Characterization of the macrocyclase involved in the biosynthesis of RiPP cyclic peptides in plants
Abstract
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.
- Authors:
-
- Univ. of Illinois at Urbana-Champaign, IL (United States)
- National Research Council of Canada, Saskatoon (Canada)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- National Institutes of Health (NIH)
- OSTI Identifier:
- 1438880
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 114; Journal Issue: 25; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; RiPP; biosynthesis; peptide; plant; orbitide
Citation Formats
Chekan, Jonathan R., Estrada, Paola, Covello, Patrick S., and Nair, Satish K. Characterization of the macrocyclase involved in the biosynthesis of RiPP cyclic peptides in plants. United States: N. p., 2017.
Web. doi:10.1073/pnas.1620499114.
Chekan, Jonathan R., Estrada, Paola, Covello, Patrick S., & Nair, Satish K. Characterization of the macrocyclase involved in the biosynthesis of RiPP cyclic peptides in plants. United States. https://doi.org/10.1073/pnas.1620499114
Chekan, Jonathan R., Estrada, Paola, Covello, Patrick S., and Nair, Satish K. Mon .
"Characterization of the macrocyclase involved in the biosynthesis of RiPP cyclic peptides in plants". United States. https://doi.org/10.1073/pnas.1620499114. https://www.osti.gov/servlets/purl/1438880.
@article{osti_1438880,
title = {Characterization of the macrocyclase involved in the biosynthesis of RiPP cyclic peptides in plants},
author = {Chekan, Jonathan R. and Estrada, Paola and Covello, Patrick S. and Nair, Satish K.},
abstractNote = {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.},
doi = {10.1073/pnas.1620499114},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 25,
volume = 114,
place = {United States},
year = {Mon Jun 05 00:00:00 EDT 2017},
month = {Mon Jun 05 00:00:00 EDT 2017}
}
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Works referenced in this record:
On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds
journal, September 2011
- White, Tina R.; Renzelman, Chad M.; Rand, Arthur C.
- Nature Chemical Biology, Vol. 7, Issue 11
Selection-Based Discovery of Druglike Macrocyclic Peptides
journal, June 2014
- Passioura, Toby; Katoh, Takayuki; Goto, Yuki
- Annual Review of Biochemistry, Vol. 83, Issue 1
Production of cyclic peptides and proteins in vivo
journal, November 1999
- Scott, C. P.; Abel-Santos, E.; Wall, M.
- Proceedings of the National Academy of Sciences, Vol. 96, Issue 24
Estrogen-Like Activity of Cyclic Peptides from Vaccaria segetalis Extracts 1
journal, December 1995
- Itokawa, Hideji; Yun, Youngsook; Morita, Hiroshi
- Planta Medica, Vol. 61, Issue 06
Structure and mechanism of the tRNA-dependent lantibiotic dehydratase NisB
journal, October 2014
- Ortega, Manuel A.; Hao, Yue; Zhang, Qi
- Nature, Vol. 517, Issue 7535
Prolyl Oligopeptidase
journal, July 1998
- Fülöp, Vilmos; Böcskei, Zsolt; Polgár, László
- Cell, Vol. 94, Issue 2
Modularity of RiPP Enzymes Enables Designed Synthesis of Decorated Peptides
journal, July 2015
- Sardar, Debosmita; Lin, Zhenjian; Schmidt, Eric W.
- Chemistry & Biology, Vol. 22, Issue 7
The prolyl oligopeptidase family
journal, February 2002
- Polgar, L.
- Cellular and Molecular Life Sciences CMLS, Vol. 59, Issue 2, p. 349-362
Dali server: conservation mapping in 3D
journal, May 2010
- Holm, Liisa; Rosenstr�m, P�ivi
- Nucleic Acids Research, Vol. 38, Issue suppl_2
Cyanobactins—ribosomal cyclic peptides produced by cyanobacteria
journal, February 2010
- Sivonen, Kaarina; Leikoski, Niina; Fewer, David P.
- Applied Microbiology and Biotechnology, Vol. 86, Issue 5
Theoretical Studies on the Deacylation Step of Serine Protease Catalysis in the Gas Phase, in Solution, and in Elastase
journal, November 2004
- Topf, Maya; Richards, W. Graham
- Journal of the American Chemical Society, Vol. 126, Issue 44
Prolyl Oligopeptidase
book, January 2013
- Ito, Kiyoshi; Nakajima, Yoshitaka; Yoshimoto, Tadashi
- Handbook of Proteolytic Enzymes
Structure of nisin
journal, September 1971
- Gross, Erhard; Morell, John L.
- Journal of the American Chemical Society, Vol. 93, Issue 18
Genome mining for ribosomally synthesized natural products
journal, February 2011
- Velásquez, Juan E.; van der Donk, Wilfred A.
- Current Opinion in Chemical Biology, Vol. 15, Issue 1
The molecular diversity of toxin gene families in lethal Amanita mushrooms
journal, June 2014
- Li, Peng; Deng, Wangqiu; Li, Taihui
- Toxicon, Vol. 83
Insights into the serine protease mechanism from atomic resolution structures of trypsin reaction intermediates
journal, April 2006
- Radisky, E. S.; Lee, J. M.; Lu, C. -J. K.
- Proceedings of the National Academy of Sciences, Vol. 103, Issue 18
Cyclotide biosynthesis
journal, August 2013
- Craik, David J.; Malik, Uru
- Current Opinion in Chemical Biology, Vol. 17, Issue 4
Dissecting the Maturation Steps of the Lasso Peptide Microcin J25 in vitro
journal, April 2012
- Yan, Kok-Phen; Li, Yanyan; Zirah, Séverine
- ChemBioChem, Vol. 13, Issue 7
Peptide Macrocyclization by a Bifunctional Endoprotease
journal, May 2015
- Bernath-Levin, Kalia; Nelson, Clark; Elliott, Alysha G.
- Chemistry & Biology, Vol. 22, Issue 5
Total Synthesis of Circular Bacteriocins by Butelase 1
journal, May 2016
- Hemu, Xinya; Qiu, Yibo; Nguyen, Giang K. T.
- Journal of the American Chemical Society, Vol. 138, Issue 22
Low-Barrier Hydrogen Bonds and Enzymatic Catalysis
journal, October 2000
- Cleland, W. W.
- Archives of Biochemistry and Biophysics, Vol. 382, Issue 1
Gene family encoding the major toxins of lethal Amanita mushrooms
journal, November 2007
- Hallen, Heather E.; Luo, Hong; Scott-Craig, John S.
- Proceedings of the National Academy of Sciences, Vol. 104, Issue 48, p. 19097-19101
Butelase 1 is an Asx-specific ligase enabling peptide macrocyclization and synthesis
journal, July 2014
- Nguyen, Giang K. T.; Wang, Shujing; Qiu, Yibo
- Nature Chemical Biology, Vol. 10, Issue 9
Structure and Mechanism of the Lantibiotic Cyclase Involved in Nisin Biosynthesis
journal, March 2006
- Li, B.
- Science, Vol. 311, Issue 5766
Induced-fit Mechanism for Prolyl Endopeptidase
journal, May 2010
- Li, Min; Chen, Changqing; Davies, David R.
- Journal of Biological Chemistry, Vol. 285, Issue 28
CASTp: computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated residues
journal, July 2006
- Dundas, J.; Ouyang, Z.; Tseng, J.
- Nucleic Acids Research, Vol. 34, Issue Web Server
Structures of Cyanobactin Maturation Enzymes Define a Family of Transamidating Proteases
journal, November 2012
- Agarwal, Vinayak; Pierce, Elizabeth; McIntosh, John
- Chemistry & Biology, Vol. 19, Issue 11
A prevalent peptide-binding domain guides ribosomal natural product biosynthesis
journal, July 2015
- Burkhart, Brandon J.; Hudson, Graham A.; Dunbar, Kyle L.
- Nature Chemical Biology, Vol. 11, Issue 8
Testing the Conformational Hypothesis of Passive Membrane Permeability Using Synthetic Cyclic Peptide Diastereomers
journal, March 2006
- Rezai, Taha; Yu, Bin; Millhauser, Glenn L.
- Journal of the American Chemical Society, Vol. 128, Issue 8
Lasso Peptides: An Intriguing Class of Bacterial Natural Products
journal, June 2015
- Hegemann, Julian D.; Zimmermann, Marcel; Xie, Xiulan
- Accounts of Chemical Research, Vol. 48, Issue 7
The biosynthesis of Caryophyllaceae-like cyclic peptides in Saponaria vaccaria L. from DNA-encoded precursors: Caryophyllaceae-like cyclic peptide biosynthesis
journal, June 2011
- Condie, Janet A.; Nowak, Goska; Reed, Darwin W.
- The Plant Journal, Vol. 67, Issue 4
Structure Determination and Total Synthesis of Bottromycin A 2 : A Potent Antibiotic against MRSA and VRE
journal, January 2009
- Shimamura, Hiroyuki; Gouda, Hiroaki; Nagai, Kenichiro
- Angewandte Chemie, Vol. 121, Issue 5
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
journal, March 2013
- Barber, Carla J. S.; Pujara, Pareshkumar T.; Reed, Darwin W.
- Journal of Biological Chemistry, Vol. 288, Issue 18
Peptide Macrocyclization Catalyzed by a Prolyl Oligopeptidase Involved in α-Amanitin Biosynthesis
journal, December 2014
- Luo, Hong; Hong, Sung-Yong; Sgambelluri, R. Michael
- Chemistry & Biology, Vol. 21, Issue 12
Ribosomal production and in vitro selection of natural product-like peptidomimetics: The FIT and RaPID systems
journal, April 2012
- Hipolito, Christopher J.; Suga, Hiroaki
- Current Opinion in Chemical Biology, Vol. 16, Issue 1-2
The mechanism of patellamide macrocyclization revealed by the characterization of the PatG macrocyclase domain
journal, July 2012
- Koehnke, Jesko; Bent, Andrew; Houssen, Wael E.
- Nature Structural & Molecular Biology, Vol. 19, Issue 8
Xanthomonas campestris PqqD in the pyrroloquinoline quinone biosynthesis operon adopts a novel saddle-like fold that possibly serves as a PQQ carrier
journal, September 2009
- Tsai, Tung-Yi; Yang, Chao-Yu; Shih, Hui-Ling
- Proteins: Structure, Function, and Bioinformatics, Vol. 76, Issue 4
Enzyme-Catalyzed Macrocyclization of Long Unprotected Peptides
journal, June 2014
- Zhang, Chi; Dai, Peng; Spokoyny, Alexander M.
- Organic Letters, Vol. 16, Issue 14
Biomimetic synthesis and optimization of cyclic peptide antibiotics
journal, August 2002
- Kohli, Rahul M.; Walsh, Christopher T.; Burkart, Michael D.
- Nature, Vol. 418, Issue 6898
Structural basis for precursor protein–directed ribosomal peptide macrocyclization
journal, September 2016
- Li, Kunhua; Condurso, Heather L.; Li, Gengnan
- Nature Chemical Biology, Vol. 12, Issue 11
Thiopeptide Antibiotics
journal, June 2005
- Bagley, Mark C.; Dale, James W.; Merritt, Eleanor A.
- ChemInform, Vol. 36, Issue 24
Two Enzymes Catalyze the Maturation of a Lasso Peptide in Escherichia coli
journal, July 2007
- Duquesne, Sophie; Destoumieux-Garzon, Delphine; Zirah, Severine
- Chemistry & Biology, Vol. 14, Issue 7, p. 793-803
Structure of a New Cyclic Nonapeptide, Segetalin F, and Vasorelaxant Activity of Segetalins from Vaccaria segetalis.
journal, December 2006
- Morita, Hiroshi; Eda, Michiko; Iizuka, Toru
- ChemInform, Vol. 37, Issue 52
Thiopeptide Antibiotics
journal, February 2005
- Bagley, Mark C.; Dale, James W.; Merritt, Eleanor A.
- Chemical Reviews, Vol. 105, Issue 2
Cyclolinopeptide A (CLA) mediates its immunosuppressive activity through cyclophilin-dependent calcineurin inactivation
journal, November 1997
- Gaymes, Terry J.; Cebrat, Marek; Siemion, Ignacy Z.
- FEBS Letters, Vol. 418, Issue 1-2
Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity
journal, February 2005
- Shan, L.; Mathews, I. I.; Khosla, C.
- Proceedings of the National Academy of Sciences, Vol. 102, Issue 10
Identification and Quantification of Cyclolinopeptides in Five Flaxseed Cultivars
journal, August 2012
- Gui, Bo; Shim, Youn Young; Datla, Raju S. S.
- Journal of Agricultural and Food Chemistry, Vol. 60, Issue 35
Kinetic Landscape of a Peptide Bond-Forming Prolyl Oligopeptidase
journal, April 2017
- Czekster, Clarissa M.; Naismith, James H.
- Biochemistry, Vol. 56, Issue 15
Structure Determination and Total Synthesis of Bottromycin A 2 : A Potent Antibiotic against MRSA and VRE
journal, January 2009
- Shimamura, Hiroyuki; Gouda, Hiroaki; Nagai, Kenichiro
- Angewandte Chemie International Edition, Vol. 48, Issue 5
Structural analysis of leader peptide binding enables leader-free cyanobactin processing
journal, June 2015
- Koehnke, Jesko; Mann, Greg; Bent, Andrew F.
- Nature Chemical Biology, Vol. 11, Issue 8
The exploration of macrocycles for drug discovery — an underexploited structural class
journal, July 2008
- Driggers, Edward M.; Hale, Stephen P.; Lee, Jinbo
- Nature Reviews Drug Discovery, Vol. 7, Issue 7
Structure and biosynthesis of a macrocyclic peptide containing an unprecedented lysine-to-tryptophan crosslink
journal, April 2015
- Schramma, Kelsey R.; Bushin, Leah B.; Seyedsayamdost, Mohammad R.
- Nature Chemistry, Vol. 7, Issue 5
Identification of serine and histidine adducts in complexes of trypsin and trypsinogen with peptide and nonpeptide boronic acid inhibitors by proton NMR spectroscopy
journal, December 1992
- Tsilikounas, Elisabeth; Kettner, Charles A.; Bachovchin, William W.
- Biochemistry, Vol. 31, Issue 51
Über ein Oligopeptid aus Leinsamen
journal, November 1959
- Kaufmann, Hans Paul; Tobschirbel, Adelheid
- Chemische Berichte, Vol. 92, Issue 11
Structure of a new cyclic nonapeptide, segetalin F, and vasorelaxant activity of segetalins from Vaccaria segetalis
journal, September 2006
- Morita, Hiroshi; Eda, Michiko; Iizuka, Toru
- Bioorganic & Medicinal Chemistry Letters, Vol. 16, Issue 17
Using Marine Natural Products to Discover a Protease that Catalyzes Peptide Macrocyclization of Diverse Substrates
journal, February 2009
- Lee, Jaeheon; McIntosh, John; Hathaway, Brian J.
- Journal of the American Chemical Society, Vol. 131, Issue 6
Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature
journal, January 2013
- Arnison, Paul G.; Bibb, Mervyn J.; Bierbaum, Gabriele
- Nat. Prod. Rep., Vol. 30, Issue 1
Ribifolin, an Orbitide from Jatropha ribifolia , and Its Potential Antimalarial Activity
journal, February 2015
- Pinto, Meri Emili F.; Batista, João M.; Koehbach, Johannes
- Journal of Natural Products, Vol. 78, Issue 3
Works referencing / citing this record:
Vacuolar processing enzymes in the plant life cycle
journal, December 2019
- Yamada, Kenji; Basak, Arpan Kumar; Goto‐Yamada, Shino
- New Phytologist, Vol. 226, Issue 1
Characterization of a dual function macrocyclase enables design and use of efficient macrocyclization substrates
journal, October 2017
- Czekster, Clarissa M.; Ludewig, Hannes; McMahon, Stephen A.
- Nature Communications, Vol. 8, Issue 1
Gene-guided discovery and engineering of branched cyclic peptides in plants
journal, October 2018
- Kersten, Roland D.; Weng, Jing-Ke
- Proceedings of the National Academy of Sciences, Vol. 115, Issue 46
Structural determinants for peptide-bond formation by asparaginyl ligases
journal, May 2019
- Hemu, Xinya; El Sahili, Abbas; Hu, Side
- Proceedings of the National Academy of Sciences
Bypassing the proline/thiazoline requirement of the macrocyclase PatG
journal, January 2017
- Oueis, E.; Stevenson, H.; Jaspars, M.
- Chemical Communications, Vol. 53, Issue 91
Structural basis of ribosomal peptide macrocyclization in plants
journal, January 2018
- Haywood, Joel; Schmidberger, Jason W.; James, Amy M.
- eLife, Vol. 7
A family of small, cyclic peptides buried in preproalbumin since the Eocene epoch
journal, February 2018
- Fisher, Mark F.; Zhang, Jingjing; Taylor, Nicolas L.
- Plant Direct, Vol. 2, Issue 2
Characterization of the Fast and Promiscuous Macrocyclase from Plant PCY1 Enables the Use of Simple Substrates
journal, January 2018
- Ludewig, Hannes; Czekster, Clarissa M.; Oueis, Emilia
- ACS Chemical Biology, Vol. 13, Issue 3
Structural basis of ribosomal peptide macrocyclization in plants
journal, January 2018
- Haywood, Joel; Schmidberger, Jason W.; James, Amy M.
- eLife, Vol. 7