67-99-2Relevant articles and documents
Transannular disulfide formation in gliotoxin biosynthesis and its role in self-resistance of the human pathogen Aspergillus fumigatus
Scharf, Daniel H.,Remme, Nicole,Heinekamp, Thorsten,Hortschansky, Peter,Brakhage, Axel A.,Hertweck, Christian
, p. 10136 - 10141 (2010)
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 H2O 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, ΔgliT 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.
Evidence for gliotoxin-glutathione conjugate adducts
Bernardo, Paul H.,Chai, Christina L.L.,Deeble, Geoffrey J.,Liu, Xue-Ming,Waring, Paul
, p. 483 - 485 (2001)
The equilibrium constant for the gliotoxin/glutathione pair was found to be 1200±100M-1 at pH 7.0 at 25°C. Under conditions where the reaction was quenched rapidly with the addition of acid, gliotoxin-glutathione conjugate adducts were detected
New insights into the disulfide bond formation enzymes in epidithiodiketopiperazine alkaloids
Liu, Huan,Fan, Jie,Zhang, Peng,Hu, Youcai,Liu, Xingzhong,Li, Shu-Ming,Yin, Wen-Bing
, p. 4132 - 4138 (2021)
Epidithiodiketopiperazines (ETPs) are a group of bioactive fungal natural products and structurally feature unique transannular disulfide bridges between α, α or α, β carbons. However, no enzyme has yet been demonstrated to catalyse α, β-disulfide bond formation in these molecules. Through genome mining and gene deletion approaches inTrichoderma hypoxylon, we identified a putative biosynthetic gene cluster of pretrichodermamide A (1), which requires a FAD-dependent oxidoreductase, TdaR, for the irregular α, β-disulfide formation in1biosynthesis.In vitroassays of TdaR, together with AclT involved in aspirochlorine and GliT involved in gliotoxin biosynthesis, proved that all three enzymes catalyse not only the conversion of red-pretrichodermamide A (4) to α, β-disulfide-containing1but also that of red-gliotoxin (5) to α, α-disulfide-containing gliotoxin (6). These results provide new insights into the thiol-disulfide oxidases responsible for the disulfide bond formation in natural products with significant substrate and catalytic promiscuities.
Synthesis and biological evaluation of epidithio-, epitetrathio-, and bis-(methylthio)diketopiperazines: Synthetic methodology, enantioselective total synthesis of epicoccin G, 8,8′-epi-ent-rostratin B, gliotoxin, gliotoxin G, emethallicin E, and haematocin and discovery of new antiviral and antimalarial agents
Nicolaou, K. C.,Lu, Min,Totokotsopoulos, Sotirios,Heretsch, Philipp,Giguere, Denis,Sun, Ya-Ping,Sarlah, David,Nguyen, Thu H.,Wolf, Ian C.,Smee, Donald F.,Day, Craig W.,Bopp, Selina,Winzeler, Elizabeth A.
, p. 17320 - 17332,13 (2020/09/02)
An improved sulfenylation method for the preparation of epidithio-, epitetrathio-, and bis-(methylthio)diketopiperazines from diketopiperazines has been developed. Employing NaHMDS and related bases and elemental sulfur or bis[bis(trimethylsilyl)amino]trisulfide (23) in THF, the developed method was applied to the synthesis of a series of natural and designed molecules, including epicoccin G (1), 8,8′-epi-ent-rostratin B (2), gliotoxin (3), gliotoxin G (4), emethallicin E (5), and haematocin (6). Biological screening of selected synthesized compounds led to the discovery of a number of nanomolar antipoliovirus agents (i.e., 46, 2,2′-epi-46, and 61) and several low-micromolar anti-Plasmodium falciparum lead compounds (i.e., 46, 2,2′-epi-46, 58, 61, and 1).
TOTAL SYNTHESIS OF GLIOTOXIN, DEHYDROGLIOTOXIN AND HYALODENDRIN
Fukuyama, Tohru,Nakatsuka, Shin-Ichi,Kishi, Yoshito
, p. 2045 - 2078 (2007/10/02)
Two general methods, Method A and Method B in Scheme 19, to synthesize epidithiapiperazinediones, are described.A total synthesis of racemic and optically active gliotoxin (1) and of racemic dehydrogliotoxin (53) was achieved by using Method A, whereas a total synthesis of racemic hyalodendrin (52) was completed by using Method B.
