skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Photoexcitation of flavoenzymes enables a stereoselective radical cyclization

Abstract

Photoexcitation is a common strategy for initiating radical reactions in chemical synthesis. We found that photoexcitation of flavin-dependent “ene”-reductases changes their catalytic function, enabling these enzymes to promote an asymmetric radical cyclization. This reactivity enables the construction of five-, six-, seven-, and eight-membered lactams with stereochemical preference conferred by the enzyme active site. After formation of a prochiral radical, the enzyme guides the delivery of a hydrogen atom from flavin—a challenging feat for small-molecule chemical reagents. The initial electron transfer occurs through direct excitation of an electron donor-acceptor complex that forms between the substrate and the reduced flavin cofactor within the enzyme active site. As a result, photoexcitation of promiscuous flavoenzymes has thus furnished a previously unknown biocatalytic reaction.

Authors:
ORCiD logo; ORCiD logo; ORCiD logo; ORCiD logo; ; ORCiD logo; ; ; ; ORCiD logo
Publication Date:
Research Org.:
Princeton Univ., NJ (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1528674
Alternate Identifier(s):
OSTI ID: 1529103
Grant/Contract Number:  
SC0019370
Resource Type:
Published Article
Journal Name:
Science
Additional Journal Information:
Journal Name: Science Journal Volume: 364 Journal Issue: 6446; Journal ID: ISSN 0036-8075
Publisher:
American Association for the Advancement of Science (AAAS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Biegasiewicz, Kyle F., Cooper, Simon J., Gao, Xin, Oblinsky, Daniel G., Kim, Ji Hye, Garfinkle, Samuel E., Joyce, Leo A., Sandoval, Braddock A., Scholes, Gregory D., and Hyster, Todd K. Photoexcitation of flavoenzymes enables a stereoselective radical cyclization. United States: N. p., 2019. Web. doi:10.1126/science.aaw1143.
Biegasiewicz, Kyle F., Cooper, Simon J., Gao, Xin, Oblinsky, Daniel G., Kim, Ji Hye, Garfinkle, Samuel E., Joyce, Leo A., Sandoval, Braddock A., Scholes, Gregory D., & Hyster, Todd K. Photoexcitation of flavoenzymes enables a stereoselective radical cyclization. United States. doi:10.1126/science.aaw1143.
Biegasiewicz, Kyle F., Cooper, Simon J., Gao, Xin, Oblinsky, Daniel G., Kim, Ji Hye, Garfinkle, Samuel E., Joyce, Leo A., Sandoval, Braddock A., Scholes, Gregory D., and Hyster, Todd K. Thu . "Photoexcitation of flavoenzymes enables a stereoselective radical cyclization". United States. doi:10.1126/science.aaw1143.
@article{osti_1528674,
title = {Photoexcitation of flavoenzymes enables a stereoselective radical cyclization},
author = {Biegasiewicz, Kyle F. and Cooper, Simon J. and Gao, Xin and Oblinsky, Daniel G. and Kim, Ji Hye and Garfinkle, Samuel E. and Joyce, Leo A. and Sandoval, Braddock A. and Scholes, Gregory D. and Hyster, Todd K.},
abstractNote = {Photoexcitation is a common strategy for initiating radical reactions in chemical synthesis. We found that photoexcitation of flavin-dependent “ene”-reductases changes their catalytic function, enabling these enzymes to promote an asymmetric radical cyclization. This reactivity enables the construction of five-, six-, seven-, and eight-membered lactams with stereochemical preference conferred by the enzyme active site. After formation of a prochiral radical, the enzyme guides the delivery of a hydrogen atom from flavin—a challenging feat for small-molecule chemical reagents. The initial electron transfer occurs through direct excitation of an electron donor-acceptor complex that forms between the substrate and the reduced flavin cofactor within the enzyme active site. As a result, photoexcitation of promiscuous flavoenzymes has thus furnished a previously unknown biocatalytic reaction.},
doi = {10.1126/science.aaw1143},
journal = {Science},
number = 6446,
volume = 364,
place = {United States},
year = {2019},
month = {6}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1126/science.aaw1143

Citation Metrics:
Cited by: 18 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Structure and Function of the Photosystem Supercomplexes
journal, March 2018


Fluorescence and optical characteristics of reduced flavines and flavoproteins
journal, January 1974

  • Ghisla, Sandro; Massey, Vincent; Lhoste, Jean-Marc
  • Biochemistry, Vol. 13, Issue 3
  • DOI: 10.1021/bi00700a029

Electron hopping through proteins
journal, November 2012

  • Warren, Jeffrey J.; Ener, Maraia E.; Vlček, Antonín
  • Coordination Chemistry Reviews, Vol. 256, Issue 21-22
  • DOI: 10.1016/j.ccr.2012.03.032

Organic Photoredox Catalysis
journal, June 2016


Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals: Miniperspective
journal, October 2014

  • Vitaku, Edon; Smith, David T.; Njardarson, Jon T.
  • Journal of Medicinal Chemistry, Vol. 57, Issue 24
  • DOI: 10.1021/jm501100b

Kinetics and Equilibrium Constants for Reactions of α-Phenyl-Substituted Cyclopropylcarbinyl Radicals
journal, April 2000

  • Halgren, Thomas A.; Roberts, John D.; Horner, John H.
  • Journal of the American Chemical Society, Vol. 122, Issue 13
  • DOI: 10.1021/ja991114h

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
  • DOI: 10.1107/S0907444996012255

Catalysis of Radical Reactions: A Radical Chemistry Perspective
journal, October 2015

  • Studer, Armido; Curran, Dennis P.
  • Angewandte Chemie International Edition, Vol. 55, Issue 1
  • DOI: 10.1002/anie.201505090

Free radicals in the synthesis of medium-sized rings
journal, July 1999


An algal photoenzyme converts fatty acids to hydrocarbons
journal, August 2017

  • Sorigué, Damien; Légeret, Bertrand; Cuiné, Stéphan
  • Science, Vol. 357, Issue 6354
  • DOI: 10.1126/science.aan6349

6-31G* basis set for third-row atoms
journal, January 2001

  • Rassolov, Vitaly A.; Ratner, Mark A.; Pople, John A.
  • Journal of Computational Chemistry, Vol. 22, Issue 9
  • DOI: 10.1002/jcc.1058

Asymmetric Reductive Carbocyclization Using Engineered Ene Reductases
journal, May 2018

  • Heckenbichler, Kathrin; Schweiger, Anna; Brandner, Lea Alexandra
  • Angewandte Chemie International Edition, Vol. 57, Issue 24
  • DOI: 10.1002/anie.201802962

Catalytic promiscuity enabled by photoredox catalysis in nicotinamide-dependent oxidoreductases
journal, June 2018

  • Biegasiewicz, Kyle F.; Cooper, Simon J.; Emmanuel, Megan A.
  • Nature Chemistry, Vol. 10, Issue 7
  • DOI: 10.1038/s41557-018-0059-y

Results obtained with the correlation energy density functionals of becke and Lee, Yang and Parr
journal, May 1989


Facile Quantum Yield Determination via NMR Actinometry
journal, March 2018


Discovery, Characterization, Engineering, and Applications of Ene-Reductases for Industrial Biocatalysis
journal, March 2018


A complete basis set model chemistry. I. The total energies of closed‐shell atoms and hydrides of the first‐row elements
journal, August 1988

  • Petersson, G. A.; Bennett, Andrew; Tensfeldt, Thomas G.
  • The Journal of Chemical Physics, Vol. 89, Issue 4
  • DOI: 10.1063/1.455064

Fragmentation of substituted acetophenones and halobenzophenone ketyls. Calibration of a mechanistic probe
journal, October 1991

  • Tanner, Dennis D.; Chen, Jian Jeffrey; Chen, Lucia
  • Journal of the American Chemical Society, Vol. 113, Issue 21
  • DOI: 10.1021/ja00021a038

Photoredox-Catalyzed Ketyl–Olefin Coupling for the Synthesis of Substituted Chromanols
journal, June 2016

  • Fava, Eleonora; Nakajima, Masaki; Nguyen, Anh L. P.
  • The Journal of Organic Chemistry, Vol. 81, Issue 16
  • DOI: 10.1021/acs.joc.6b01006

How good are my data and what is the resolution?
journal, June 2013

  • Evans, Philip R.; Murshudov, Garib N.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 69, Issue 7
  • DOI: 10.1107/S0907444913000061

Effects of temperature on atom transfer cyclization reactions of allylic .alpha.-iodo esters and amides
journal, April 1991

  • Curran, Dennis P.; Tamine, John
  • The Journal of Organic Chemistry, Vol. 56, Issue 8
  • DOI: 10.1021/jo00008a032

Structure and Function of DNA Photolyase and Cryptochrome Blue-Light Photoreceptors
journal, June 2003


Systematic Approach to Conformational Sampling for Assigning Absolute Configuration Using Vibrational Circular Dichroism
journal, September 2013

  • Sherer, Edward C.; Lee, Claire H.; Shpungin, Joseph
  • Journal of Medicinal Chemistry, Vol. 57, Issue 2
  • DOI: 10.1021/jm401600u

Self‐consistent molecular orbital methods. XXIII. A polarization‐type basis set for second‐row elements
journal, October 1982

  • Francl, Michelle M.; Pietro, William J.; Hehre, Warren J.
  • The Journal of Chemical Physics, Vol. 77, Issue 7, p. 3654-3665
  • DOI: 10.1063/1.444267

Enantioselective synthesis of an ophiobolin sesterterpene via a programmed radical cascade
journal, May 2016


XDS
journal, January 2010

  • Kabsch, Wolfgang
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
  • DOI: 10.1107/S0907444909047337

Photoreduction of flavoproteins and other biological compounds catalyzed by deazaflavins. Appendix: photochemical formation of deazaflavin dimers
journal, January 1978

  • Massey, Vincent; Hemmerich, Peter; Knappe, W. R.
  • Biochemistry, Vol. 17, Issue 1
  • DOI: 10.1021/bi00594a002

Enzymatic assembly of DNA molecules up to several hundred kilobases
journal, April 2009

  • Gibson, Daniel G.; Young, Lei; Chuang, Ray-Yuan
  • Nature Methods, Vol. 6, Issue 5, p. 343-345
  • DOI: 10.1038/nmeth.1318

Enantioselective Radical Processes
journal, August 2003

  • Sibi, Mukund P.; Manyem, Shankar; Zimmerman, Jake
  • Chemical Reviews, Vol. 103, Issue 8
  • DOI: 10.1021/cr020044l

Iridium-Catalyzed Asymmetric Hydrogenation of β,γ-Unsaturated γ-Lactams: Scope and Mechanistic Studies
journal, February 2017


6-31G * basis set for atoms K through Zn
journal, July 1998

  • Rassolov, Vitaly A.; Pople, John A.; Ratner, Mark A.
  • The Journal of Chemical Physics, Vol. 109, Issue 4
  • DOI: 10.1063/1.476673

Light-Dependent Protochlorophyllide Oxidoreductase: Phylogeny, Regulation, and Catalytic Properties
journal, August 2015


Density‐functional thermochemistry. III. The role of exact exchange
journal, April 1993

  • Becke, Axel D.
  • The Journal of Chemical Physics, Vol. 98, Issue 7, p. 5648-5652
  • DOI: 10.1063/1.464913

Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density
journal, January 1988


Biocatalytic retrosynthesis
journal, April 2013

  • Turner, Nicholas J.; O'Reilly, Elaine
  • Nature Chemical Biology, Vol. 9, Issue 5
  • DOI: 10.1038/nchembio.1235

Enantioselective Hydrogen Atom Transfer: Discovery of Catalytic Promiscuity in Flavin-Dependent ‘Ene’-Reductases
journal, August 2017

  • Sandoval, Braddock A.; Meichan, Andrew J.; Hyster, Todd K.
  • Journal of the American Chemical Society, Vol. 139, Issue 33
  • DOI: 10.1021/jacs.7b05468

A novel computational method for comparing vibrational circular dichroism spectra
journal, August 2010

  • Shen, Jian; Zhu, Chengyue; Reiling, Stephan
  • Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, Vol. 76, Issue 3-4
  • DOI: 10.1016/j.saa.2010.04.014

Total synthesis of complex terpenoids employing radical cascade processes
journal, January 2018

  • Hung, Kevin; Hu, Xirui; Maimone, Thomas J.
  • Natural Product Reports, Vol. 35, Issue 2
  • DOI: 10.1039/C7NP00065K

LOV Domains in the Design of Photoresponsive Enzymes
journal, June 2018


Carbohydrate-derived thiols as protic polarity-reversal catalysts for enantioselective radical-chain reactions
journal, May 2002

  • Cai, Yudong; Roberts, Brian P.; Tocher, Derek A.
  • Journal of the Chemical Society, Perkin Transactions 1, Issue 11
  • DOI: 10.1039/b202022j

Catalytic Promiscuity in Biocatalysis: Using Old Enzymes to Form New Bonds and Follow New Pathways
journal, November 2004

  • Bornscheuer, Uwe T.; Kazlauskas, Romas J.
  • Angewandte Chemie International Edition, Vol. 43, Issue 45, p. 6032-6040
  • DOI: 10.1002/anie.200460416

Ab initio calculation of atomic axial tensors and vibrational rotational strengths using density functional theory
journal, April 1996


Photo-Biocatalysis: Biotransformations in the Presence of Light
journal, April 2019


A complete basis set model chemistry. II. Open‐shell systems and the total energies of the first‐row atoms
journal, May 1991

  • Petersson, G. A.; Al‐Laham, Mohammad A.
  • The Journal of Chemical Physics, Vol. 94, Issue 9
  • DOI: 10.1063/1.460447

Building Bridges: Biocatalytic C–C-Bond Formation toward Multifunctional Products
journal, June 2016


Highly enantioselective synthesis of anti aryl β-hydroxy α-amino esters via DKR transfer hydrogenation
journal, April 2011


Energy distributions in multiple photon absorption experiments
journal, March 2004

  • Mehlig, K.; Hansen, K.; Hedén, M.
  • The Journal of Chemical Physics, Vol. 120, Issue 9
  • DOI: 10.1063/1.1643896

Accessing non-natural reactivity by irradiating nicotinamide-dependent enzymes with light
journal, December 2016

  • Emmanuel, Megan A.; Greenberg, Norman R.; Oblinsky, Daniel G.
  • Nature, Vol. 540, Issue 7633
  • DOI: 10.1038/nature20569

Phaser crystallographic software
journal, July 2007

  • McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
  • Journal of Applied Crystallography, Vol. 40, Issue 4
  • DOI: 10.1107/S0021889807021206

Self—Consistent Molecular Orbital Methods. XII. Further Extensions of Gaussian—Type Basis Sets for Use in Molecular Orbital Studies of Organic Molecules
journal, March 1972

  • Hehre, W. J.; Ditchfield, R.; Pople, J. A.
  • The Journal of Chemical Physics, Vol. 56, Issue 5, p. 2257-2261
  • DOI: 10.1063/1.1677527