Abstract
The discovery and understanding of the mode of action of new antimicrobial agents is extremely urgent, since fungal infections cause 1.5 million deaths annually. Antifungal peptides and proteins represent a significant group of compounds that are able to kill pathogenic fungi. Based on phylogenetic analyses the ascomycetous, cysteine-rich antifungal proteins can be divided into three different groups: Penicillium chrysogenum antifungal protein (PAF), Neosartorya fischeri antifungal protein 2 (NFAP2) and “bubble-proteins” (BP) produced, for example, by P. brevicompactum. They all dominantly have β-strand secondary structures that are stabilized by several disulfide bonds. The PAF group (AFP antifungal protein from Aspergillus giganteus, PAF and PAFB from P. chrysogenum, Neosartorya fischeri antifungal protein (NFAP)) is the best characterized with their common β-barrel tertiary structure. These proteins and variants can efficiently be obtained either from fungi production or by recombinant expression. However, chemical synthesis may be a complementary aid for preparing unusual modifications, e.g., the incorporation of non-coded amino acids, fluorophores, or even unnatural disulfide bonds. Synthetic variants up to ca. 6–7 kDa can also be put to good use for corroborating structure determination. A short overview of the structural peculiarities of antifungal β-strand disulfide bridged proteins will be given. Here, we describe the structural propensities of some known antifungal proteins from filamentous fungi which can also be prepared with modern synthetic chemistry methods.
Highlights
Fungal infections represent a globally increasing health problem
Thirty-four of them were studied by Nuclear Magnetic Resonance (NMR), and only nine by X-ray crystallography. Fifteen of these proteins are secreted by filamentous ascomycetes. Compared to these bewildering numbers, the structures here are limited (Table 1) and this review focuses on antifungal β-strand proteins
Efficient production of antifungal proteins from filamentous fungi or their variants have become available recently from wild type or mutant strains, and sometimes by heterologous expression. Their tertiary structures are solved by NMR or X-ray crystallography, possibly equipped with in silico methods
Summary
Fungal infections represent a globally increasing health problem. There is a competition between pathogenic microbes and the efficacy of host-defense mechanisms [1]. The antimicrobial peptide database (APD), http://aps.unmc.edu/AP/main.php contains more than 3000 sequences [8], and among them 1084 antifungal peptides can be found They may be classified as α, β, αβ, and non-αβ, depending on their constituent secondary structures of α-helices and/or β-strands. The scope of this review is to cover recent progress in structure determination and synthetic chemistry of antifungal β-strand, disulfide proteins. 2. Structure Determination of Antifungal Disulfide β-Strand Proteins from Filamentous Fungi. Besides some smaller peptides, the X-ray structure of the bubble protein in the antifungal protein family was published [11], PDB code: 1uoy It has a globular, all-β secondary structure (except a short helix) with a new fold, and surface electrostatic charge similar to the Williopsis mrakii killer toxin.
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