Polyketide biosynthesis and discovery

Trans-AT PKSs are highly complex natural product enzymes that synthesize bioactive metabolites. They are a major enzyme class encoded in bacterial genomes. The Piel group is interested in understanding trans-AT PKS biosynthetic machineries, and in developing new computational tools for polyketide discovery.

trans-AT PKS enzymology

The trans-acyltransferase polyketide synthases (trans-AT PKSs) are a widespread family of biosynthetic enzymes. They build up bioactive metabolites such as clinical antibiotics. The Piel group is interested in understanding the enzymology of these remarkable machineries. Key contributions include:

Entire biosynthetic pathway characterization
Discovery of new PKS module chemistry
Studies towards combinatorial polyketide libraries
Development of computational tools

Trans-AT PKS research in the Piel group — Overview on trans-AT PKS biosynthesis research in the Piel group. A) Biosynthetic principle of cis-AT and trans-AT PKSs. B) Phylogenetic ketosynthase tree, adapted from Helfrich et al., Nat. Chem. Biol. 2019. C) Examples of trans-AT PKS modules that were characterized in the Piel group.

Genome mining tools and strategies

A common challenge in the discovery of new natural products is the reisolation of known compounds. We develop and apply strategies to predict natural product structures from genomic data (see Tools). This allows us to:

identify promising producer organisms
eliminate already reported metabolites
rapidly recognize novel entities

We isolate prioritized compounds and characterize their structures. Then, we subject them to pharmacological tests in our group and by collaborators.

Enlarged view: Natural product discovery by genome mining — Structure prediction through genome mining

Related publications (selection)

Minas HA, François RMM, Hemmerling F, Fraley AE, Dieterich CL, Rüdisser SH, Meoded RA, Collin S, Weissman KJ, Gruez A, Piel J. "Modular Oxime Formation by a trans-AT Polyketide Synthase." Angew. Chem. Int. Ed. (2023) e202304481. external pageAbstract

Fraley AE, Dell M, Schmalhofer M, Meoded RA, Bergande C, Groll M, Piel J. "Heterocomplex structure of a polyketide synthase component involved in modular backbone halogenation." Structure (2023) 31, 5, 565-572.e4. external pageAbstract

Fraley AE, Dieterich CL, Mabesoone MFJ, Minas HA, Meoded RA, Hemmerling F, Piel J. "Structure of a Promiscuous Thioesterase Domain Responsible for Branching Acylation in Polyketide Biosynthesis." Angew. Chem. Int. Ed. (2022) 61, 39, e202206385. external pageAbstract

Hemmerling F, Meoded RA, Fraley AE, Minas HA, Dieterich CL, Rust M, Ueoka R, Jensen K, Helfrich EJN, Bergande C, Biedermann M, Magnus N, Piechulla B, Piel J. "Modular Halogenation, α-Hydroxylation, and Acylation by a Remarkably Versatile Polyketide Synthase." Angew. Chem. Int. Ed. (2022) 61, 11, e202116614. external pageAbstract

Meoded RA, Ueoka R, Helfrich EJN, Jensen K, Magnus N, Piechulla B, Piel J. "A Polyketide Synthase Component for Oxygen Insertion into Polyketide Backbones." Angew. Chem. Int. Ed. (2018) 57, 36, 11644-11648. external pageAbstract

Ueoka R, Bortfeld-Miller M, Morinaka BI, Vorholt JA, Piel J. "Toblerols: Cyclopropanol-Containing Polyketide Modulators of Antibiosis in Methylobacteria." Angew. Chem. Int. Ed. (2018) 57, 4, 977-981. external pageAbstract

Helfrich EJN, Piel J. "Biosynthesis of polyketides by trans-AT polyketide synthases." Nat. Prod. Rep. (2016) 2, 231-316. external pageAbstract

Pöplau P, Frank S, Morinaka BI, Piel J. "An enzymatic domain for the formation of cyclic ethers in complex polyketides." Angew. Chem. Int. Ed. (2013) 52, 50, 13215-8. external pageAbstract

Jensen K, Niederkrüger H, Zimmermann K, Vagstad AL, Moldenhauer J, Brendel N, Frank S, Pöplau P, Kohlhaas C, Townsend CA, Oldiges M, Hertweck C, Piel J. "Polyketide proofreading by an acyltransferase-like enzyme." Chem. Biol. (2012) 19, 3, 329-39. external pageAbstract

Moldenhauer J, Götz DC, Albert CR, Bischof SK, Schneider K, Süssmuth RD, Engeser M, Gross H, Bringmann G, Piel J. "The final steps of bacillaene biosynthesis in Bacillus amyloliquefaciens FZB42: direct evidence for beta,gamma dehydration by a trans-acyltransferase polyketide synthase." Angew. Chem. Int. Ed. (2010) 49, 8, 1465-7. external pageAbstract

Moldenhauer J, Chen XH, Borriss R, Piel J. "Biosynthesis of the antibiotic bacillaene, the product of a giant polyketide synthase complex of the trans-AT family." Angew. Chem. Int. Ed. (2007) 46, 43, 8195-7. external pageAbstract

Ueoka R, Sondermann P, Leopold-Messer S, Liu Y, Suo R, Bhushan A, Vadakumchery L, Greczmiel U, Yashiroda Y, Kimura H, Nishimura S, Hoshikawa Y, Yoshida M, Oxenius A, Matsunaga S, Williamson RT, Carreira EM, Piel J. "Genome-based discovery and total synthesis of janustatins, potent cytotoxins from a plant-associated bacterium." Nat Chem. (2022), 10, 1193-1201. external pageAbstract

Hemmerling F, Piel J. "Strategies to access biosynthetic novelty in bacterial genomes for drug discovery." Nat. Rev. Drug. Discov. (2022) 5, 59-378. external pageAbstract

Helfrich EJN, Ueoka R, Chevrette MG, Hemmerling F, Lu X, Leopold-Messer S, Minas HA, Burch AY, Lindow SE, Piel J, Medema MH. "Evolution of combinatorial diversity in trans-acyltransferase polyketide synthase assembly lines across bacteria." Nat. Commun. (2021) 12, 1, 1422. external pageAbstract

Helfrich EJN, Ueoka R, Dolev A, Rust M, Meoded RA, Bhushan A, Califano G, Costa R, Gugger M, Steinbeck C, Moreno P, Piel J. "Automated structure prediction of trans-acyltransferase polyketide synthase products." Nat. Chem. Biol. (2019) 8, 813-821. external pageAbstract

Ueoka R, Uria AR, Reiter S, Mori T, Karbaum P, Peters EE, Helfrich EJ, Morinaka BI, Gugger M, Takeyama H, Matsunaga S, Piel J. "Metabolic and evolutionary origin of actin-binding polyketides from diverse organisms" Nat Chem Biol (2015) 9, 705-12. external pageAbstract

Wilson MC, Piel J "Metagenomic Approaches for Exploiting Uncultivated Bacteria as Resource for Novel Biosynthetic Enzymology" Chem. Biol. (2013) 20, 636-647. external pageAbstract

Piel J. “Approaches to capturing and designing biologically active small molecules produced by uncultured microbes” Annu. Rev. Microbiol. (2011) 65, 431-453. external pageAbstract

Fisch KM, Gurgui C, Heycke N, van der Sar SA, Anderson SA, Vebb VL, Taudien S, Platzer M, Rubio BK, Robinson SJ, Crews P, Piel J. “Polyketide assembly lines of uncultivated sponge symbionts from structure-based gene targeting” Nat. Chem. Biol., (2009) 5, 494-501. external pageAbstract

Nguyen T, Ishida K, Jenke-Kodama H, Dittmann E, Gurgui C, Hochmuth T, Taudien S, Platzer M, Hertweck C, Piel J. "Exploiting the mosaic structure of trans-acyltransferase polyketide synthases for natural product discovery and pathway dissection." Nat. Biotechnol. (2008) 2, 225-33. external pageAbstract