Molecular BioSystems

doi: 10.1039/c4mb90031fpmid: N/A

Yan, Renxiang; Wang, Xiaofeng; Huang, Lanqing; Lin, Jun; Cai, Weiwen; Zhang, Ziding

doi: 10.1039/c4mb00272epmid: 25014909

G protein coupled receptors (GPCRs), also known as seven-transmembrane domain receptors, pass through the cellular membrane seven times and play diverse biological roles in the cells such as signaling, transporting of molecules and cell–cell communication. In this work, we develop a web server, namely the GPCRserver, which is capable of identifying GPCRs from genomic sequences, and locating their transmembrane regions. The GPCRserver contains three modules: (1) the Trans-GPCR for the transmembrane region prediction by using sequence evolutionary profiles with the assistance of neural network training, (2) the SSEA-GPCR for identifying GPCRs from genomic data by using secondary structure element alignment, and (3) the PPA-GPCR for identifying GPCRs by using profile-to-profile alignment. Our predictor was strictly benchmarked and showed its favorable performance in the real application. The web server and stand-alone programs are publicly available at http://genomics.fzu.edu.cn/GPCR/index.html.

Asby, D. J.; Cuda, F.; Hoakwie, F.; Miranda, E.; Tavassoli, A.

doi: 10.1039/c4mb00351apmid: 25091694

Hypoxia inducible factor-1 (HIF-1) directs the cellular response to low oxygen and plays a key role in tumour survival and growth. Here we use an inhibitor of the HIF-1α/HIF-1β protein–protein interaction to show the presence of an epigenetically controlled transactivation loop whereby the HIF-1 transcription factor promotes the expression of its own α-subunit in hypoxic cancer cells.

Ding, Fei; Peng, Wei; Peng, Yu-Kui; Jiang, Yu-Ting

doi: 10.1039/c4mb00220bpmid: 25016933

In the present work, the molecular recognition of the oldest active amphenicols by the most popular renal carrier, lysozyme, was deciphered by using fluorescence, circular dichroism (CD) and molecular modeling at the molecular scale. Steady state fluorescence data showed that the recognition of amphenicol by lysozyme yields a static type of fluorescence quenching. This corroborates time-resolved fluorescence results that lysozyme–amphenicol adduct formation has a moderate affinity of 104 M−1, and the driving forces were found to be chiefly hydrogen bonds, hydrophobic interactions and π stacking. Far-UV CD spectra confirmed that the spatial structure of lysozyme was slightly changed with a distinct reduction of α-helices in the presence of amphenicol, suggesting partial destabilization of the protein. Furthermore, via the extrinsic 8-anilino-1-naphthalenesulfonic acid fluorescence spectral properties and molecular modeling, one could see that the amphenicol binding site was situated at the deep crevice on the protein surface, and the ligand was also near to several crucial amino acid residues, such as Trp-62, Trp-63 and Arg-73. Simultaneously, contrastive studies of protein–amphenicols revealed clearly that some substituting groups, e.g. nitryl in the molecular structure of ligands, may be vitally important for the recognition activity of amphenicols with lysozyme. Due to the connection of amphenicols with fatal detrimental effects and because lysozyme has been applied as a drug carrier for proximal tubular targeting, the discussion herein is necessary for rational antibiotic use, development of safe antibiotics and particularly a better appraisal of the risks associated with human exposure to toxic agrochemicals.

Zhang, Xinzhuang; Gu, Jiangyong; Cao, Liang; Li, Na; Ma, Yiming; Su, Zhenzhen; Ding, Gang; Chen, Lirong; Xu, Xiaojie; Xiao, Wei

doi: 10.1039/c4mb00164hpmid: 25000319

Traditional Chinese medicine (TCM) is a multi-component and multi-target agent and could treat complex diseases in a holistic way, especially infection diseases. However, the underlying pharmacology remains unclear. Fortunately, network pharmacology by integrating system biology and polypharmacology provides a strategy to address this issue. In this work, Reduning Injection (RDN), a well-used TCM treatment in the clinic for upper respiratory tract infections (URTIs), was investigated to interpret the molecular mechanism and predict new clinical directions by integrating molecular docking, network analysis and cell-based assays. 32 active ingredients and 38 potential targets were identified. In vitro experiments confirmed the bioactivities of the compounds against lipopolysaccharide (LPS)-stimulated PGE2 and NO production in RAW264.7 cells. Moreover, network analysis showed that RDN could not only inhibit viral replication but also alleviate the sickness symptoms of URTIs through directly targeting the key proteins in the respiratory viral life cycle and indirectly regulating host immune systems. In addition, other clinical applications of RDN such as neoplasms, cardiovascular diseases and immune system diseases were predicted on the basis of the relationships between targets and diseases.

Fang, Xin; Reifman, Jaques; Wallqvist, Anders

doi: 10.1039/c4mb00115jpmid: 25001103

The human malaria parasite Plasmodium falciparum goes through a complex life cycle, including a roughly 48-hour-long intraerythrocytic developmental cycle (IDC) in human red blood cells. A better understanding of the metabolic processes required during the asexual blood-stage reproduction will enhance our basic knowledge of P. falciparum and help identify critical metabolic reactions and pathways associated with blood-stage malaria. We developed a metabolic network model that mechanistically links time-dependent gene expression, metabolism, and stage-specific growth, allowing us to predict the metabolic fluxes, the biomass production rates, and the timing of production of the different biomass components during the IDC. We predicted time- and stage-specific production of precursors and macromolecules for P. falciparum (strain HB3), allowing us to link specific metabolites to specific physiological functions. For example, we hypothesized that coenzyme A might be involved in late-IDC DNA replication and cell division. Moreover, the predicted ATP metabolism indicated that energy was mainly produced from glycolysis and utilized for non-metabolic processes. Finally, we used the model to classify the entire tricarboxylic acid cycle into segments, each with a distinct function, such as superoxide detoxification, glutamate/glutamine processing, and metabolism of fumarate as a byproduct of purine biosynthesis. By capturing the normal metabolic and growth progression in P. falciparum during the IDC, our model provides a starting point for further elucidation of strain-specific metabolic activity, host–parasite interactions, stress-induced metabolic responses, and metabolic responses to antimalarial drugs and drug candidates.

Chaleckis, Romanas; Ebe, Masahiro; Pluskal, Tomáš; Murakami, Itsuo; Kondoh, Hiroshi; Yanagida, Mitsuhiro

doi: 10.1039/c4mb00346bpmid: 25010571

Metabolomics, a modern branch of chemical biology, provides qualitative and quantitative information about the metabolic states of organisms or cells at the molecular level. Here we report non-targeted, metabolomic analyses of human blood, using liquid chromatography-mass spectrometry (LC-MS). We compared the blood metabolome to the previously reported metabolome of the fission yeast, Schizosaccharomyces pombe. The two metabolomic datasets were highly similar: 101 of 133 compounds identified in human blood (75%) were also present in S. pombe, and 45 of 57 compounds enriched in red blood cells (RBCs) (78%) were also present in yeast. The most abundant metabolites were ATP, glutathione, and glutamine. Apart from these three, the next most abundant metabolites were also involved in energy metabolism, anti-oxidation, and amino acid metabolism. We identified fourteen new blood compounds, eight of which were enriched in RBCs: citramalate, GDP-glucose, trimethyl-histidine, trimethyl-phenylalanine, trimethyl-tryptophan, trimethyl-tyrosine, UDP-acetyl-glucosamine, UDP-glucuronate, dimethyl-lysine, glutamate methyl ester, N-acetyl-(iso)leucine, N-acetyl-glutamate, N2-acetyl-lysine, and N6-acetyl-lysine. Ten of the newly identified blood metabolites were also detected in S. pombe, and ten of the 14 newly identified blood metabolites were methylated or acetylated amino acids. Trimethylated or acetylated free amino acids were also abundant in white blood cells. It may be possible to investigate their physiological roles using yeast genetics.

He, Xiaojun; Li, Jia; Zhang, Hong; Tan, Lifeng

doi: 10.1039/c4mb00304gpmid: 25010433

There is renewed interest in investigating triplex nucleic acids because triplexes may be implicated in a range of cellular functions. However, the stabilization of triplex nucleic acids is essential to achieve their biological functions. In contrast to triplex DNA, little has been reported concerning the recognition of triplex RNA by transition-metal complexes at present. We report here a ruthenium(ii) polypyridyl complex, [Ru(bpy)2(mdpz)]2+ (bpy = 2,2′-bipyridine; mdpz = 7,7′-methylenedioxyphenyl-dipyrido-[3,2-a:2′,3′-c]phenazine), as a sensitive luminescent probe for poly(U)·poly(A)*poly(U), which can strongly stabilize the triplex RNA from 37.5 to 53.1 °C in solution. The main results further advance our knowledge on the triplex RNA-binding by metal complexes, particularly ruthenium(ii) complexes.