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      Exploring the Chemodiversity and Biological Activities of the Secondary Metabolites from the Marine Fungus Neosartorya pseudofischeri

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          Abstract

          The production of fungal metabolites can be remarkably influenced by various cultivation parameters. To explore the biosynthetic potentials of the marine fungus, Neosartorya pseudofischeri, which was isolated from the inner tissue of starfish Acanthaster planci, glycerol-peptone-yeast extract (GlyPY) and glucose-peptone-yeast extract (GluPY) media were used to culture this fungus. When cultured in GlyPY medium, this fungus produced two novel diketopiperazines, neosartins A and B ( 1 and 2), together with six biogenetically-related known diketopiperazines,1,2,3,4-tetrahydro-2,3-dimethyl-1,4-dioxopyrazino[1,2-a]indole ( 3), 1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole ( 4), 1,2,3,4-tetrahydro-2-methyl-1,3,4-trioxopyrazino[1,2-a] indole ( 5), 6-acetylbis(methylthio)gliotoxin ( 10), bisdethiobis(methylthio)gliotoxin ( 11), didehydrobisdethiobis(methylthio)gliotoxin ( 12) and N-methyl-1 H-indole-2-carboxamide ( 6). However, a novel tetracyclic-fused alkaloid, neosartin C ( 14), a meroterpenoid, pyripyropene A ( 15), gliotoxin ( 7) and five known gliotoxin analogues, acetylgliotoxin ( 8), reduced gliotoxin ( 9), 6-acetylbis(methylthio)gliotoxin ( 10), bisdethiobis(methylthio) gliotoxin ( 11) and bis- N-norgliovictin ( 13), were obtained when grown in glucose-containing medium (GluPY medium). This is the first report of compounds 3, 4, 6, 9, 10 and 12 as naturally occurring. Their structures were determined mainly by MS, 1D and 2D NMR data. The possible biosynthetic pathways of gliotoxin-related analogues and neosartin C were proposed. The antibacterial activity of compounds 214 and the cytotoxic activity of compounds 4, 5 and 713 were evaluated. Their structure-activity relationships are also preliminarily discussed.

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          Transannular disulfide formation in gliotoxin biosynthesis and its role in self-resistance of the human pathogen Aspergillus fumigatus.

          Gliotoxin (1), the infamous representative of the group of epipolythiodioxopiperazines (ETPs), is a virulence factor of the human pathogenic fungus Aspergillus fumigatus. The unique redox-sensitive transannular disulfide bridge is critical for deleterious effects caused by redox cycling and protein conjugation in the host. Through a combination of genetic, biochemical, and chemical analyses, we found that 1 results from GliT-mediated oxidation of the corresponding dithiol. In vitro studies using purified GliT demonstrate that the FAD-dependent, homodimeric enzyme utilizes molecular oxygen as terminal electron acceptor with concomitant formation of H(2)O(2). In analogy to the thiol-disulfide oxidoreductase superfamily, a model for dithiol-disulfide exchange involving the conserved CxxC motif is proposed. Notably, while all studied disulfide oxidases invariably form intra- or interchenar disulfide bonds in peptides, GliT is the first studied enzyme producing an epidithio bond. Furthermore, through sensitivity assays using wild type, Delta gliT mutant, and complemented strain, we found that GliT confers resistance to the producing organism. A phylogenetic study revealed that GliT falls into a clade of yet fully uncharacterized fungal gene products deduced from putative ETP biosynthesis gene loci. GliT thus not only represents the prototype of ETP-forming enzymes in eukaryotes but also delineates a novel mechanism for self-resistance.
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            GliP, a multimodular nonribosomal peptide synthetase in Aspergillus fumigatus, makes the diketopiperazine scaffold of gliotoxin.

            The fungal metabolite gliotoxin has a redox-active disulfide bridge spanning carbons 3 and 6 of a diketopiperazine (DKP) scaffold. The proposed DKP synthetase, GliP, from Aspergillus fumigatus Af293, is a three module (A1-T1-C1-A2-T2-C2-T3) 236 kDa protein that can be overproduced in soluble form in Escherichia coli. Once primed on its three thiolation domains with phosphopantetheine prosthetic groups, GliP activates and tethers l-Phe on T1 and l-Ser on T2, before generating the l-Phe-l-Ser-S-T2 dipeptidyl enzyme intermediate. Release of the dipeptide as the cyclic DKP happens slowly both in wild-type GliP and in enzyme forms where C2 and T3 have been mutationally inactivated. The lack of a thioesterase domain in GliP may account both for the slow release and for the directed fate of intramolecular cyclization to create the DKP scaffold for subsequent elaboration to gliotoxin.
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              Epigenetic Tailoring for the Production of Anti-Infective Cytosporones from the Marine Fungus Leucostoma persoonii

              Recent genomic studies have demonstrated that fungi can possess gene clusters encoding for the production of previously unobserved secondary metabolites. Activation of these attenuated or silenced genes to obtain either improved titers of known compounds or new ones altogether has been a subject of considerable interest. In our efforts to discover new chemotypes that are effective against infectious diseases, including malaria and methicillin-resistant Staphylococcus aureus (MRSA), we have isolated a strain of marine fungus, Leucostoma persoonii, that produces bioactive cytosporones. Epigenetic modifiers employed to activate secondary metabolite genes resulted in enhanced production of known cytosporones B (1, 360%), C (2, 580%) and E (3, 890%), as well as the production of the previously undescribed cytosporone R (4). Cytosporone E was the most bioactive, displaying an IC90 of 13 µM toward Plasmodium falciparum, with A549 cytotoxicity IC90 of 437 µM, representing a 90% inhibition therapeutic index (TI90 = IC90 A459/IC90 P. falciparum) of 33. In addition, cytosporone E was active against MRSA with a minimal inhibitory concentration (MIC) of 72 µM and inhibition of MRSA biofilm at roughly half that value (minimum biofilm eradication counts, MBEC90, was found to be 39 µM).
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                Author and article information

                Contributors
                Role: External Editor
                Journal
                Mar Drugs
                Mar Drugs
                marinedrugs
                Marine Drugs
                MDPI
                1660-3397
                24 November 2014
                November 2014
                : 12
                : 11
                : 5657-5676
                Affiliations
                [1 ]School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; E-Mails: natprodlwl@ 123456gmail.com (W.-L.L.); lexiu2012@ 123456163.com (X.L.); junxu@ 123456biochemomes.com (J.X.); kunchao89@ 123456gmail.com (K.-C.H.); lssydp@ 123456mail.sysu.edu.cn (D.-P.Y.)
                [2 ]Guangdong Technology Research Center for Advanced Chinese Medicine, Guangzhou 510006, China
                [3 ]School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China; E-Mail: ceslhj@ 123456mail.sysu.edu.cn
                [4 ]Guangdong Institute of Gastroenterology, Guangzhou 510655, China; E-Mails: morningyang100@ 123456gmail.com (X.-L.Y.); junxiong_ch@ 123456sina.com (J.-X.C.); huanliang.liu@ 123456gmail.com (H.-L.L.)
                [5 ]Guangdong Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou 510655, China
                [6 ]The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
                [7 ]Institute of Chinese Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China; E-Mails: wanglaiyou@ 123456gdpu.edu.cn (L.-Y.W.); kuntengwang@ 123456gmail.com (K.-T.W.)
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: lanwj@ 123456mail.sysu.edu.cn ; Tel.: +86-20-3994-3042; Fax: +86-20-3994-3000.
                Article
                marinedrugs-12-05657
                10.3390/md12115657
                4245550
                25421322
                3bcc5d96-33b5-4a94-97f9-3c2199796696
                © 2014 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                marine fungus,neosartorya pseudofischeri,neosartin,diketopiperazine,antibacterial activity,cytotoxic activity

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