STRING and STITCH: known and predicted interactions between proteins and chemicals

Information on protein-protein and protein-chemical interactions is essential for understanding cellular functions. The STRING and STITCH web resources integrate interaction evidence derived from pathways, automatic literature mining, primary experimental data, and genomic context. The resulting interaction networks cover 1.5 million proteins from 373 organisms and 68,000 chemicals

Alkynyl ethers of glucans as intermediates for glycostructures

In der vorliegenden Arbeit wurden zur Entwicklung von Intermediaten für Glycostrukturen Glucane alkinyliert, wobei Grundgerüst (Dextran, Amylose, Methylcellulose), Molmasse, Spacerlänge (Pentinyl-C5, Hexinyl-C6), Substitutionsgrad (DS 0,06 bis 0,60) und Substituentenverteilung variiert wurden. Die terminalen Alkingruppen dienten dann zur Kopplung von Aziden mittels „Click“-Reaktion, wodurch Amino-, Carboxy- und Thiolgruppen eingeführt werden konnten. Alle Produkte wurden mittels ATR-IR-Spektroskopie, Elementaranalyse und NMR-Spektroskopie charakterisiert sowie nach Depolymerisation mittels Gaschromatographie und Massenspektrometrie analysiert. Die Reaktivität in den α-1,6-verknüpften Dextranen war in der Reihe O-2 > O-4 ≥ O-3, die in der α-1,4-verknüpften Amylose O-2 > O-6 > O-3, wobei hier die Regioselektivität mit steigender Basenmenge und höherem Substitutionsgrad zu O-6 > O-2 > O-3 verschoben werden konnte. Bei Methylcellulosen waren die Pentinylreste infolge des Angebots noch „freier Plätze“ bevorzugt in Position 3 zu finden. Die relative Reaktivität folgte aber der Reihe O-2 > O-6 > O-3. Während Glucane und ihre Derivate immer eine Verteilung von Molmasse und Substitutionsgrad aufweisen, sind definierte Glycostrukturen nur mittels de novo Synthese, z. B. aus funktionalisierten Oligosaccharidelementen zugänglich. Durch Ringöffnung von permethyliertem γ-Cyclodextrin konnten Maltooligosylchloride erhalten werden, deren Überführung in Azide mit anschließender Kopplung an multifunktionale Alkinylkernmoleküle allerdings nicht erfolgreich war. Sterisch weniger anspruchsvolle Azide sowie Tetra-O-methyl-glucoseazid als Kohlenhydrat-Modellsubstanz konnten dagegen mittels „Click“-Reaktion erfolgreich an Tetra-O-propargyl-pentaerythrit und Tetra-O-pentinyl-pentaerythrit addiert werden, wie durch ATR-IR-Spektroskopie, Elementaranalyse, NMR-Spektroskopie und ESI-Massenspektrometrie bestätigt wurde. Die Konfiguration des Azids und somit der „Click“-Produkte war überwiegend α.In the present work intermediates for glycostructures were prepared by alkynylation of glucans. Polysaccharide backbone (dextran, amylose, methylcellulose), molar mass, spacer length (pentynyl-C5, hexynyl-C6), degree of substitution (DS 0.06 up to 0.60), and substituent distribution were varied. The terminal alkynyl groups were then used for coupling of azides by “click” reaction for introducing amino, carboxy, and thiol groups. All products were characterized by ATR-IR spectroscopy, elemental analysis and NMR spectroscopy, and analyzed after depolymerization by gas-liquid chromatography and mass spectrometry (GLC-MS). In the α-1,6-linked dextrans reactivity followed the order O-2 > O-4 ≥ O-3 while in the α-1,4-linked amylose O-2 > O-6 > O-3 was observed, but here the regioselectivity was shifted to O-6 > O-2 > O-3 with increasing amount of the base and higher degree of substitution. In methylcelluloses the pentynyl residues were preferred in position 3, due to the availability of “free positions”. But the relative reactivity followed the sequence O-2 > O-6 > O-3. While glucans and their derivatives always exhibit a distribution of molar mass and degree of substitution, defined glycostructures can only be achieved by de novo synthesis, e.g. from functionalized oligosaccharide units. However, the conversion of maltooligosyl chlorides, provided by ring opening of permethylated γ-cyclodextrin, into azides and subsequent coupling on multifunctional alkynyl core molecules was not successful. However, less sterically demanding azides as well as tetra-O-methyl glucose azide as carbohydrate model substance could be added to tetra-O-propargyl pentaerythritol and tetra-O-pentynyl pentaerythritol by “click” reaction. Characterization by ATR-IR spectroscopy, elemental analysis, NMR spectroscopy and ESI mass spectrometry showed the successful formation of the triazole structures. The configuration of azide and thus the “click” products was predominantly α

Polyunsaturated Fatty Acids and Risk of Ischemic Stroke

Ischemic stroke is a major cause of death and morbidity worldwide. It has been suggested that polyunsaturated fatty acids (PUFAs) may be associated with a lower risk ischemic stroke, but this has been far less studied than their role for coronary heart disease. In this paper, we summarize the main findings from previous follow-up studies investigating associations between intake or biomarkers of the major PUFAs including alpha-linolenic acid (ALA), marine n-3 PUFAs and linoleic acid (LA) and the development of ischemic stroke. Several follow-up studies have suggested that marine n-3 PUFAs may be associated with a lower risk of ischemic stroke although results have not been consistent and limited knowledge exist on the individual marine n-3 PUFAs and ischemic stroke and its subtypes. The role of ALA is less clear, but most studies have not supported that ALA is appreciably associated with ischemic stroke risk. Some studies have supported that LA might be associated with a lower risk of total ischemic stroke, while limited evidence exist on PUFAs and ischemic stroke subtypes. The associations may depend on the macronutrients that PUFAs replace and this substitution aspect together with focus on dietary patterns represent interesting areas for future research

STITCH: interaction networks of chemicals and proteins

The knowledge about interactions between proteins and small molecules is essential for the understanding of molecular and cellular functions. However, information on such interactions is widely dispersed across numerous databases and the literature. To facilitate access to this data, STITCH (‘search tool for interactions of chemicals') integrates information about interactions from metabolic pathways, crystal structures, binding experiments and drug-target relationships. Inferred information from phenotypic effects, text mining and chemical structure similarity is used to predict relations between chemicals. STITCH further allows exploring the network of chemical relations, also in the context of associated binding proteins. Each proposed interaction can be traced back to the original data sources. Our database contains interaction information for over 68 000 different chemicals, including 2200 drugs, and connects them to 1.5 million genes across 373 genomes and their interactions contained in the STRING database. STITCH is available at http://stitch.embl.d

Prediction of effective genome size in metagenomic samples

We introduce a novel computational approach to predict effective genome size (EGS; a measure that includes multiple plasmid copies, inserted sequences, and associated phages and viruses) from short sequencing reads of environmental genomics (or metagenomics) projects. We observe considerable EGS differences between environments and link this with ecologic complexity as well as species composition (for instance, the presence of eukaryotes). For example, we estimate EGS in a complex, organism-dense farm soil sample at about 6.3 megabases (Mb) whereas that of the bacteria therein is only 4.7 Mb; for bacteria in a nutrient-poor, organism-sparse ocean surface water sample, EGS is as low as 1.6 Mb. The method also permits evaluation of completion status and assembly bias in single-genome sequencing projects