SM with influence on virulence of fungi in the respective host system.

<p>Animal cell: <b>Gliotoxin</b> acts on the mitochondrial protein Bak, which leads to apoptosis and inhibits the activation of NFκB through blocking proteasomal activity; <b>DHN-melanin</b> from <i>A. fumigatus</i> inhibits vH⁺-ATPase activity and therefore acidification of the phagolysosome, which counteracts killing of the conidia. Fungi: <b>Siderophores</b> are released by the fungus to ensure iron availability; <b>DHN-melanin</b> from plant pathogens is crucial for appressorium formation and counteracting reactive oxygen species (ROS) produced by the plant through hypersensitive response (HR) to prevent the spread of fungal infection; <b>DOPA-melanin</b> produced by <i>C. neoformans</i> from external precursors is an important part of the fungal capsule. Plant cell: <b>Cytochalasins</b> block cytokinesis; <b>T-Toxin</b> inhibits mitochondrial energy production; <b>Fumonisin</b>, <b>AAL-Toxin</b>, and <b>Cyperin</b> affect the membrane integrity; <b>Auxin</b> and <b>Gibberellins</b> act as phytohormones and alter transcription activity; <b>HC-Toxin</b> inhibits histone deacetylase; after light-driven activation both <b>Cercosporin</b> and <b>Elsinochromes</b> produce ROS, which damage the cell; <b>Sirodesmin</b> induces ROS and the formation of protein-conjugates; <b>Tentoxin</b> inhibits chloroplastidial energy production; <b>Fusicoccin</b> mediates irreversible stomata opening; <b>Beticolin</b> forms pores in the membrane and leads to leakage of the cell.</p

Gliotoxin Biosynthesis: Structure, Mechanism, and Metal Promiscuity of Carboxypeptidase GliJ

The formation of glutathione (GSH) conjugates, best known from the detoxification of xenobiotics, is a widespread strategy to incorporate sulfur into biomolecules. The biosynthesis of gliotoxin, a virulence factor of the human pathogenic fungus <i>Aspergillus fumigatus</i>, involves attachment of two GSH molecules and their sequential decomposition to yield two reactive thiol groups. The degradation of the GSH moieties requires the activity of the Cys–Gly carboxypeptidase GliJ, for which we describe the X-ray structure here. The enzyme forms a homodimer with each monomer comprising one active site. Two metal ions are present per proteolytic center, thus assigning GliJ to the diverse family of dinuclear metallohydrolases. Depending on availability, Zn²⁺, Fe²⁺, Fe³⁺, Mn²⁺, Cu²⁺, Co²⁺, or Ni²⁺ ions are accepted as cofactors. Despite this high metal promiscuity, a preference for zinc versus iron and manganese was noted. Mutagenesis experiments revealed details of metal coordination, and molecular modeling delivered insights into substrate recognition and processing by GliJ. The latter results suggest a reaction mechanism in which the two scissile peptide bonds of one gliotoxin precursor molecule are hydrolyzed sequentially and in a given order

Star-Shaped Drug Carriers for Doxorubicin with POEGMA and POEtOxMA Brush-like Shells: A Structural, Physical, and Biological Comparison

The synthesis of amphiphilic star-shaped poly­(ε-caprolactone)-<i>block</i>-poly­(oligo­(ethylene glycol)­methacrylate)­s ([PCL₁₈-<i>b</i>-POEGMA]₄) and poly­(ε-caprolactone)-<i>block</i>-poly­(oligo­(2-ethyl-2-oxazoline)­methacrylate)­s ([PCL₁₈-<i>b</i>-POEtOxMA]₄) is presented. Unimolecular behavior in aqueous systems is observed with the tendency to form loose aggregates for both hydrophilic shell types. The comparison of OEGMA and OEtOxMA reveals that the molar mass of the macromonomer in the hydrophilic shell rather than the mere length is the crucial factor to form an efficiently stabilizing hydrophilic shell. A hydrophilic/lipophilic balance of 0.8 is shown to stabilize unimolecular micelles in water. An extensive in vitro biological evaluation shows neither blood nor cytotoxicity. The applicability of the polymers as drug delivery systems was proven by the encapsulation of the anticancer drug doxorubicin, whose cytotoxic effect was retarded in comparison to the free drug