Reconstitution of Enzymatic Carbon-Sulfur Bond Formation Reveals Detoxification-Like Strategy in Fungal Toxin Biosynthesis

被引：11

作者：

Scharf, Daniel H. ^{[1
,4
]}

Dworschak, Jan D. ^{[2
]}

Chankhamjon, Pranatchareeya ^{[2
,5
]}

Scherlach, Kirstin ^{[2
]}

Heinekamp, Thorsten ^{[1
]}

Brakhage, Axel A. ^{[1
,3
]}

Hertweck, Christian ^{[2
,3
]}

机构：

[1] Leibniz Inst Nat Prod Res & Infect Biol HKI, Dept Mol & Appl Microbiol, D-07745 Jena, Germany

[2] Leibniz Inst Nat Prod Res & Infect Biol HKI, Dept Biomol Chem, D-07745 Jena, Germany

[3] Friedrich Schiller Univ Jena, D-07743 Jena, Germany

[4] Stanford Univ, Mol & Cellular Physiol, Stanford, CA 94305 USA

[5] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA

来源：

ACS CHEMICAL BIOLOGY | 2018年 / 13卷 / 09期

关键词：

GLIOTOXIN BIOSYNTHESIS; ASPERGILLUS-FUMIGATUS; NATURAL-PRODUCTS; GENE-CLUSTER; GLIP; CHEMISTRY; VIRULENCE; DELETION; MODEL; ATOMS;

D O I：

10.1021/acschembio.8b00413

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Gliotoxin is a virulence factor of the human pathogen Aspergillus fumigatus, the leading cause of invasive aspergillosis. The activity of this metabolite is mediated by a transannular disulfide bond, a hallmark of the epipolythiodiketopiperazine (ETP) family. Through the creation of fungal gene deletion mutants and heterologous protein expression, we unveiled the critical role of the cytochrome P450 monooxygenase (CYP450) GIiC for the stepwise bishydroxylation of the diketopiperazine (DKP) core. We show for the first time the formation of the C-S bond from the DKP in a combined assay of GIiC and the glutathione-S-transferase (GST) GIiG in vitro. Furthermore, we present experimental evidence for an intermediary imine species. The flexible substrate scope of GIiC and GliG in combination parallels P450/GST pairs used in eukaryotic phase I/II detoxification pathways.

引用

页码：2508 / 2512

页数：5

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