Über die Isolierung neuer Stoffwechselprodukte aus <i>Penicillium brefeldianum</i> D<scp>ODGE</scp>

Härri, E.; Loeffler, W.; Sigg, H. P.; Stähelin, H.; Tamm, Christoph

doi:10.1002/hlca.19630460419

Cited by 159 publications

(55 citation statements)

References 13 publications

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“…lactone (18). Phenotypes such as endomembrane bodies (P1 and P2), apparent cytoplasmic localization (P8), or vacuolar body formation (P12), were displayed for the examined markers in different combinations (SI Appendix, Fig.…”

Section: High-content Cellular Screen For Molecules Affects the Recycmentioning

confidence: 99%

Clusters of bioactive compounds target dynamic endomembrane networks in vivo

Drakakaki

Robert

Szatmári

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

117

148

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Endomembrane trafficking relies on the coordination of a highly complex, dynamic network of intracellular vesicles. Understanding the network will require a dissection of cargo and vesicle dynamics at the cellular level in vivo. This is also a key to establishing a link between vesicular networks and their functional roles in development. We used a high-content intracellular screen to discover small molecules targeting endomembrane trafficking in vivo in a complex eukaryote, Arabidopsis thaliana. Tens of thousands of molecules were prescreened and a selected subset was interrogated against a panel of plasma membrane (PM) and other endomembrane compartment markers to identify molecules that altered vesicle trafficking. The extensive image dataset was transformed by a flexible algorithm into a marker-by-phenotype-by-treatment time matrix and revealed groups of molecules that induced similar subcellular fingerprints (clusters). This matrix provides a platform for a systems view of trafficking. Molecules from distinct clusters presented avenues and enabled an entry point to dissect recycling at the PM, vacuolar sorting, and cell-plate maturation. Bioactivity in human cells indicated the value of the approach to identifying small molecules that are active in diverse organisms for biology and drug discovery.chemical genomics | high content screen | endosidin | endosome T he coordination of multicellular growth to establish and maintain the morphology of eukaryotic organisms during development is orchestrated by complex regulatory processes in which vesicular trafficking within the endomembrane system is essential (1, 2). The endomembrane system is a network of interconnected pathways required to establish signaling, cell-tocell communication, cell polarity, and cell shape in response to developmental or environmental stimuli (3). Eukaryotic cells possess the ability to internalize their plasma membrane (PM) and thus rapidly remodel their protein content (4), which is essential for polar growth, cytokinesis, hormone perception and transport, response to pathogens, and metal detoxification (5-8).To dissect the endomembrane network from a systems perspective and to understand protein functions within the network, it is necessary to perturb trafficking in a controlled fashion and to examine the consequences on growth and development. The ability to induce and evaluate subcellular phenotypes at a significant scale based on combinations of multiple endomembranespecific markers is critical for characterization of the network. In this regard, small molecules are promising for the efficient discovery and evaluation of complex intracellular phenotypes because, for any molecule, lines expressing different endomembrane fluorescent protein markers can be efficiently interrogated in parallel (3).In a previous pilot screen we identified endosidin 1 (ES1), a compound that arrests PIN2 and BRI1 in SYP61 aggregates, named ES1 bodies (9). We have used a modified high-throughput confocal-based screen focused on the rapid recycling of PM ...

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Section: High-content Cellular Screen For Molecules Affects the Recycmentioning

confidence: 99%

Clusters of bioactive compounds target dynamic endomembrane networks in vivo

Drakakaki

Robert

Szatmári

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

117

148

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“…1 In an early study of this compound, the (6S)-chirality, trans-junction between the two rings and the E-stereochemistry of the conjugated double bond were established. 3 The solid-state stereochemical features of 1 were obtained from an x-ray crystallographic study. 4 Weber et al 4 also noted that the antiperiplanar (ca 180°) relationships found for H(1)-C(1)-C(14a)-H(14a) and H(11)-C(11)-C(11a)-H(11a) in the solid-state were also retained in CDCl 3 solution, as indicated by their vicinal coupling constants of ca 9 Hz.…”

Section: Introductionmentioning

confidence: 99%

NMR structure determination of brefeldin-A, a 13-membered ring fungal metabolite

Glaser

Shiftan

Froimowitz³

2000

Magn. Reson. Chem.

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Dissolution of brefeldin‐A in CDCl3 afforded two species in the ratio 13 : 1. Vicinal proton–proton coupling constants and NOE intensity enhancement measurements showed that the 13‐membered ring conformation found by x‐ray crystallography in the solid state appears to be preferred also in the solution‐state major species. The observance of signals from a solution‐state minor species (e.g. for the C‐15 methyl) shows that at least one other 13‐membered ring conformation exists in a small amount. While some degree of conformational flexibility for the major species cyclopentyl ring cannot be ruled out, the O‐13 hydroxyl group is clearly axially disposed in the solution state as it is in the crystal. Comparison of the solution‐state 13C NMR chemical shifts of the major species with those values measured by solid‐state cross‐polarization magic angle spinning show fairly good agreement with differences usually of 1 ppm, or less, with the exception of C‐2,8,6,11,15 signals where differences were ca 2–3 ppm. Copyright © 2000 John Wiley & Sons, Ltd.

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“…Two types of ARF GEP have been distinguished by their susceptibility to inhibition by brefeldin A (BFA), a macrocyclic lactone synthesized from palmitate by a variety of fungi (15) and initially identified as an antiviral agent (16). After it was found that BFA inhibits an early step in secretion causing retention of secretory and membrane proteins in the ER of many cells (17), it became an important tool for the study of intracellular vesicular trafficking.…”

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confidence: 99%

Brefeldin A Inhibited Activity of the Sec7 Domain of p200, a Mammalian Guanine Nucleotide-exchange Protein for ADP-ribosylation Factors

Morinaga

Adamik

Moss

et al. 1999

Journal of Biological Chemistry

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A brefeldin A (BFA)-inhibited guanine nucleotide-exchange protein (GEP) for ADP-ribosylation factors (ARF) was purified earlier from bovine brain cytosol. Cloning and expression of the cDNA confirmed that the recombinant protein (p200) is a BFA-sensitive ARF GEP. p200 contains a domain that is 50% identical in amino acid sequence to a region in yeast Sec7, termed the Sec7 domain. Sec7 domains have been identified also in other proteins with ARF GEP activity, some of which are not inhibited by BFA. To identify structural elements that influence GEP activity and its BFA sensitivity, several truncated mutants of p200 were made. Deletion of sequence C-terminal to the Sec7 domain did not affect GEP activity. A protein lacking 594 amino acids at the N terminus, as well as sequence following the Sec7 domain, also had high activity. The mutant lacking 630 N-terminal amino acids was, however, only 1% as active, as was the Sec7 domain itself (mutant lacking 697 Nterminal residues). It appears that the Sec7 domain of p200 contains the catalytic site but additional sequence (perhaps especially that between positions 595 and 630) modifies activity dramatically. Myristoylated recombinant ARFs were better than non-myristoylated as substrates; ARFs 1 and 3 were better than ARF5, and no activity was detected with ARF6. Physical interaction of the Sec7 domain with an ARF1 mutant was demonstrated, but it was much weaker than that of the cytohesin-1 Sec7 domain with the same ARF protein. Effects of BFA on p200 and all mutants with high activity were similar with ϳ50% inhibition at <50 M. The inactive BFA analogue B36 did not inhibit the Sec7 domain or p200. Thus, the Sec7 domain of p200, like that of Sec7 itself (Sata, M., Donaldson, J. G., Moss, J., and Vaughan, M. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 4204 -4208), plays a role in BFA inhibition as well as in GEP activity, although the latter is markedly modified by other structural elements.

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Über die Isolierung neuer Stoffwechselprodukte aus Penicillium brefeldianum DODGE

Cited by 159 publications

References 13 publications

Clusters of bioactive compounds target dynamic endomembrane networks in vivo

Clusters of bioactive compounds target dynamic endomembrane networks in vivo

NMR structure determination of brefeldin-A, a 13-membered ring fungal metabolite

Brefeldin A Inhibited Activity of the Sec7 Domain of p200, a Mammalian Guanine Nucleotide-exchange Protein for ADP-ribosylation Factors

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