a lethal parasitic disease, is caused by the protozoan parasite Leishmania donovani. The absence of an effective vaccine, drug toxicity and parasite resistance necessitates the identification of n...
Visceral leishmaniasis, a lethal parasitic disease, is caused by the protozoan parasite Leishmania donovani. The absence of an effective vaccine, drug toxicity and parasite resistance necessitates the identification of novel drug targets. Reconstruction of genome-scale metabolic models and their simulation has been established as an important tool for systems-level understanding of a microorganism's metabolism. In this work, amalgamating the tools and techniques of computational systems biology with rigorous manual curation, a constraint-based metabolic model for Leishmania donovani BPK282A1 has been developed. New functional annotations for 18 formerly hypothetical or erroneously annotated genes (encountered during iterative refinement of the model) have been proposed. Further, to formulate an accurate biomass objective function, experimental determination of previously uncharacterized biomass constituents was performed. The developed model is a highly compartmentalized metabolic model, comprising 1159 reactions, 1135 metabolites and 604 genes. The model exhibited around 76% accuracy for the prediction of experimental phenotypes of gene knockout studies and drug inhibition assays. Employing in silico gene knockout studies, we identified 28 essential genes with negligible sequence identity to the human proteins. Moreover, by dissecting the functional interdependencies of metabolic pathways, 70 synthetic lethal pairs were identified. Finally, in order to delineate stage-specific metabolism, gene-expression data of the amastigote stage residing in human macrophages were integrated into the model. By comparing the flux distribution, we illustrated the stage-specific differences in metabolism and environmental conditions that are in good agreement with the experimental findings. The developed model can serve as a highly enriched knowledgebase of legacy data and an important tool for generating experimentally verifiable hypotheses.
Cancerous perturbations within the ERK, PI3K/Akt, and Wnt/β-catenin signaling network constitutively activate inter-pathway positive feedback loops.
Padala RR, Karnawat R, Viswanathan SB … +2 more , Thakkar AV, Das AB
Mol Biosyst · 2017 May · PMID 28367561 · Publisher ↗
Perturbations in molecular signaling pathways are a result of genetic or epigenetic alterations, which may lead to malignant transformation of cells. Despite cellular robustness, specific genetic or epigenetic changes of...
Perturbations in molecular signaling pathways are a result of genetic or epigenetic alterations, which may lead to malignant transformation of cells. Despite cellular robustness, specific genetic or epigenetic changes of any gene can trigger a cascade of failures, which result in the malfunctioning of cell signaling pathways and lead to cancer phenotypes. The extent of cellular robustness has a link with the architecture of the network such as feedback and feedforward loops. Perturbation in components within feedback loops causes a transition from a regulated to a persistently activated state and results in uncontrolled cell growth. This work represents the mathematical and quantitative modeling of ERK, PI3K/Akt, and Wnt/β-catenin signaling crosstalk to show the dynamics of signaling responses during genetic and epigenetic changes in cancer. ERK, PI3K/Akt, and Wnt/β-catenin signaling crosstalk networks include both intra and inter-pathway feedback loops which function in a controlled fashion in a healthy cell. Our results show that cancerous perturbations of components such as EGFR, Ras, B-Raf, PTEN, and components of the destruction complex cause extreme fragility in the network and constitutively activate inter-pathway positive feedback loops. We observed that the aberrant signaling response due to the failure of specific network components is transmitted throughout the network via crosstalk, generating an additive effect on cancer growth and proliferation.
Inhibition of the MurA enzyme in Fusobacterium nucleatum by potential inhibitors identified through computational and in vitro approaches.
Kumar A, Saranathan R, Prashanth K … +2 more , Tiwary BK, Krishna R
Mol Biosyst · 2017 May · PMID 28358152 · Publisher ↗
Fusobacterium nucleatum plays a key role in several diseases such as periodontitis, gingivitis, appendicitis, and inflammatory bowel disease (IBD). The development of antibiotic resistance by this bacterium demands novel...
Fusobacterium nucleatum plays a key role in several diseases such as periodontitis, gingivitis, appendicitis, and inflammatory bowel disease (IBD). The development of antibiotic resistance by this bacterium demands novel therapeutic intervention. Our recent study has reported UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA) as one of the potential target proteins in F. nucleatum. In this study, we proposed two novel MurA inhibitors through in silico screening and evaluated their mode of inhibition by in vitro experiments. It was found that MurA structural arrangement (inside-out α/β barrel) was stabilized by L/FXXXG(A) motif-based interactions. The protein was maintained in an open or substrate-free conformation due to repulsive forces between two parallelly arranged positively charged residues of domain I and II. In this conformation, we identified six best compounds that held key interactions with the substrate-binding pocket via a structure-based virtual screening of natural and chemical compound libraries. However, among these, only orientin and quercetin-3-O-d-glucuronide (Q3G) showed better interaction capability through consistent H-bond occupancy and lowest binding free energy during molecular dynamic simulations. In vitro inhibition studies evidenced the mixed and uncompetitive mode of inhibition by orientin and Q3G, respectively, with purified MurA protein. This explains the binding of orientin in both open and closed (substrate-bound) conformations of MurA, and Q3G binding in only closed conformation. Therefore, the Q3G binding mode was predicted on a MurA-substrate complex, which highlighted its constant H-bond with Cys118, a phosphoenolpyruvate (PEP) interacting residue. This suggests that Q3G may interrupt the PEP binding, thereby inhibiting the MurA activity. Thus, the current study discusses the structure of MurA and demonstrates the inhibitory action of two novel compounds.
Quantitative proteomic characterization of redox-dependent post-translational modifications on protein cysteines.
Duan J, Gaffrey MJ, Qian WJ
Mol Biosyst · 2017 May · PMID 28357434 · Full text
Protein thiols play a crucial role in redox signaling, in the regulation of enzymatic activity and protein function, and in maintaining redox homeostasis in living systems. The unique chemical reactivity of the thiol gro...
Protein thiols play a crucial role in redox signaling, in the regulation of enzymatic activity and protein function, and in maintaining redox homeostasis in living systems. The unique chemical reactivity of the thiol group makes protein cysteines susceptible to reactions with reactive oxygen and nitrogen species that form various reversible and irreversible post-translational modifications (PTMs). The reversible PTMs in particular are major components of redox signaling and are involved in the regulation of various cellular processes under physiological and pathological conditions. The biological significance of these redox PTMs in both healthy and disease states has been increasingly recognized. Herein, we review recent advances in quantitative proteomic approaches for investigating redox PTMs in complex biological systems, including general considerations of sample processing, chemical or affinity enrichment strategies, and quantitative approaches. We also highlight a number of redox proteomic approaches that enable effective profiling of redox PTMs for specific biological applications. Although technical limitations remain, redox proteomics is paving the way to a better understanding of redox signaling and regulation in both healthy and disease states.
How RNase HI (Escherichia coli) promoted site-selective hydrolysis works on RNA in duplex with carba-LNA and LNA substituted antisense strands in an antisense strategy context?
Plashkevych O, Li Q, Chattopadhyaya J
Mol Biosyst · 2017 May · PMID 28352859 · Publisher ↗
A detailed kinetic study of 36 single modified AON-RNA heteroduplexes shows that substitution of a single native nucleotide in the antisense strand (AON) by locked nucleic acid (LNA) or by diastereomerically pure carba-L...
A detailed kinetic study of 36 single modified AON-RNA heteroduplexes shows that substitution of a single native nucleotide in the antisense strand (AON) by locked nucleic acid (LNA) or by diastereomerically pure carba-LNA results in site-dependent modulation of RNase H promoted cleavage of complementary mRNA strands by 2 to 5 fold at 5'-GpN-3' cleavage sites, giving up to 70% of the RNA cleavage products. The experiments have been performed using RNase HI of Escherichia coli. The 2nd best cleavage site, being the 5'-ApN-3' sites, cleaves up to 23%, depending upon the substitution site in 36 isosequential complementary AONs. A comparison of the modified AON promoted RNA cleavage rates with that of the native AON shows that sequence-specificity is considerably enhanced as a result of modification. Clearly, relatively weaker 5'-purine (Pu)-pyrimidine (Py)-3' stacking in the complementary RNA strand is preferred (giving ∼90% of total cleavage products), which plays an important role in RNase H promoted RNA cleavage. A plausible mechanism of RNase H mediated cleavage of the RNA has been proposed to be two-fold, dictated by the balancing effect of the aromatic character of the purine aglycone: first, the locally formed 9-guanylate ion (pK 9.3, ∼18-20% N1 ionized at pH 8) alters the adjoining sugar-phosphate backbone around the scissile phosphate, transforming its sugar N/S conformational equilibrium, to preferential S-type, causing preferential cleavage at 5'-GpN-3' sites around the center of 20 mer complementary mRNA. Second, the weaker nearest-neighbor strength of 5'-Pu-p-Py-3' stacking promotes preferential 5'-GpN-3' and 5'-ApN-3' cleavage, providing ∼90% of the total products, compared to ∼50% in that of the native one, because of the cLNA/LNA substituent effect on the neighboring 5'-Pu-p-Py-3' sites, providing both local steric flexibility and additional hydration. This facilitates both the water and water/Mg ion availability at the cleavage site causing sequence-specific hydrolysis of the phosphodiester bond of scissile phosphate. The enhancement of the total rate of cleavage of the complementary mRNA strand by up to 25%, presented in this work, provides opportunities to engineer a single modification site in appropriately substituted AONs to design an effective antisense strategy based on the nucleolytic stability of the AON strand versus RNase H capability to cleave the complementary RNA strand.
Outstanding Reviewers for Molecular BioSystems in 2016.
Mol Biosyst · 2017 Mar · PMID 28350032 · Publisher ↗
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Stereoselective binding of agonists to the β-adrenergic receptor: insights into molecular details and thermodynamics from molecular dynamics simulations.
Plazinska A, Plazinski W
Mol Biosyst · 2017 May · PMID 28338133 · Publisher ↗
The β-adrenergic receptor (β-AR) is one of the most studied G-protein-coupled receptors. When interacting with ligand molecules, it exhibits a binding characteristic that is strongly dependent on ligand stereoconfigurati...
The β-adrenergic receptor (β-AR) is one of the most studied G-protein-coupled receptors. When interacting with ligand molecules, it exhibits a binding characteristic that is strongly dependent on ligand stereoconfiguration. In particular, many experimental and theoretical studies confirmed that stereoisomers of an important β-AR agonist, fenoterol, are associated with diverse mechanisms of binding and activation of β-AR. The objective of the present study was to explore the stereoselective binding of fenoterol to β-AR through the application of an advanced computational methodology based on enhanced-sampling molecular dynamics simulations and potentials of interactions tailored to investigate the stereorecognition effects. The results remain in very good, quantitative agreement with the experimental data (measured in the context of ligand-receptor affinities and their dependence on the temperature), which provides an additional validation for the applied computational protocols. Additionally, our results contribute to the understanding of stereoselective agonist binding by β-AR. Although the significant role of the N293 residue is confirmed, we additionally show that stereorecognition does not depend solely on the N293-ligand interactions; the stereoselective effects rely on the co-operation of several residues located on both the 6th and 7th transmembrane domains and on extracellular loops. The magnitude and character of the contributions of these residues may be very diverse and result in either enhancing or reducing the stereoselective effects. The same is true when considering the enthalpic and entropic contributions to the binding free energies, which also are dependent on the ligand stereoconfiguration.
Prediction of metabolic fluxes from gene expression data with Huber penalty convex optimization function.
Zhang SW, Gou WL, Li Y
Mol Biosyst · 2017 May · PMID 28338129 · Publisher ↗
As one of the critical parameters of a metabolic pathway, the metabolic flux in a metabolic network serves as an essential role in physiology and pathology. Constraint-based metabolic models are the widely used framework...
As one of the critical parameters of a metabolic pathway, the metabolic flux in a metabolic network serves as an essential role in physiology and pathology. Constraint-based metabolic models are the widely used frameworks for predicting metabolic fluxes in genome-scale metabolic networks. Integrating the transcriptomic data into the constraint-based metabolic models can effectively predict context-specific fluxes across different conditions. However, these methods always need user-defined thresholds to identify the expression levels of metabolic genes or restrain the rate of biomass production, and the predictive results are sensitive to the thresholds. In this work, we present the Huber penalty convex optimization function (HPCOF) combined with the flux minimization principle to predict metabolic fluxes. Our HPCOF method integrates gene expression profiles into the genome-scale metabolic models (GEMs) to reduce the sensitivity to outliers, and uses continuous expression data to avoid selection of arbitrary threshold parameters. In the case studies of Saccharomyces cerevisiae (S. cerevisiae) and Escherichia coli (E. coli) strains under different conditions, the results show that our HPCOF method has a better fit to the experimentally measured values, and has a higher Pearson correlation coefficient, a smaller P-value and a lower sum of squared error than other methods. The HPCOF code can be freely downloaded from for academic users.
Molecular dynamics simulations elucidate conformational selection and induced fit mechanisms in the binding of PD-1 and PD-L1.
Liu W, Huang B, Kuang Y … +1 more , Liu G
Mol Biosyst · 2017 May · PMID 28327740 · Publisher ↗
Blockage of the interactions between immunologic checkpoint protein PD-1 and its ligand PD-L1 showed efficacy for cancer treatment. X-ray structures have captured static conformational snapshots of PD-1 and revealed that...
Blockage of the interactions between immunologic checkpoint protein PD-1 and its ligand PD-L1 showed efficacy for cancer treatment. X-ray structures have captured static conformational snapshots of PD-1 and revealed that the CC' loop adopts an open conformation in the apo-protein but turns into a closed form and interacts with PD-L1 in the complex. This structural heterogeneity brings difficulties for structure-based drug discovery targeting PD-1. To gain insights into the role of the CC' loop in molecular recognition, we have undertaken a comparative study between the open and closed conformations in apo-PD-1 and the PD-1/PD-L1 complex using molecular dynamics simulations. Results show that the moderate stability of intramolecular hydrogen bonds between SER71 and THR120 allows the CC' loop to sample both the open and closed states in apo-PD-1. Binding of PD-L1 accelerates the open-to-closed switch and locks the loop in the closed state through four newly formed intermolecular hydrogen bonds. Thus, we suggest a complex binding mechanism between PD-1 and PD-L1 where both the conformational selection and induced fit theories play a role.
The nature of the conserved basic amino acid sequences found among 437 heparin binding proteins determined by network analysis.
Rudd TR, Preston MD, Yates EA
Mol Biosyst · 2017 May · PMID 28317949 · Publisher ↗
In multicellular organisms, a large number of proteins interact with the polyanionic polysaccharides heparan sulphate (HS) and heparin. These interactions are usually assumed to be dominated by charge-charge interactions...
In multicellular organisms, a large number of proteins interact with the polyanionic polysaccharides heparan sulphate (HS) and heparin. These interactions are usually assumed to be dominated by charge-charge interactions between the anionic carboxylate and/or sulfate groups of the polysaccharide and cationic amino acids of the protein. A major question is whether there exist conserved amino acid sequences for HS/heparin binding among these diverse proteins. Potentially conserved HS/heparin binding sequences were sought amongst 437 HS/heparin binding proteins. Amino acid sequences were extracted and compared using a Levenshtein distance metric. The resultant similarity matrices were visualised as graphs, enabling extraction of strongly conserved sequences from highly variable primary sequences while excluding short, core regions. This approach did not reveal extensive, conserved HS/heparin binding sequences, rather a number of shorter, more widely spaced sequences that may work in unison to form heparin-binding sites on protein surfaces, arguing for convergent evolution. Thus, it is the three-dimensional arrangement of these conserved motifs on the protein surface, rather than the primary sequence per se, which are the evolutionary elements.
Comparison of Leptospira interrogans and Leptospira biflexa genomes: analysis of potential leptospiral-host interactions.
Mehrotra P, Ramakrishnan G, Dhandapani G … +2 more , Srinivasan N, Madanan MG
Mol Biosyst · 2017 May · PMID 28294222 · Publisher ↗
Leptospirosis, a potentially life-threatening disease, remains the most widespread zoonosis caused by pathogenic species of Leptospira. The pathogenic spirochaete, Leptospira interrogans, is characterized by its ability...
Leptospirosis, a potentially life-threatening disease, remains the most widespread zoonosis caused by pathogenic species of Leptospira. The pathogenic spirochaete, Leptospira interrogans, is characterized by its ability to permeate human host tissues rapidly and colonize multiple organs in the host. In spite of the efforts taken to comprehend the pathophysiology of the pathogen and the heterogeneity posed by L. interrogans, the current knowledge on the mechanism of pathogenesis is modest. In an attempt to contribute towards the same, we demonstrate the use of an established structure-based protocol coupled with information on subcellular localization of proteins and their tissue-specificity, in recognizing a set of 49 biologically feasible interactions potentially mediated by proteins of L. interrogans in humans. We have also presented means to adjudge the physicochemical viability of the predicted host-pathogen interactions, for selected cases, in terms of interaction energies and geometric shape complementarity of the interacting proteins. Comparative analyses of proteins of L. interrogans and the saprophytic spirochaete, Leptospira biflexa, and their predicted involvement in interactions with human hosts, aided in underpinning the functional relevance of leptospiral-host protein-protein interactions specific to L. interrogans as well as those specific to L. biflexa. Our study presents characteristics of the pathogenic L. interrogans that are predicted to facilitate its ability to persist in human hosts.
The Ca-ATPase pump facilitates bidirectional proton transport across the sarco/endoplasmic reticulum.
Espinoza-Fonseca LM
Mol Biosyst · 2017 Mar · PMID 28290590 · Full text
Ca transport across the sarco/endoplasmic reticulum (SR) plays an essential role in intracellular Ca homeostasis, signalling, cell differentiation and muscle contractility. During SR Ca uptake and release, proton fluxes...
Ca transport across the sarco/endoplasmic reticulum (SR) plays an essential role in intracellular Ca homeostasis, signalling, cell differentiation and muscle contractility. During SR Ca uptake and release, proton fluxes are required to balance the charge deficit generated by the exchange of Ca and other ions across the SR. During Ca uptake by the SR Ca-ATPase (SERCA), two protons are countertransported from the SR lumen to the cytosol, thus partially compensating for the charge moved by Ca transport. Studies have shown that protons are also transported from the cytosol to the lumen during Ca release, but a transporter that facilitates proton transport into the SR lumen has not been described. In this article we propose that SERCA forms pores that facilitate bidirectional proton transport across the SR. We describe the location and structure of water-filled pores in SERCA that form cytosolic and luminal pathways for protons to cross the SR membrane. Based on this structural information, we suggest mechanistic models for proton translocation to the cytosol during active Ca transport, and into the SR lumen during SERCA inhibition by endogenous regulatory proteins. Finally, we discuss the physiological consequences of SERCA-mediated bidirectional proton transport across the SR membrane of muscle and non-muscle cells.
Optimal parameter values for the control of gene regulation.
Brajesh RG, Raj N, Saini S
Mol Biosyst · 2017 Mar · PMID 28271105 · Publisher ↗
How does a transcription network arrive at the particular values of biochemical interactions defining it? These interactions define DNA-transcription factor interaction, degradation rates of proteins, promoter strengths,...
How does a transcription network arrive at the particular values of biochemical interactions defining it? These interactions define DNA-transcription factor interaction, degradation rates of proteins, promoter strengths, and communication of the environmental signal with the network. What is the structure of the fitness landscape that is defined by the space that these parameters can take on? To answer these questions, we simulate the simplest regulatory network: a transcription factor, R, and a target protein, T. We use a cost-benefit analysis to evolve the network and eventually arrive at values of parameters which maximize fitness. We show that for a given topology, multiple parameter sets exist which confer maximal fitness to the cell, and that pairwise correlations exist between parameters in optimal sets. In addition, our results indicate that in the parameter space defining the interactions in a topology, a highly rugged fitness landscape exists.
Metabolic profiling study of shikonin's cytotoxic activity in the Huh7 human hepatoma cell line.
Spyrelli ED, Kyriazou AV, Virgiliou C … +5 more , Nakas A, Deda O, Papageorgiou VP, Assimopoulou AN, Gika HG
Mol Biosyst · 2017 May · PMID 28265634 · Publisher ↗
Shikonin and its enantiomer alkannin, which are natural products, have been extensively studied in vitro and in vivo for, among others, their antitumor activity. The investigation of the molecular pathways involved in th...
Shikonin and its enantiomer alkannin, which are natural products, have been extensively studied in vitro and in vivo for, among others, their antitumor activity. The investigation of the molecular pathways involved in their action is of interest, since they are not yet clearly defined. Metabolic profiling in cells can provide a picture of a cell's phenotype upon intervention, assisting in the elucidation of the mechanism of action. In this study, the cytotoxic effect of shikonin on a human hepatocarcinoma cell line was studied. Huh7 cells were treated with shikonin at 5 μM, and it was found that shikonin markedly inhibited cell growth. Metabolic profiling indicated alterations in the metabolic content of the cells and the culture media upon treatment, detecting the metabolic response of the cells. This study demonstrates the potential of metabolomics to improve knowledge on the mechanisms involved in shikonin's antitumor action.
Screening methods for identifying pharmacological chaperones.
Shin MH, Lim HS
Mol Biosyst · 2017 Mar · PMID 28265599 · Publisher ↗
Protein folding is crucial for most proteins to achieve their correct three-dimensional conformations and function properly. Defects in protein folding frequently caused by mutations lead to a range of protein misfolding...
Protein folding is crucial for most proteins to achieve their correct three-dimensional conformations and function properly. Defects in protein folding frequently caused by mutations lead to a range of protein misfolding diseases, including Alzheimer's disease, Parkinson's disease, cystic fibrosis, amyloidosis, Gaucher disease, etc. One approach to treat these devastating diseases would be to use pharmacological chaperones, which are small-molecules that bind to and stabilize misfolded proteins, thereby correcting their pathogenic misfolding and rescuing their functions. As such, pharmacological chaperone therapy holds great promise for the treatment of numerous protein misfolding diseases. In this review, we highlight recent strategies for identifying small-molecules that act as pharmacological chaperones and revert protein misfolding diseases, with a focus on reports within the last five years.
Consensus architecture of promoters and transcription units in Escherichia coli: design principles for synthetic biology.
Rangel-Chavez C, Galan-Vasquez E, Martinez-Antonio A
Mol Biosyst · 2017 Mar · PMID 28256660 · Publisher ↗
Genetic information in genomes is ordered, arranged in such a way that it constitutes a code, the so-called cis regulatory code. The regulatory machinery of the cell, termed trans-factors, decodes and expresses this info...
Genetic information in genomes is ordered, arranged in such a way that it constitutes a code, the so-called cis regulatory code. The regulatory machinery of the cell, termed trans-factors, decodes and expresses this information. In this way, genomes maintain a potential repertoire of genetic programs, parts of which are executed depending on the presence of active regulators in each condition. These genetic programs, executed by the regulatory machinery, have functional units in the genome delimited by punctuation-like marks. In genetic terms, these informational phrases correspond to transcription units, which are the minimal genetic information expressed consistently from initiation to termination marks. Between the start and final punctuation marks, additional marks are present that are read by the transcriptional and translational machineries. In this work, we look at all the experimentally described and predicted genetic elements in the bacterium Escherichia coli K-12 MG1655 and define a comprehensive architectural organization of transcription units to reveal the natural genome-design and to guide the construction of synthetic genetic programs.
Environmental factors and risk of aggressive prostate cancer among a population of New Zealand men - a genotypic approach.
Vaidyanathan V, Naidu V, Kao CH … +13 more , Karunasinghe N, Bishop KS, Wang A, Pallati R, Shepherd P, Masters J, Zhu S, Goudie M, Krishnan M, Jabed A, Marlow G, Narayanan A, Ferguson LR
Mol Biosyst · 2017 Mar · PMID 28252132 · Publisher ↗
Prostate cancer is one of the most significant health concerns for men worldwide. Numerous researchers carrying out molecular diagnostics have indicated that genetic interactions with biological and behavioral factors pl...
Prostate cancer is one of the most significant health concerns for men worldwide. Numerous researchers carrying out molecular diagnostics have indicated that genetic interactions with biological and behavioral factors play an important role in the overall risk and prognosis of this disease. Single nucleotide polymorphisms (SNPs) are increasingly becoming strong biomarker candidates to identify susceptibility to prostate cancer. We carried out a gene × environment interaction analysis linked to aggressive and non-aggressive prostate cancer (PCa) with a number of SNPs. By using this method, we identified the susceptible alleles in a New Zealand population, and examined the interaction with environmental factors. We have identified a number of SNPs that have risk associations both with and without environmental interaction. The results indicate that certain SNPs are associated with disease vulnerability based on behavioral factors. The list of genes with SNPs identified as being associated with the risk of PCa in a New Zealand population is provided in the graphical abstract.
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