Characterization of the macrocyclase involved in the biosynthesis of RiPP cyclic peptides in plants

Chekan, Jonathan R.; Estrada, Paola; Covello, Patrick S.; Nair, Satish K.

doi:10.1073/pnas.1620499114

Characterization of the macrocyclase involved in the biosynthesis of RiPP cyclic peptides in plants

Journal Article · Mon Jun 05 00:00:00 EDT 2017 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1620499114· OSTI ID:1438880

Chekan, Jonathan R. ^[1]; Estrada, Paola ^[1]; Covello, Patrick S. ^[2]; Nair, Satish K. ^[1]

Univ. of Illinois at Urbana-Champaign, IL (United States)
National Research Council of Canada, Saskatoon (Canada)

Enzymes that can catalyze the macrocyclization of linear peptide substrates have long been sought for the production of libraries of structurally diverse scaffolds via combinatorial gene assembly as well as to afford rapid in vivo screening methods. Orbitides are plant ribosomally synthesized and posttranslationally modified peptides (RiPPs) of various sizes and topologies, several of which are shown to be biologically active. The diversity in size and sequence of orbitides suggests that the corresponding macrocyclases may be ideal catalysts for production of cyclic peptides. Here we present the biochemical characterization and crystal structures of the plant enzyme PCY1 involved in orbitide macrocyclization. These studies demonstrate how the PCY1 S9A protease fold has been adapted for transamidation, rather than hydrolysis, of acyl-enzyme intermediates to yield cyclic products. Notably, PCY1 uses an unusual strategy in which the cleaved C-terminal follower peptide from the substrate stabilizes the enzyme in a productive conformation to facilitate macrocyclization of the N-terminal fragment. The broad substrate tolerance of PCY1 can be exploited as a biotechnological tool to generate structurally diverse arrays of macrocycles, including those with nonproteinogenic elements.

View Accepted Manuscript (DOE)

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: National Institutes of Health (NIH)

OSTI ID:: 1438880

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 25 Vol. 114; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (59)

Structure Determination and Total Synthesis of Bottromycin A ₂ : A Potent Antibiotic against MRSA and VRE Shimamura, Hiroyuki; Gouda, Hiroaki; Nagai, Kenichiro Angewandte Chemie, Vol. 121, Issue 5 https://doi.org/10.1002/ange.200804138	journal	January 2009
Structure Determination and Total Synthesis of Bottromycin A ₂ : A Potent Antibiotic against MRSA and VRE Shimamura, Hiroyuki; Gouda, Hiroaki; Nagai, Kenichiro Angewandte Chemie International Edition, Vol. 48, Issue 5 https://doi.org/10.1002/anie.200804138	journal	January 2009
Über ein Oligopeptid aus Leinsamen Kaufmann, Hans Paul; Tobschirbel, Adelheid Chemische Berichte, Vol. 92, Issue 11 https://doi.org/10.1002/cber.19590921122	journal	November 1959
Dissecting the Maturation Steps of the Lasso Peptide Microcin J25 in vitro Yan, Kok-Phen; Li, Yanyan; Zirah, Séverine ChemBioChem, Vol. 13, Issue 7 https://doi.org/10.1002/cbic.201200016	journal	April 2012
Thiopeptide Antibiotics Bagley, Mark C.; Dale, James W.; Merritt, Eleanor A. ChemInform, Vol. 36, Issue 24 https://doi.org/10.1002/chin.200524278	journal	June 2005
Structure of a New Cyclic Nonapeptide, Segetalin F, and Vasorelaxant Activity of Segetalins from Vaccaria segetalis. Morita, Hiroshi; Eda, Michiko; Iizuka, Toru ChemInform, Vol. 37, Issue 52 https://doi.org/10.1002/chin.200652195	journal	December 2006
Xanthomonas campestris PqqD in the pyrroloquinoline quinone biosynthesis operon adopts a novel saddle-like fold that possibly serves as a PQQ carrier Tsai, Tung-Yi; Yang, Chao-Yu; Shih, Hui-Ling Proteins: Structure, Function, and Bioinformatics, Vol. 76, Issue 4 https://doi.org/10.1002/prot.22461	journal	September 2009
Low-Barrier Hydrogen Bonds and Enzymatic Catalysis Cleland, W. W. Archives of Biochemistry and Biophysics, Vol. 382, Issue 1 https://doi.org/10.1006/abbi.2000.2011	journal	October 2000
The prolyl oligopeptidase family Polgar, L. Cellular and Molecular Life Sciences CMLS, Vol. 59, Issue 2, p. 349-362 https://doi.org/10.1007/s00018-002-8427-5	journal	February 2002
Cyanobactins—ribosomal cyclic peptides produced by cyanobacteria Sivonen, Kaarina; Leikoski, Niina; Fewer, David P. Applied Microbiology and Biotechnology, Vol. 86, Issue 5 https://doi.org/10.1007/s00253-010-2482-x	journal	February 2010
Cyclolinopeptide A (CLA) mediates its immunosuppressive activity through cyclophilin-dependent calcineurin inactivation Gaymes, Terry J.; Cebrat, Marek; Siemion, Ignacy Z. FEBS Letters, Vol. 418, Issue 1-2 https://doi.org/10.1016/S0014-5793(97)01345-8	journal	November 1997
Prolyl Oligopeptidase Fülöp, Vilmos; Böcskei, Zsolt; Polgár, László Cell, Vol. 94, Issue 2 https://doi.org/10.1016/S0092-8674(00)81416-6	journal	July 1998
Prolyl Oligopeptidase Ito, Kiyoshi; Nakajima, Yoshitaka; Yoshimoto, Tadashi Handbook of Proteolytic Enzymes https://doi.org/10.1016/b978-0-12-382219-2.00742-0	book	January 2013
Structure of a new cyclic nonapeptide, segetalin F, and vasorelaxant activity of segetalins from Vaccaria segetalis Morita, Hiroshi; Eda, Michiko; Iizuka, Toru Bioorganic & Medicinal Chemistry Letters, Vol. 16, Issue 17 https://doi.org/10.1016/j.bmcl.2006.06.083	journal	September 2006
Genome mining for ribosomally synthesized natural products Velásquez, Juan E.; van der Donk, Wilfred A. Current Opinion in Chemical Biology, Vol. 15, Issue 1 https://doi.org/10.1016/j.cbpa.2010.10.027	journal	February 2011
Ribosomal production and in vitro selection of natural product-like peptidomimetics: The FIT and RaPID systems Hipolito, Christopher J.; Suga, Hiroaki Current Opinion in Chemical Biology, Vol. 16, Issue 1-2 https://doi.org/10.1016/j.cbpa.2012.02.014	journal	April 2012
Cyclotide biosynthesis Craik, David J.; Malik, Uru Current Opinion in Chemical Biology, Vol. 17, Issue 4 https://doi.org/10.1016/j.cbpa.2013.05.033	journal	August 2013
Two Enzymes Catalyze the Maturation of a Lasso Peptide in Escherichia coli Duquesne, Sophie; Destoumieux-Garzon, Delphine; Zirah, Severine Chemistry & Biology, Vol. 14, Issue 7, p. 793-803 https://doi.org/10.1016/j.chembiol.2007.06.004	journal	July 2007
Structures of Cyanobactin Maturation Enzymes Define a Family of Transamidating Proteases Agarwal, Vinayak; Pierce, Elizabeth; McIntosh, John Chemistry & Biology, Vol. 19, Issue 11 https://doi.org/10.1016/j.chembiol.2012.09.012	journal	November 2012
Peptide Macrocyclization Catalyzed by a Prolyl Oligopeptidase Involved in α-Amanitin Biosynthesis Luo, Hong; Hong, Sung-Yong; Sgambelluri, R. Michael Chemistry & Biology, Vol. 21, Issue 12 https://doi.org/10.1016/j.chembiol.2014.10.015	journal	December 2014
Peptide Macrocyclization by a Bifunctional Endoprotease Bernath-Levin, Kalia; Nelson, Clark; Elliott, Alysha G. Chemistry & Biology, Vol. 22, Issue 5 https://doi.org/10.1016/j.chembiol.2015.04.010	journal	May 2015
Modularity of RiPP Enzymes Enables Designed Synthesis of Decorated Peptides Sardar, Debosmita; Lin, Zhenjian; Schmidt, Eric W. Chemistry & Biology, Vol. 22, Issue 7 https://doi.org/10.1016/j.chembiol.2015.06.014	journal	July 2015
The molecular diversity of toxin gene families in lethal Amanita mushrooms Li, Peng; Deng, Wangqiu; Li, Taihui Toxicon, Vol. 83 https://doi.org/10.1016/j.toxicon.2014.02.020	journal	June 2014
Lasso Peptides: An Intriguing Class of Bacterial Natural Products Hegemann, Julian D.; Zimmermann, Marcel; Xie, Xiulan Accounts of Chemical Research, Vol. 48, Issue 7 https://doi.org/10.1021/acs.accounts.5b00156	journal	June 2015
Kinetic Landscape of a Peptide Bond-Forming Prolyl Oligopeptidase Czekster, Clarissa M.; Naismith, James H. Biochemistry, Vol. 56, Issue 15 https://doi.org/10.1021/acs.biochem.7b00012	journal	April 2017
Identification of serine and histidine adducts in complexes of trypsin and trypsinogen with peptide and nonpeptide boronic acid inhibitors by proton NMR spectroscopy Tsilikounas, Elisabeth; Kettner, Charles A.; Bachovchin, William W. Biochemistry, Vol. 31, Issue 51 https://doi.org/10.1021/bi00166a019	journal	December 1992
Thiopeptide Antibiotics Bagley, Mark C.; Dale, James W.; Merritt, Eleanor A. Chemical Reviews, Vol. 105, Issue 2 https://doi.org/10.1021/cr0300441	journal	February 2005
Structure of nisin Gross, Erhard; Morell, John L. Journal of the American Chemical Society, Vol. 93, Issue 18 https://doi.org/10.1021/ja00747a073	journal	September 1971
Theoretical Studies on the Deacylation Step of Serine Protease Catalysis in the Gas Phase, in Solution, and in Elastase Topf, Maya; Richards, W. Graham Journal of the American Chemical Society, Vol. 126, Issue 44 https://doi.org/10.1021/ja047010a	journal	November 2004
Testing the Conformational Hypothesis of Passive Membrane Permeability Using Synthetic Cyclic Peptide Diastereomers Rezai, Taha; Yu, Bin; Millhauser, Glenn L. Journal of the American Chemical Society, Vol. 128, Issue 8 https://doi.org/10.1021/ja0563455	journal	March 2006
Using Marine Natural Products to Discover a Protease that Catalyzes Peptide Macrocyclization of Diverse Substrates Lee, Jaeheon; McIntosh, John; Hathaway, Brian J. Journal of the American Chemical Society, Vol. 131, Issue 6 https://doi.org/10.1021/ja8092168	journal	February 2009
Total Synthesis of Circular Bacteriocins by Butelase 1 Hemu, Xinya; Qiu, Yibo; Nguyen, Giang K. T. Journal of the American Chemical Society, Vol. 138, Issue 22 https://doi.org/10.1021/jacs.6b04310	journal	May 2016
Identification and Quantification of Cyclolinopeptides in Five Flaxseed Cultivars Gui, Bo; Shim, Youn Young; Datla, Raju S. S. Journal of Agricultural and Food Chemistry, Vol. 60, Issue 35 https://doi.org/10.1021/jf301847u	journal	August 2012
Ribifolin, an Orbitide from Jatropha ribifolia , and Its Potential Antimalarial Activity Pinto, Meri Emili F.; Batista, João M.; Koehbach, Johannes Journal of Natural Products, Vol. 78, Issue 3 https://doi.org/10.1021/np5007668	journal	February 2015
Enzyme-Catalyzed Macrocyclization of Long Unprotected Peptides Zhang, Chi; Dai, Peng; Spokoyny, Alexander M. Organic Letters, Vol. 16, Issue 14 https://doi.org/10.1021/ol501609y	journal	June 2014
Biomimetic synthesis and optimization of cyclic peptide antibiotics Kohli, Rahul M.; Walsh, Christopher T.; Burkart, Michael D. Nature, Vol. 418, Issue 6898 https://doi.org/10.1038/nature00907	journal	August 2002
Structure and mechanism of the tRNA-dependent lantibiotic dehydratase NisB Ortega, Manuel A.; Hao, Yue; Zhang, Qi Nature, Vol. 517, Issue 7535 https://doi.org/10.1038/nature13888	journal	October 2014
Structure and biosynthesis of a macrocyclic peptide containing an unprecedented lysine-to-tryptophan crosslink Schramma, Kelsey R.; Bushin, Leah B.; Seyedsayamdost, Mohammad R. Nature Chemistry, Vol. 7, Issue 5 https://doi.org/10.1038/nchem.2237	journal	April 2015
Butelase 1 is an Asx-specific ligase enabling peptide macrocyclization and synthesis Nguyen, Giang K. T.; Wang, Shujing; Qiu, Yibo Nature Chemical Biology, Vol. 10, Issue 9 https://doi.org/10.1038/nchembio.1586	journal	July 2014
Structural analysis of leader peptide binding enables leader-free cyanobactin processing Koehnke, Jesko; Mann, Greg; Bent, Andrew F. Nature Chemical Biology, Vol. 11, Issue 8 https://doi.org/10.1038/nchembio.1841	journal	June 2015
A prevalent peptide-binding domain guides ribosomal natural product biosynthesis Burkhart, Brandon J.; Hudson, Graham A.; Dunbar, Kyle L. Nature Chemical Biology, Vol. 11, Issue 8 https://doi.org/10.1038/nchembio.1856	journal	July 2015
Structural basis for precursor protein–directed ribosomal peptide macrocyclization Li, Kunhua; Condurso, Heather L.; Li, Gengnan Nature Chemical Biology, Vol. 12, Issue 11 https://doi.org/10.1038/nchembio.2200	journal	September 2016
On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds White, Tina R.; Renzelman, Chad M.; Rand, Arthur C. Nature Chemical Biology, Vol. 7, Issue 11 https://doi.org/10.1038/nchembio.664	journal	September 2011
The exploration of macrocycles for drug discovery — an underexploited structural class Driggers, Edward M.; Hale, Stephen P.; Lee, Jinbo Nature Reviews Drug Discovery, Vol. 7, Issue 7 https://doi.org/10.1038/nrd2590	journal	July 2008
The mechanism of patellamide macrocyclization revealed by the characterization of the PatG macrocyclase domain Koehnke, Jesko; Bent, Andrew; Houssen, Wael E. Nature Structural & Molecular Biology, Vol. 19, Issue 8 https://doi.org/10.1038/nsmb.2340	journal	July 2012
Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature Arnison, Paul G.; Bibb, Mervyn J.; Bierbaum, Gabriele Nat. Prod. Rep., Vol. 30, Issue 1 https://doi.org/10.1039/C2NP20085F	journal	January 2013
Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature Arnison, Paul G.; Bibb, Mervyn J.; Bierbaum, Gabriele Nat. Prod. Rep., Vol. 30, Issue 1 https://doi.org/10.1039/c2np20085f	journal	January 2013
Estrogen-Like Activity of Cyclic Peptides from Vaccaria segetalis Extracts ¹ Itokawa, Hideji; Yun, Youngsook; Morita, Hiroshi Planta Medica, Vol. 61, Issue 06 https://doi.org/10.1055/s-2006-959373	journal	December 1995
Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity Shan, L.; Mathews, I. I.; Khosla, C. Proceedings of the National Academy of Sciences, Vol. 102, Issue 10 https://doi.org/10.1073/pnas.0408286102	journal	February 2005
Insights into the serine protease mechanism from atomic resolution structures of trypsin reaction intermediates Radisky, E. S.; Lee, J. M.; Lu, C. -J. K. Proceedings of the National Academy of Sciences, Vol. 103, Issue 18 https://doi.org/10.1073/pnas.0601910103	journal	April 2006
Gene family encoding the major toxins of lethal Amanita mushrooms Hallen, Heather E.; Luo, Hong; Scott-Craig, John S. Proceedings of the National Academy of Sciences, Vol. 104, Issue 48, p. 19097-19101 https://doi.org/10.1073/pnas.0707340104	journal	November 2007
Production of cyclic peptides and proteins in vivo Scott, C. P.; Abel-Santos, E.; Wall, M. Proceedings of the National Academy of Sciences, Vol. 96, Issue 24 https://doi.org/10.1073/pnas.96.24.13638	journal	November 1999
Induced-fit Mechanism for Prolyl Endopeptidase Li, Min; Chen, Changqing; Davies, David R. Journal of Biological Chemistry, Vol. 285, Issue 28 https://doi.org/10.1074/jbc.M109.092692	journal	May 2010
The Two-step Biosynthesis of Cyclic Peptides from Linear Precursors in a Member of the Plant Family Caryophyllaceae Involves Cyclization by a Serine Protease-like Enzyme Barber, Carla J. S.; Pujara, Pareshkumar T.; Reed, Darwin W. Journal of Biological Chemistry, Vol. 288, Issue 18 https://doi.org/10.1074/jbc.M112.437947	journal	March 2013
CASTp: computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated residues Dundas, J.; Ouyang, Z.; Tseng, J. Nucleic Acids Research, Vol. 34, Issue Web Server https://doi.org/10.1093/nar/gkl282	journal	July 2006
Dali server: conservation mapping in 3D Holm, Liisa; Rosenstrï¿½m, Pï¿½ivi Nucleic Acids Research, Vol. 38, Issue suppl_2 https://doi.org/10.1093/nar/gkq366	journal	May 2010
The biosynthesis of Caryophyllaceae-like cyclic peptides in Saponaria vaccaria L. from DNA-encoded precursors: Caryophyllaceae-like cyclic peptide biosynthesis Condie, Janet A.; Nowak, Goska; Reed, Darwin W. The Plant Journal, Vol. 67, Issue 4 https://doi.org/10.1111/j.1365-313X.2011.04626.x	journal	June 2011
Structure and Mechanism of the Lantibiotic Cyclase Involved in Nisin Biosynthesis Li, B. Science, Vol. 311, Issue 5766 https://doi.org/10.1126/science.1121422	journal	March 2006
Selection-Based Discovery of Druglike Macrocyclic Peptides Passioura, Toby; Katoh, Takayuki; Goto, Yuki Annual Review of Biochemistry, Vol. 83, Issue 1 https://doi.org/10.1146/annurev-biochem-060713-035456	journal	June 2014

Cited By (9)

A family of small, cyclic peptides buried in preproalbumin since the Eocene epoch Fisher, Mark F.; Zhang, Jingjing; Taylor, Nicolas L. Plant Direct, Vol. 2, Issue 2 https://doi.org/10.1002/pld3.42	journal	February 2018
Characterization of the Fast and Promiscuous Macrocyclase from Plant PCY1 Enables the Use of Simple Substrates Ludewig, Hannes; Czekster, Clarissa M.; Oueis, Emilia ACS Chemical Biology, Vol. 13, Issue 3 https://doi.org/10.1021/acschembio.8b00050	journal	January 2018
Structural basis of ribosomal peptide macrocyclization in plants Haywood, Joel; Schmidberger, Jason W.; James, Amy M. eLife, Vol. 7 https://doi.org/10.7554/elife.32955	journal	January 2018
Insights into AMS/PCAT transporters from biochemical and structural characterization of a double Glycine motif protease Bobeica, Silvia C.; Dong, Shi-Hui; Huo, Liujie eLife, Vol. 8 https://doi.org/10.7554/elife.42305	journal	January 2019
Characterization of a dual function macrocyclase enables design and use of efficient macrocyclization substrates Czekster, Clarissa M.; Ludewig, Hannes; McMahon, Stephen A. Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/s41467-017-00862-4	journal	October 2017
Bypassing the proline/thiazoline requirement of the macrocyclase PatG Oueis, E.; Stevenson, H.; Jaspars, M. Chemical Communications, Vol. 53, Issue 91 https://doi.org/10.1039/c7cc06550g	journal	January 2017
Gene-guided discovery and engineering of branched cyclic peptides in plants Kersten, Roland D.; Weng, Jing-Ke Proceedings of the National Academy of Sciences, Vol. 115, Issue 46 https://doi.org/10.1073/pnas.1813993115	journal	October 2018
Structural determinants for peptide-bond formation by asparaginyl ligases Hemu, Xinya; El Sahili, Abbas; Hu, Side Proceedings of the National Academy of Sciences https://doi.org/10.1073/pnas.1818568116	journal	May 2019
Vacuolar processing enzymes in the plant life cycle Yamada, Kenji; Basak, Arpan Kumar; Goto‐Yamada, Shino New Phytologist, Vol. 226, Issue 1 https://doi.org/10.1111/nph.16306	journal	December 2019

Similar Records

Steric complementarity directs sequence promiscuous leader binding in RiPP biosynthesis

Journal Article · Mon Nov 11 19:00:00 EST 2019 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:1578220

Structural basis for precursor protein-directed ribosomal peptide macrocyclization

Journal Article · Thu Nov 10 23:00:00 EST 2016 · Nature Chemical Biology · OSTI ID:1330886

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
RiPP
biosynthesis
orbitide
peptide
plant

Characterization of the macrocyclase involved in the biosynthesis of RiPP cyclic peptides in plants

Citation Formats

References (59)

Cited By (9)

Similar Records

Related Subjects