The structure of SpnF a standalone enzyme that catalyzes [4 + 2] cycloaddition
Abstract
In the biosynthetic pathway of the spinosyn insecticides, the tailoring enzyme SpnF performs a [4 + 2] cycloaddition on a 22-membered macrolactone to forge an embedded cyclohexene ring. To learn more about this reaction, which could potentially proceed through a Diels-Alder mechanism, in this paper we determined the 1.50-Å-resolution crystal structure of SpnF bound to S-adenosylhomocysteine. Finally, this sets the stage for advanced experimental and computational studies to determine the precise mechanism of SpnF-mediated cyclization.
- Authors:
-
- Univ. of Texas, Austin, TX (United States). Dept. of Molecular Biosciences
- Univ. of Texas, Austin, TX (United States). College of Pharmacy. Division of Medicinal Chemistry
- Univ. of Texas, Austin, TX (United States). College of Pharmacy. Division of Medicinal Chemistry. Dept. of Chemistry
- Univ. of Texas, Austin, TX (United States). Dept. of Molecular Biosciences. Dept. of Chemistry
- Publication Date:
- Research Org.:
- Univ. of Texas, Austin, TX (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Inst. of Health (NIH) (United States); Welch Foundation (United States)
- OSTI Identifier:
- 1177446
- Grant/Contract Number:
- AC02-06CH11357; GM106112; GM035906; GM040541; F-1712; F-1511
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Chemical Biology
- Additional Journal Information:
- Journal Volume: 11; Journal Issue: 4; Journal ID: ISSN 1552-4450
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES; Biochemistry; Biosynthesis; Natural products; X-ray crystallography
Citation Formats
Fage, Christopher D., Isiorho, Eta A., Liu, Yungnan, Wagner, Drew T., Liu, Hung-wen, and Keatinge-Clay, Adrian T. The structure of SpnF a standalone enzyme that catalyzes [4 + 2] cycloaddition. United States: N. p., 2015.
Web. doi:10.1038/nchembio.1768.
Fage, Christopher D., Isiorho, Eta A., Liu, Yungnan, Wagner, Drew T., Liu, Hung-wen, & Keatinge-Clay, Adrian T. The structure of SpnF a standalone enzyme that catalyzes [4 + 2] cycloaddition. United States. https://doi.org/10.1038/nchembio.1768
Fage, Christopher D., Isiorho, Eta A., Liu, Yungnan, Wagner, Drew T., Liu, Hung-wen, and Keatinge-Clay, Adrian T. Mon .
"The structure of SpnF a standalone enzyme that catalyzes [4 + 2] cycloaddition". United States. https://doi.org/10.1038/nchembio.1768. https://www.osti.gov/servlets/purl/1177446.
@article{osti_1177446,
title = {The structure of SpnF a standalone enzyme that catalyzes [4 + 2] cycloaddition},
author = {Fage, Christopher D. and Isiorho, Eta A. and Liu, Yungnan and Wagner, Drew T. and Liu, Hung-wen and Keatinge-Clay, Adrian T.},
abstractNote = {In the biosynthetic pathway of the spinosyn insecticides, the tailoring enzyme SpnF performs a [4 + 2] cycloaddition on a 22-membered macrolactone to forge an embedded cyclohexene ring. To learn more about this reaction, which could potentially proceed through a Diels-Alder mechanism, in this paper we determined the 1.50-Å-resolution crystal structure of SpnF bound to S-adenosylhomocysteine. Finally, this sets the stage for advanced experimental and computational studies to determine the precise mechanism of SpnF-mediated cyclization.},
doi = {10.1038/nchembio.1768},
journal = {Nature Chemical Biology},
number = 4,
volume = 11,
place = {United States},
year = {Mon Mar 02 00:00:00 EST 2015},
month = {Mon Mar 02 00:00:00 EST 2015}
}
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Works referenced in this record:
The structures of type I polyketide synthases
journal, January 2012
- Keatinge-Clay, Adrian T.
- Natural Product Reports, Vol. 29, Issue 10
Type II polyketide synthases: gaining a deeper insight into enzymatic teamwork
journal, January 2007
- Hertweck, Christian; Luzhetskyy, Andriy; Rebets, Yuri
- Nat. Prod. Rep., Vol. 24, Issue 1
Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization
journal, October 2009
- Crawford, Jason M.; Korman, Tyler P.; Labonte, Jason W.
- Nature, Vol. 461, Issue 7267
Crystal structure and functional analysis of tetracenomycin ARO/CYC: Implications for cyclization specificity of aromatic polyketides
journal, April 2008
- Ames, B. D.; Korman, T. P.; Zhang, W.
- Proceedings of the National Academy of Sciences, Vol. 105, Issue 14
The Calicheamicin Gene Cluster and Its Iterative Type I Enediyne PKS
journal, August 2002
- Ahlert, J.
- Science, Vol. 297, Issue 5584
Mechanistic Insights into Polycycle Formation by Reductive Cyclization in Ikarugamycin Biosynthesis
journal, April 2014
- Zhang, Guangtao; Zhang, Wenjun; Zhang, Qingbo
- Angewandte Chemie International Edition, Vol. 53, Issue 19
The spinosyn family of insecticides: realizing the potential of natural products research
journal, February 2010
- Kirst, Herbert A.
- The Journal of Antibiotics, Vol. 63, Issue 3
Enzyme-catalysed [4+2] cycloaddition is a key step in the biosynthesis of spinosyn A
journal, May 2011
- Kim, Hak Joong; Ruszczycky, Mark W.; Choi, Sei-hyun
- Nature, Vol. 473, Issue 7345
Synthesen in der hydroaromatischen Reihe, IV. Mitteilung: Über die Anlagerung von Maleinsäure-anhydrid an arylierte Diene, Triene und Fulvene (Mitbearbeitet von Paul Pries)
journal, September 1929
- Diels, Otto; Alder, Kurt
- Berichte der deutschen chemischen Gesellschaft (A and B Series), Vol. 62, Issue 8
Current developments and challenges in the search for a naturally selected Diels-Alderase
journal, April 2012
- Kim, Hak Joong; Ruszczycky, Mark W.; Liu, Hung-wen
- Current Opinion in Chemical Biology, Vol. 16, Issue 1-2
Insight into a natural Diels–Alder reaction from the structure of macrophomate synthase
journal, March 2003
- Ose, Toyoyuki; Watanabe, Kenji; Mie, Takashi
- Nature, Vol. 422, Issue 6928
Macrophomate Synthase: QM/MM Simulations Address the Diels−Alder versus Michael−Aldol Reaction Mechanism
journal, March 2005
- Guimarães, Cristiano Ruch Werneck; Udier-Blagović, Marina; Jorgensen, William L.
- Journal of the American Chemical Society, Vol. 127, Issue 10
The Putative Diels−Alderase Macrophomate Synthase is an Efficient Aldolase
journal, June 2008
- Serafimov, Jörg M.; Gillingham, Dennis; Kuster, Simon
- Journal of the American Chemical Society, Vol. 130, Issue 25
Impact of scaffold rigidity on the design and evolution of an artificial Diels-Alderase
journal, May 2014
- Preiswerk, N.; Beck, T.; Schulz, J. D.
- Proceedings of the National Academy of Sciences, Vol. 111, Issue 22
Chemoenzymatic Synthesis of Spinosyn A
journal, October 2014
- Kim, Hak Joong; Choi, Sei-hyun; Jeon, Byung-sun
- Angewandte Chemie International Edition, Vol. 53, Issue 49
Architectures, mechanisms and molecular evolution of natural product methyltransferases
journal, January 2012
- Liscombe, David K.; Louie, Gordon V.; Noel, Joseph P.
- Natural Product Reports, Vol. 29, Issue 10
Dali server: conservation mapping in 3D
journal, May 2010
- Holm, Liisa; Rosenstr�m, P�ivi
- Nucleic Acids Research, Vol. 38, Issue suppl_2
Butenyl-spinosyns, a natural example of genetic engineering of antibiotic biosynthetic genes
journal, September 2005
- Hahn, Donald R.; Gustafson, Gary; Waldron, Clive
- Journal of Industrial Microbiology & Biotechnology, Vol. 33, Issue 2
UFF, a full periodic table force field for molecular mechanics and molecular dynamics simulations
journal, December 1992
- Rappe, A. K.; Casewit, C. J.; Colwell, K. S.
- Journal of the American Chemical Society, Vol. 114, Issue 25, p. 10024-10035
Evaluation of DOCK 6 as a pose generation and database enrichment tool
journal, May 2012
- Brozell, Scott R.; Mukherjee, Sudipto; Balius, Trent E.
- Journal of Computer-Aided Molecular Design, Vol. 26, Issue 6
Concerted, highly asynchronous, enzyme-catalyzed [4 + 2] cycloaddition in the biosynthesis of spinosyn A; computational evidence
journal, January 2012
- Hess, B. Andes; Smentek, Lidia
- Organic & Biomolecular Chemistry, Vol. 10, Issue 37
Structure and Mechanism of the 6-Deoxyerythronolide B Synthase
journal, June 2007
- Khosla, Chaitan; Tang, Yinyan; Chen, Alice Y.
- Annual Review of Biochemistry, Vol. 76, Issue 1
XDS
journal, January 2010
- Kabsch, Wolfgang
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
Better models by discarding data?
journal, June 2013
- Diederichs, K.; Karplus, P. A.
- Acta Crystallographica Section D Biological Crystallography, Vol. 69, Issue 7
Overview of the CCP 4 suite and current developments
journal, March 2011
- Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D.
- Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
Phaser crystallographic software
journal, July 2007
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Journal of Applied Crystallography, Vol. 40, Issue 4
Automated macromolecular model building for X-ray crystallography using ARP/wARP version 7
journal, June 2008
- Langer, Gerrit; Cohen, Serge X.; Lamzin, Victor S.
- Nature Protocols, Vol. 3, Issue 7
Coot model-building tools for molecular graphics
journal, November 2004
- Emsley, Paul; Cowtan, Kevin
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
Refinement of Macromolecular Structures by the Maximum-Likelihood Method
journal, May 1997
- Murshudov, G. N.; Vagin, A. A.; Dodson, E. J.
- Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3
PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
3V: cavity, channel and cleft volume calculator and extractor
journal, May 2010
- Voss, N. R.; Gerstein, M.
- Nucleic Acids Research, Vol. 38, Issue Web Server
Avogadro: an advanced semantic chemical editor, visualization, and analysis platform
journal, August 2012
- Hanwell, Marcus D.; Curtis, Donald E.; Lonie, David C.
- Journal of Cheminformatics, Vol. 4, Issue 1
Mechanistic Insights into Polycycle Formation by Reductive Cyclization in Ikarugamycin Biosynthesis
journal, April 2014
- Zhang, Guangtao; Zhang, Wenjun; Zhang, Qingbo
- Angewandte Chemie, Vol. 126, Issue 19
Type II Polyketide Synthases: Gaining a Deeper Insight into Enzymatic Teamwork
journal, June 2007
- Hertweck, Christian; Luzhetskyy, Andriy; Rebets, Yuri
- ChemInform, Vol. 38, Issue 23
A computational study on the interactions between a layered imine-based COF structure and selected anticancer drugs
journal, January 2021
- Ghadari, Rahim; Ghanbari, Sevda; Mohammadzadeh, Yousef
- Journal of Molecular Modeling, Vol. 27, Issue 2
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation
journal, February 2021
- Tillu, Vikas A.; Rae, James; Gao, Ya
- Nature Communications, Vol. 12, Issue 1
Overview of the CCP4 suite and current developments.
text, January 2011
- Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D.
- Apollo - University of Cambridge Repository
Chemoenzymatic Synthesis of Spinosyn A
journal, October 2014
- Kim, Hak Joong; Choi, Sei-hyun; Jeon, Byung-sun
- Angewandte Chemie, Vol. 126, Issue 49
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
text, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Apollo - University of Cambridge Repository
MMFF VI. MMFF94s option for energy minimization studies
journal, May 1999
- Halgren, Thomas A.
- Journal of Computational Chemistry, Vol. 20, Issue 7
Mechanistic Insights into Polycycle Formation by Reductive Cyclization in Ikarugamycin Biosynthesis
journal, April 2014
- Zhang, Guangtao; Zhang, Wenjun; Zhang, Qingbo
- Angewandte Chemie International Edition, Vol. 53, Issue 19
AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading
journal, January 2009
- Trott, Oleg; Olson, Arthur J.
- Journal of Computational Chemistry
Current developments and challenges in the search for a naturally selected Diels-Alderase
journal, April 2012
- Kim, Hak Joong; Ruszczycky, Mark W.; Liu, Hung-wen
- Current Opinion in Chemical Biology, Vol. 16, Issue 1-2
Macrophomate Synthase: QM/MM Simulations Address the Diels−Alder versus Michael−Aldol Reaction Mechanism
journal, March 2005
- Guimarães, Cristiano Ruch Werneck; Udier-Blagović, Marina; Jorgensen, William L.
- Journal of the American Chemical Society, Vol. 127, Issue 10
The Putative Diels−Alderase Macrophomate Synthase is an Efficient Aldolase
journal, June 2008
- Serafimov, Jörg M.; Gillingham, Dennis; Kuster, Simon
- Journal of the American Chemical Society, Vol. 130, Issue 25
The spinosyn family of insecticides: realizing the potential of natural products research
journal, February 2010
- Kirst, Herbert A.
- The Journal of Antibiotics, Vol. 63, Issue 3
Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization
journal, October 2009
- Crawford, Jason M.; Korman, Tyler P.; Labonte, Jason W.
- Nature, Vol. 461, Issue 7267
Automated macromolecular model building for X-ray crystallography using ARP/wARP version 7
journal, June 2008
- Langer, Gerrit; Cohen, Serge X.; Lamzin, Victor S.
- Nature Protocols, Vol. 3, Issue 7
The structures of type I polyketide synthases
journal, January 2012
- Keatinge-Clay, Adrian T.
- Natural Product Reports, Vol. 29, Issue 10
Concerted, highly asynchronous, enzyme-catalyzed [4 + 2] cycloaddition in the biosynthesis of spinosyn A; computational evidence
journal, January 2012
- Hess, B. Andes; Smentek, Lidia
- Organic & Biomolecular Chemistry, Vol. 10, Issue 37
Crystal structure and functional analysis of tetracenomycin ARO/CYC: Implications for cyclization specificity of aromatic polyketides
journal, April 2008
- Ames, B. D.; Korman, T. P.; Zhang, W.
- Proceedings of the National Academy of Sciences, Vol. 105, Issue 14
Impact of scaffold rigidity on the design and evolution of an artificial Diels-Alderase
journal, May 2014
- Preiswerk, N.; Beck, T.; Schulz, J. D.
- Proceedings of the National Academy of Sciences, Vol. 111, Issue 22
Dali server: conservation mapping in 3D
journal, May 2010
- Holm, Liisa; Rosenstr�m, P�ivi
- Nucleic Acids Research, Vol. 38, Issue suppl_2
The Calicheamicin Gene Cluster and Its Iterative Type I Enediyne PKS
journal, August 2002
- Ahlert, J.
- Science, Vol. 297, Issue 5584
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
text, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Apollo - University of Cambridge Repository
Works referencing / citing this record:
Eine pericyclische Reaktionskaskade in der Leporin-Biosynthese
journal, February 2018
- Glöckle, Anna; Gulder, Tobias A. M.
- Angewandte Chemie, Vol. 130, Issue 11
Control of the Stereochemical Course of [4+2] Cycloaddition during trans -Decalin Formation by Fsa2-Family Enzymes
journal, July 2018
- Kato, Naoki; Nogawa, Toshihiko; Takita, Ryo
- Angewandte Chemie, Vol. 130, Issue 31
Cucurbit[7]uril as a Supramolecular Artificial Enzyme for Diels-Alder Reactions
journal, November 2017
- Palma, Aniello; Artelsmair, Markus; Wu, Guanglu
- Angewandte Chemie International Edition, Vol. 56, Issue 49
A Pericyclic Reaction Cascade in Leporin Biosynthesis
journal, February 2018
- Glöckle, Anna; Gulder, Tobias A. M.
- Angewandte Chemie International Edition, Vol. 57, Issue 11
Control of the Stereochemical Course of [4+2] Cycloaddition during trans -Decalin Formation by Fsa2-Family Enzymes
journal, July 2018
- Kato, Naoki; Nogawa, Toshihiko; Takita, Ryo
- Angewandte Chemie International Edition, Vol. 57, Issue 31
Strategies for Enhancing the Yield of the Potent Insecticide Spinosad in Actinomycetes
journal, July 2018
- Tao, Hui; Zhang, Yuchen; Deng, Zixin
- Biotechnology Journal, Vol. 14, Issue 1
Biocatalytic Strategies towards [4+2] Cycloadditions
journal, March 2019
- Lichman, Benjamin R.; O'Connor, Sarah E.; Kries, Hajo
- Chemistry - A European Journal, Vol. 25, Issue 28
The Iboga Alkaloids
book, January 2017
- Lavaud, Catherine; Massiot, Georges
- Progress in the Chemistry of Organic Natural Products 105
Fungal biotransformation of tanshinone results in [4+2] cycloaddition with sorbicillinol: evidence for enzyme catalysis and increased antibacterial activity
journal, May 2016
- He, Wenni; Liu, Miaomiao; Li, Xiaolin
- Applied Microbiology and Biotechnology, Vol. 100, Issue 19
Recent advances of Diels–Alderases involved in natural product biosynthesis
journal, June 2016
- Minami, Atsushi; Oikawa, Hideaki
- The Journal of Antibiotics, Vol. 69, Issue 7
A chemocentric view of the natural product inventory
journal, August 2015
- Walsh, Christopher T.
- Nature Chemical Biology, Vol. 11, Issue 9
Structural basis for stereoselective dehydration and hydrogen-bonding catalysis by the SAM-dependent pericyclase LepI
journal, July 2019
- Cai, Yujuan; Hai, Yang; Ohashi, Masao
- Nature Chemistry, Vol. 11, Issue 9
Fungal indole alkaloid biogenesis through evolution of a bifunctional reductase/Diels–Alderase
journal, September 2019
- Dan, Qingyun; Newmister, Sean A.; Klas, Kimberly R.
- Nature Chemistry, Vol. 11, Issue 11
The hidden enzymology of bacterial natural product biosynthesis
journal, June 2019
- Scott, Thomas A.; Piel, Jörn
- Nature Reviews Chemistry, Vol. 3, Issue 7
Unexpected enzyme-catalysed [4+2] cycloaddition and rearrangement in polyether antibiotic biosynthesis
journal, October 2019
- Little, Rory; Paiva, Fernanda C. R.; Jenkins, Robert
- Nature Catalysis, Vol. 2, Issue 11
Total synthesis of (−)-aritasone via the ultra-high pressure hetero-Diels–Alder dimerisation of (−)-pinocarvone
journal, January 2017
- Uroos, Maliha; Pitt, Phillip; Harwood, Laurence M.
- Org. Biomol. Chem., Vol. 15, Issue 40
Stereoconfining macrocyclizations in the total synthesis of natural products
journal, January 2019
- Zheng, Kuan; Hong, Ran
- Natural Product Reports, Vol. 36, Issue 11
Crystal structure of LepI, a multifunctional SAM-dependent enzyme which catalyzes pericyclic reactions in leporin biosynthesis
journal, January 2019
- Chang, Zhenying; Ansbacher, Tamar; Zhang, Lilan
- Organic & Biomolecular Chemistry, Vol. 17, Issue 8
Terpene synthases in disguise: enzymology, structure, and opportunities of non-canonical terpene synthases
journal, January 2020
- Rudolf, Jeffrey D.; Chang, Chin-Yuan
- Natural Product Reports, Vol. 37, Issue 3
Investigation of the mechanism of the SpnF-catalyzed [4+2]-cycloaddition reaction in the biosynthesis of spinosyn A
journal, September 2017
- Jeon, Byung-sun; Ruszczycky, Mark W.; Russell, William K.
- Proceedings of the National Academy of Sciences, Vol. 114, Issue 39
Influence of water and enzyme SpnF on the dynamics and energetics of the ambimodal [6+4]/[4+2] cycloaddition
journal, January 2018
- Yang, Zhongyue; Yang, Song; Yu, Peiyuan
- Proceedings of the National Academy of Sciences, Vol. 115, Issue 5
The Performance of Several Docking Programs at Reproducing Protein–Macrolide-Like Crystal Structures
journal, January 2017
- Castro-Alvarez, Alejandro; Costa, Anna; Vilarrasa, Jaume
- Molecules, Vol. 22, Issue 1
Heterologous Expression of Ilicicolin H Biosynthetic Gene Cluster and Production of a New Potent Antifungal Reagent, Ilicicolin J
journal, June 2019
- Lin, Xiaojing; Yuan, Siwen; Chen, Senhua
- Molecules, Vol. 24, Issue 12
Cucurbit[7]uril as a Supramolecular Artificial Enzyme for Diels-Alder Reactions
journal, November 2017
- Palma, Aniello; Artelsmair, Markus; Wu, Guanglu
- Angewandte Chemie, Vol. 129, Issue 49
Fungal Indole Alkaloid Biogenesis Through Evolution of a Bifunctional Reductase/Diels-Alderase
journal, December 2018
- Dan, Qingyun; Newmister, Sean A.; Klas, Kimberly R.
- Biological and Medicinal Chemistry
Computational Insights into an Enzyme-Catalyzed [4+2] Cycloaddition
journal, November 2017
- Zheng, Yiying; Thiel, Walter
- The Journal of Organic Chemistry, Vol. 82, Issue 24
Decoding cyclase-dependent assembly of hapalindole and fischerindole alkaloids
journal, March 2017
- Li, Shasha; Lowell, Andrew N.; Newmister, Sean A.
- Nature Chemical Biology, Vol. 13, Issue 5
Biosynthesis of Grandione: An Example of Tandem Hetero Diels-Alder/Retro-Claisen Rearrangement Reaction?
journal, September 2018
- Quijano-Quiñones, Ramiro; Castro-Segura, Carolina; Mena-Rejón, Gonzalo
- Molecules, Vol. 23, Issue 10
Heterologous Expression of Ilicicolin H Biosynthetic Gene Cluster and Production of a New Potent Antifungal Reagent, Ilicicolin J
journal, June 2019
- Lin, Xiaojing; Yuan, Siwen; Chen, Senhua
- Molecules, Vol. 24, Issue 12