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Diketopiperazine Formation in Fungi Requires Dedicated Cyclization and Thiolation Domains

Baccile, Joshua A. and Le, Henry H. and Pfannenstiel, Brandon T. and Bok, Jin Woo and Gomez, Christian and Brandenburger, Eileen and Hoffmeister, Dirk and Keller, Nancy P. and Schroeder, Frank C. (2019) Diketopiperazine Formation in Fungi Requires Dedicated Cyclization and Thiolation Domains. Angewandte Chemie International Edition, 58 (41). pp. 14589-14593. ISSN 1433-7851. https://resolver.caltech.edu/CaltechAUTHORS:20190903-130241562

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Abstract

Cyclization of linear dipeptidyl precursors derived from nonribosomal peptide synthetases (NRPSs) into 2,5‐diketopiperazines (DKPs) is a crucial step in the biosynthesis of a large number of bioactive natural products. However, the mechanism of DKP formation in fungi has remained unclear, despite extensive studies of their biosyntheses. Here we show that DKP formation en route to the fungal virulence factor gliotoxin requires a seemingly extraneous couplet of condensation (C) and thiolation (T) domains in the NRPS GliP. In vivo truncation of GliP to remove the CT couplet or just the T domain abrogated production of gliotoxin and all other gli pathway metabolites. Point mutation of conserved active sites in the C and T domains diminished cyclization activity of GliP in vitro and abolished gliotoxin biosynthesis in vivo. Verified NRPSs of other fungal DKPs terminate with similar CT domain couplets, suggesting a conserved strategy for DKP biosynthesis by fungal NRPSs.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1002/anie.201909052DOIArticle
ORCID:
AuthorORCID
Baccile, Joshua A.0000-0003-4334-755X
Keller, Nancy P.0000-0002-4386-9473
Schroeder, Frank C.0000-0002-4420-0237
Additional Information:© 2019 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim. Manuscript received: July 22, 2019; Accepted manuscript online: July 24, 2019; Version of record online: August 28, 2019. This research was funded by an NIH Chemical Biology Interface (CBI) Training Grant (5T32GM008500) to J.A.B., an NIH Predoctoral Training Program in Genetics Grant (5T32GM007133‐40) to B.T.P., and NIH R01GM112739‐01 to N.P.K. and F.C.S. We thank Prof. Robert Cramer for the kind gift of the GliP plasmid. The authors declare no conflict of interest.
Funders:
Funding AgencyGrant Number
NIH Predoctoral Fellowship5T32GM008500
NIH Predoctoral Fellowship5T32GM007133‐40
NIHR01GM112739‐01
Subject Keywords:biosynthesis; cyclization; gliotoxin; natural products; nonribosomal peptide synthetase
Issue or Number:41
Record Number:CaltechAUTHORS:20190903-130241562
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190903-130241562
Official Citation:J. A. Baccile, H. H. Le, B. T. Pfannenstiel, J. W. Bok, C. Gomez, E. Brandenburger, D. Hoffmeister, N. P. Keller, F. C. Schroeder, Angew. Chem. Int. Ed. 2019, 58, 14589. https://doi.org/10.1002/anie.201909052
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:98398
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:03 Sep 2019 20:22
Last Modified:09 Mar 2020 13:18

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