Discovery of the cryptic function of terpene cyclases as aromatic prenyltransferases

He, Haibing; Bian, Guangkai; Herbst-Gervasoni, Corey J.; Mori, Takahiro; Shinsky, Stephen A.; Hou, Anwei; Mu, Xin; Huang, Minjian; Cheng, Shu; Deng, Zixin; Christianson, David W.; Abe, Ikuro; Liu, Tiangang

doi:10.1038/s41467-020-17642-2

Discovery of the cryptic function of terpene cyclases as aromatic prenyltransferases

Journal Article · Fri Aug 07 00:00:00 EDT 2020 · Nature Communications

DOI:https://doi.org/10.1038/s41467-020-17642-2· OSTI ID:1659315

He, Haibing ^[1]; Bian, Guangkai ^[2]; Herbst-Gervasoni, Corey J. ^[3]; ^[1]; Shinsky, Stephen A. ^[3]; Hou, Anwei ^[2]; Mu, Xin ^[2]; Huang, Minjian ^[2]; Cheng, Shu ^[2]; Deng, Zixin ^[2]; Christianson, David W. ^[3]; ^[1]; ^[2]

Univ. of Tokyo (Japan)
Wuhan Univ. (China)
Pennsylvania State Univ., University Park, PA (United States)

Catalytic versatility is an inherent property of many enzymes. In nature, terpene cyclases comprise the foundation of molecular biodiversity as they generate diverse hydrocarbon scaffolds found in thousands of terpenoid natural products. Here, we report that the catalytic activity of the terpene cyclases AaTPS and FgGS can be switched from cyclase to aromatic prenyltransferase at basic pH to generate prenylindoles. The crystal structures of AaTPS and FgGS provide insights into the catalytic mechanism of this cryptic function. Moreover, aromatic prenyltransferase activity discovered in other terpene cyclases indicates that this cryptic function is broadly conserved among the greater family of terpene cyclases. We suggest that this cryptic function is chemoprotective for the cell by regulating isoprenoid diphosphate concentrations so that they are maintained below toxic thresholds.

View Accepted Manuscript (DOE)

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

Sponsoring Organization:: FOREIGN

OSTI ID:: 1659315

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 11; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (56)

A Clade II-D Fungal Chimeric Diterpene Synthase from Colletotrichum gloeosporioides Produces Dolasta-1(15),8-diene Bian, Guangkai; Rinkel, Jan; Wang, Zhangqian Angewandte Chemie International Edition, Vol. 57, Issue 48 https://doi.org/10.1002/anie.201809954	journal	October 2018
Production of taxadiene by engineering of mevalonate pathway in Escherichia coli and endophytic fungus Alternaria alternata TPF6 Bian, Guangkai; Yuan, Yujie; Tao, Hui Biotechnology Journal, Vol. 12, Issue 4 https://doi.org/10.1002/biot.201600697	journal	March 2017
In vitro reconstitution of mevalonate pathway and targeted engineering of farnesene overproduction in Escherichia coli : In Vitro Reconstitution of Mevalonate Pathway Zhu, Fayin; Zhong, Xiaofang; Hu, Mengzhu Biotechnology and Bioengineering, Vol. 111, Issue 7 https://doi.org/10.1002/bit.25198	journal	February 2014
Correlation analysis of targeted proteins and metabolites to assess and engineer microbial isopentenol production: Targeted Proteomics-Based Correlation Analysis George, Kevin W.; Chen, Amy; Jain, Aakriti Biotechnology and Bioengineering, Vol. 111, Issue 8 https://doi.org/10.1002/bit.25226	journal	May 2014
CdpNPT, an N-Prenyltransferase fromAspergillus fumigatus: Overproduction, Purification and Biochemical Characterisation Yin, Wen-Bing; Ruan, Han-Li; Westrich, Lucia ChemBioChem, Vol. 8, Issue 10 https://doi.org/10.1002/cbic.200700079	journal	July 2007
Sesquiterpenoids Produced by Combining Two Sesquiterpene Cyclases with Promiscuous Myxobacterial CYP260B1 Yuan, Yujie; Litzenburger, Martin; Cheng, Shu ChemBioChem, Vol. 20, Issue 5 https://doi.org/10.1002/cbic.201800670	journal	January 2019
Overcoming Expression and Purification Problems of RhoGDI Using a Family of “Parallel” Expression Vectors Sheffield, Peter; Garrard, Sarah; Derewenda, Zygmunt Protein Expression and Purification, Vol. 15, Issue 1 https://doi.org/10.1006/prep.1998.1003	journal	February 1999
Isoprenoid Drugs, Biofuels, and Chemicals—Artemisinin, Farnesene, and Beyond George, Kevin W.; Alonso-Gutierrez, Jorge; Keasling, Jay D. Biotechnology of Isoprenoids https://doi.org/10.1007/10_2014_288	book	January 2015
The ABBA family of aromatic prenyltransferases: broadening natural product diversity Tello, M.; Kuzuyama, T.; Heide, L. Cellular and Molecular Life Sciences, Vol. 65, Issue 10 https://doi.org/10.1007/s00018-008-7579-3	journal	February 2008
Synthesis of 3-ω-epoxido farnesyl indoles, intermediates in the biogenesis of sesquiterpenic indole alkaloids Mirand, Catherine; de Maindreville, Michèle Döé; Lévy, Jean Tetrahedron Letters, Vol. 26, Issue 33 https://doi.org/10.1016/S0040-4039(00)98704-5	journal	January 1985
Prenyl transfer to aromatic substrates: genetics and enzymology Heide, Lutz Current Opinion in Chemical Biology, Vol. 13, Issue 2 https://doi.org/10.1016/j.cbpa.2009.02.020	journal	April 2009
Strategies for terpenoid overproduction and new terpenoid discovery Bian, Guangkai; Deng, Zixin; Liu, Tiangang Current Opinion in Biotechnology, Vol. 48 https://doi.org/10.1016/j.copbio.2017.07.002	journal	December 2017
Releasing the potential power of terpene synthases by a robust precursor supply platform Bian, Guangkai; Han, Yichao; Hou, Anwei Metabolic Engineering, Vol. 42 https://doi.org/10.1016/j.ymben.2017.04.006	journal	July 2017
Integrated analysis of isopentenyl pyrophosphate (IPP) toxicity in isoprenoid-producing Escherichia coli George, Kevin W.; Thompson, Mitchell G.; Kim, Joonhoon Metabolic Engineering, Vol. 47 https://doi.org/10.1016/j.ymben.2018.03.004	journal	May 2018
Substitution of Aromatic Residues with Polar Residues in the Active Site Pocket of epi -Isozizaene Synthase Leads to the Generation of New Cyclic Sesquiterpenes Blank, Patrick N.; Barrow, Golda H.; Chou, Wayne K. W. Biochemistry, Vol. 56, Issue 43 https://doi.org/10.1021/acs.biochem.7b00895	journal	October 2017
Structural and Chemical Biology of Terpenoid Cyclases Christianson, David W. Chemical Reviews, Vol. 117, Issue 17 https://doi.org/10.1021/acs.chemrev.7b00287	journal	August 2017
Amphiphilic Indole Derivatives as Antimycobacterial Agents: Structure–Activity Relationships and Membrane Targeting Properties Yang, Tianming; Moreira, Wilfried; Nyantakyi, Samuel Agyei Journal of Medicinal Chemistry, Vol. 60, Issue 7 https://doi.org/10.1021/acs.jmedchem.6b01530	journal	March 2017
Metabolic Engineering-Based Rapid Characterization of a Sesquiterpene Cyclase and the Skeletons of Fusariumdiene and Fusagramineol from Fusarium graminearum Bian, Guangkai; Hou, Anwei; Yuan, Yujie Organic Letters, Vol. 20, Issue 6 https://doi.org/10.1021/acs.orglett.8b00366	journal	February 2018
Structure and Function of Fusicoccadiene Synthase, a Hexameric Bifunctional Diterpene Synthase Chen, Mengbin; Chou, Wayne K. W.; Toyomasu, Tomonobu ACS Chemical Biology, Vol. 11, Issue 4 https://doi.org/10.1021/acschembio.5b00960	journal	January 2016
X-ray Crystal Structure of Aristolochene Synthase from Aspergillus terreus and Evolution of Templates for the Cyclization of Farnesyl Diphosphate ^† ^, ^‡ Shishova, Ekaterina Y.; Di Costanzo, Luigi; Cane, David E. Biochemistry, Vol. 46, Issue 7 https://doi.org/10.1021/bi0622524	journal	February 2007
Pre-Steady-State Kinetic Analysis of the Trichodiene Synthase Reaction Pathway ^† Cane, David E.; Chiu, Hsien-Tai; Liang, Po-Huang Biochemistry, Vol. 36, Issue 27 https://doi.org/10.1021/bi963018o	journal	July 1997
Pre-Steady-State Study of Recombinant Sesquiterpene Cyclases ^† Mathis, Jeffery R.; Back, Kyoungwhan; Starks, Courtney Biochemistry, Vol. 36, Issue 27 https://doi.org/10.1021/bi963019g	journal	July 1997
Multisite Prenylation of 4-Substituted Tryptophans by Dimethylallyltryptophan Synthase Rudolf, Jeffrey D.; Wang, Hong; Poulter, C. Dale Journal of the American Chemical Society, Vol. 135, Issue 5 https://doi.org/10.1021/ja310734n	journal	January 2013
Synthesis and Biological Evaluation of (−)- and (+)-Debromoflustramine B and Its Analogues as Selective Butyrylcholinesterase Inhibitors Rivera-Becerril, Ernesto; Joseph-Nathan, Pedro; Pérez-Álvarez, Víctor M. Journal of Medicinal Chemistry, Vol. 51, Issue 17 https://doi.org/10.1021/jm800277g	journal	September 2008
Enantioselective Total Syntheses of (−)-7β H -Eudesmane-4α,11-diol and (+)- ent -7β H -Eudesmane-4α,11-diol Shimoma, Fumito; Kondo, Hisao; Yuuya, Saori Journal of Natural Products, Vol. 61, Issue 1 https://doi.org/10.1021/np9702906	journal	January 1998
Structural basis for the promiscuous biosynthetic prenylation of aromatic natural products Kuzuyama, Tomohisa; Noel, Joseph P.; Richard, Stéphane B. Nature, Vol. 435, Issue 7044 https://doi.org/10.1038/nature03668	journal	June 2005
Designed divergent evolution of enzyme function Yoshikuni, Yasuo; Ferrin, Thomas E.; Keasling, Jay D. Nature, Vol. 440, Issue 7087 https://doi.org/10.1038/nature04607	journal	February 2006
UbiX is a flavin prenyltransferase required for bacterial ubiquinone biosynthesis White, Mark D.; Payne, Karl A. P.; Fisher, Karl Nature, Vol. 522, Issue 7557 https://doi.org/10.1038/nature14559	journal	June 2015
Engineering a mevalonate pathway in Escherichia coli for production of terpenoids Martin, Vincent J. J.; Pitera, Douglas J.; Withers, Sydnor T. Nature Biotechnology, Vol. 21, Issue 7 https://doi.org/10.1038/nbt833	journal	June 2003
The function of terpene natural products in the natural world Gershenzon, Jonathan; Dudareva, Natalia Nature Chemical Biology, Vol. 3, Issue 7 https://doi.org/10.1038/nchembio.2007.5	journal	June 2007
Molecular insights into the enzyme promiscuity of an aromatic prenyltransferase Chen, Ridao; Gao, Bingquan; Liu, Xiao Nature Chemical Biology, Vol. 13, Issue 2 https://doi.org/10.1038/nchembio.2263	journal	December 2016
Template-based protein structure modeling using the RaptorX web server Källberg, Morten; Wang, Haipeng; Wang, Sheng Nature Protocols, Vol. 7, Issue 8 https://doi.org/10.1038/nprot.2012.085	journal	July 2012
The UbiX flavin prenyltransferase reaction mechanism resembles class I terpene cyclase chemistry Marshall, Stephen A.; Payne, Karl A. P.; Fisher, Karl Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-10220-1	journal	May 2019
Prenylated indole derivatives from fungi: structure diversity, biological activities, biosynthesis and chemoenzymatic synthesis Li, Shu-Ming Nat. Prod. Rep., Vol. 27, Issue 1 https://doi.org/10.1039/B909987P	journal	January 2010
Identifying and manipulating structural determinates linking catalytic specificities in terpene synthases Greenhagen, B. T.; O'Maille, P. E.; Noel, J. P. Proceedings of the National Academy of Sciences, Vol. 103, Issue 26 https://doi.org/10.1073/pnas.0601605103	journal	June 2006
MEGA7: Molecular Evolutionary Genetics Analysis Version 7.0 for Bigger Datasets Kumar, Sudhir; Stecher, Glen; Tamura, Koichiro Molecular Biology and Evolution, Vol. 33, Issue 7 https://doi.org/10.1093/molbev/msw054	journal	March 2016
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
Overproduction, purification and characterization of FgaPT2, a dimethylallyltryptophan synthase from Aspergillus fumigatus Unsöld, Inge A.; Li, Shu-Ming Microbiology, Vol. 151, Issue 5 https://doi.org/10.1099/mic.0.27759-0	journal	May 2005
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
Iterative model building, structure refinement and density modification with the PHENIX AutoBuild wizard Terwilliger, Thomas C.; Grosse-Kunstleve, Ralf W.; Afonine, Pavel V. Acta Crystallographica Section D Biological Crystallography, Vol. 64, Issue 1 https://doi.org/10.1107/S090744490705024X	journal	December 2007
Decision-making in structure solution using Bayesian estimates of map quality: the PHENIX AutoSol wizard Terwilliger, Thomas C.; Adams, Paul D.; Read, Randy J. Acta Crystallographica Section D Biological Crystallography, Vol. 65, Issue 6 https://doi.org/10.1107/S0907444909012098	journal	May 2009
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
iMOSFLM : a new graphical interface for diffraction-image processing with MOSFLM Battye, T. Geoff G.; Kontogiannis, Luke; Johnson, Owen Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910048675	journal	March 2011
Towards automated crystallographic structure refinement with phenix.refine Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Echols, Nathaniel Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4 https://doi.org/10.1107/S0907444912001308	journal	March 2012
How good are my data and what is the resolution? Evans, Philip R.; Murshudov, Garib N. Acta Crystallographica Section D Biological Crystallography, Vol. 69, Issue 7 https://doi.org/10.1107/S0907444913000061	journal	June 2013
Isoprenoid Pathway Optimization for Taxol Precursor Overproduction in Escherichia coli Ajikumar, P. K.; Xiao, W.-H.; Tyo, K. E. J. Science, Vol. 330, Issue 6000, p. 70-74 https://doi.org/10.1126/science.1191652	journal	September 2010
Structural Insights into Ubiquinone Biosynthesis in Membranes Cheng, W.; Li, W. Science, Vol. 343, Issue 6173 https://doi.org/10.1126/science.1246774	journal	February 2014
Structural Basis for Cyclic Terpene Biosynthesis by Tobacco 5-Epi-Aristolochene Synthase Starks, C. M. Science, Vol. 277, Issue 5333 https://doi.org/10.1126/science.277.5333.1815	journal	September 1997
Trinuclear metal clusters in catalysis by terpenoid synthases Aaron, Julie A.; Christianson, David W. Pure and Applied Chemistry, Vol. 82, Issue 8 https://doi.org/10.1351/PAC-CON-09-09-37	journal	May 2010
Structure of a Membrane-Embedded Prenyltransferase Homologous to UBIAD1 Huang, Hua; Levin, Elena J.; Liu, Shian PLoS Biology, Vol. 12, Issue 7 https://doi.org/10.1371/journal.pbio.1001911	journal	July 2014
Indole Prenyltransferases from Fungi: A New Enzyme Group with High Potential for the Production of Prenylated Indole Derivatives Steffan, N.; Grundmann, A.; Yin, W. -B. Current Medicinal Chemistry, Vol. 16, Issue 2 https://doi.org/10.2174/092986709787002772	journal	January 2009

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