Enhanced active-site electric field accelerates enzyme catalysis

Zheng, Chu; Ji, Zhe; Mathews, Irimpan I.; Boxer, Steven G.

doi:10.1038/s41557-023-01287-x

Enhanced active-site electric field accelerates enzyme catalysis

Journal Article · Thu Aug 10 00:00:00 EDT 2023 · Nature Chemistry

DOI:https://doi.org/10.1038/s41557-023-01287-x· OSTI ID:2405210

^[1]; ^[2]; Mathews, Irimpan I. ^[3]; ^[2]

Stanford Univ., CA (United States); SLAC
Stanford Univ., CA (United States)
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

In this study, the design and improvement of enzymes based on physical principles remain challenging. Here we demonstrate that the principle of electrostatic catalysis can be leveraged to substantially improve a natural enzyme’s activity. We enhanced the active-site electric field in horse liver alcohol dehydrogenase by replacing the serine hydrogen-bond donor with threonine and replacing the catalytic Zn²⁺ with Co²⁺. Based on the electric field enhancement, we make a quantitative prediction of rate acceleration—50-fold faster than the wild-type enzyme—which was in close agreement with experimental measurements. The effects of the hydrogen bonding and metal coordination, two distinct chemical forces, are described by a unified physical quantity—electric field, which is quantitative, and shown here to be additive and predictive. These results suggest a new design paradigm for both biological and non-biological catalysts.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2405210

Journal Information:: Nature Chemistry, Journal Name: Nature Chemistry Journal Issue: 12 Vol. 15; ISSN 1755-4330

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (45)

Structure of the complex of active site metal-depleted horse liver alcohol dehydrogenase and NADH. Schneider, G.; Eklund, H.; Cedergren-Zeppezauer, E. The EMBO Journal, Vol. 2, Issue 5 https://doi.org/10.1002/j.1460-2075.1983.tb01485.x	journal	May 1983
Directed evolution of biocatalysts Arnold, Frances H.; Volkov, Alexander A. Current Opinion in Chemical Biology, Vol. 3, Issue 1 https://doi.org/10.1016/S1367-5931(99)80010-6	journal	February 1999
Inversion of substrate stereoselectivity of horse liver alcohol dehydrogenase by substitutions of Ser-48 and Phe-93 Kim, Keehyuk; Plapp, Bryce V. Chemico-Biological Interactions, Vol. 276 https://doi.org/10.1016/j.cbi.2016.12.016	journal	October 2017
De novo enzymes by computational design Kries, Hajo; Blomberg, Rebecca; Hilvert, Donald Current Opinion in Chemical Biology, Vol. 17, Issue 2 https://doi.org/10.1016/j.cbpa.2013.02.012	journal	April 2013
Horse Liver Alcohol Dehydrogenase: Zinc Coordination and Catalysis Plapp, Bryce V.; Savarimuthu, Baskar Raj; Ferraro, Daniel J. Biochemistry, Vol. 56, Issue 28 https://doi.org/10.1021/acs.biochem.7b00446	journal	July 2017
Computational Design of Synthetic Enzymes Vaissier Welborn, Valerie; Head-Gordon, Teresa Chemical Reviews, Vol. 119, Issue 11 https://doi.org/10.1021/acs.chemrev.8b00399	journal	October 2018
Characterizing Ion-Polymer Interactions in Aqueous Environment with Electric Fields Vaissier Welborn, Valerie; Archer, William R.; Schulz, Michael D. Journal of Chemical Information and Modeling, Vol. 63, Issue 7 https://doi.org/10.1021/acs.jcim.2c01048	journal	December 2022
Vibrational Stark Effects of Carbonyl Probes Applied to Reinterpret IR and Raman Data for Enzyme Inhibitors in Terms of Electric Fields at the Active Site Schneider, Samuel H.; Boxer, Steven G. The Journal of Physical Chemistry B, Vol. 120, Issue 36 https://doi.org/10.1021/acs.jpcb.6b08133	journal	August 2016
Solvent-Independent Anharmonicity for Carbonyl Oscillators Schneider, Samuel H.; Kratochvil, Huong T.; Zanni, Martin T. The Journal of Physical Chemistry B, Vol. 121, Issue 10 https://doi.org/10.1021/acs.jpcb.7b00537	journal	March 2017
Direct Look at the Electric Field in Ketosteroid Isomerase and Its Variants Hennefarth, Matthew R.; Alexandrova, Anastassia N. ACS Catalysis, Vol. 10, Issue 17 https://doi.org/10.1021/acscatal.0c02795	journal	August 2020
Computational Optimization of Electric Fields for Improving Catalysis of a Designed Kemp Eliminase Vaissier, Valerie; Sharma, Sudhir C.; Schaettle, Karl ACS Catalysis, Vol. 8, Issue 1 https://doi.org/10.1021/acscatal.7b03151	journal	December 2017
Measuring Electric Fields and Noncovalent Interactions Using the Vibrational Stark Effect Fried, Stephen D.; Boxer, Steven G. Accounts of Chemical Research, Vol. 48, Issue 4 https://doi.org/10.1021/ar500464j	journal	March 2015
Source of Catalysis in the Lactate Dehydrogenase System. Ground-State Interactions in the Enzyme.cntdot.Substrate Complex Deng, Hua; Zheng, Jie; Clarke, Anthony Biochemistry, Vol. 33, Issue 8 https://doi.org/10.1021/bi00174a042	journal	March 1994
Active site specific cadmium(II)-substituted horse liver alcohol dehydrogenase: crystal structures of the free enzyme, its binary complex with NADH, and the ternary complex with NADH and bound p-bromobenzyl alcohol Schneider, Gunter; Cedergren-Zeppezauer, Eila; Knight, Stefan Biochemistry, Vol. 24, Issue 25 https://doi.org/10.1021/bi00346a070	journal	December 1985
Yeast Alcohol Dehydrogenase Structure and Catalysis Raj, Savarimuthu Baskar; Ramaswamy, S.; Plapp, Bryce V. Biochemistry, Vol. 53, Issue 36 https://doi.org/10.1021/bi5006442	journal	September 2014
Toward Accurate Screening in Computer-Aided Enzyme Design Roca, Maite; Vardi-Kilshtain, Alexandra; Warshel, Arieh Biochemistry, Vol. 48, Issue 14 https://doi.org/10.1021/bi802191b	journal	March 2009
Binding of Formamides to Liver Alcohol Dehydrogenase ^† ^, ^‡ Ramaswamy, S.; Scholze, Michael; Plapp, Bryce V. Biochemistry, Vol. 36, Issue 12 https://doi.org/10.1021/bi962491z	journal	March 1997
A Raman Spectroscopic Characterization of Bonding in the Complex of Horse Liver Alcohol Dehydrogenase with NADH and N -Cyclohexylformamide Deng, Hua; Schindler, John F.; Berst, Kristine B. Biochemistry, Vol. 37, Issue 40 https://doi.org/10.1021/bi981477e	journal	September 1998
Electrostatic Basis for Enzyme Catalysis Warshel, Arieh; Sharma, Pankaz K.; Kato, Mitsunori Chemical Reviews, Vol. 106, Issue 8 https://doi.org/10.1021/cr0503106	journal	August 2006
Four-parameter equation for predicting enthalpies of adduct formation Drago, Russell S.; Vogel, Glenn C.; Needham, Terence E. Journal of the American Chemical Society, Vol. 93, Issue 23 https://doi.org/10.1021/ja00752a010	journal	November 1971
Correction to “Hyperstability and Substrate Promiscuity in Laboratory Resurrections of Precambrian β-Lactamases” Risso, Valeria A.; Gavira, Jose A.; Mejia-Carmona, Diego F. Journal of the American Chemical Society, Vol. 135, Issue 28 https://doi.org/10.1021/ja404387m	journal	July 2013
Origin of the Catalytic Power of Acetylcholinesterase: Computer Simulation Studies Fuxreiter, Monika; Warshel, Arieh Journal of the American Chemical Society, Vol. 120, Issue 1 https://doi.org/10.1021/ja972326m	journal	January 1998
Electric-Field Mediated Chemistry: Uncovering and Exploiting the Potential of (Oriented) Electric Fields to Exert Chemical Catalysis and Reaction Control Shaik, Sason; Danovich, David; Joy, Jyothish Journal of the American Chemical Society, Vol. 142, Issue 29 https://doi.org/10.1021/jacs.0c05128	journal	June 2020
Energetic Basis and Design of Enzyme Function Demonstrated Using GFP, an Excited-State Enzyme Lin, Chi-Yun; Romei, Matthew G.; Mathews, Irimpan I. Journal of the American Chemical Society, Vol. 144, Issue 9 https://doi.org/10.1021/jacs.1c12305	journal	February 2022
Energetics and Dynamics of Enzymatic Reactions Villà, Jordi; Warshel, Arieh The Journal of Physical Chemistry B, Vol. 105, Issue 33 https://doi.org/10.1021/jp011048h	journal	August 2001
Electrostatic catalysis of a Diels–Alder reaction Aragonès, Albert C.; Haworth, Naomi L.; Darwish, Nadim Nature, Vol. 531, Issue 7592 https://doi.org/10.1038/nature16989	journal	March 2016
The coming of age of de novo protein design Huang, Po-Ssu; Boyken, Scott E.; Baker, David Nature, Vol. 537, Issue 7620 https://doi.org/10.1038/nature19946	journal	September 2016
Oriented electric fields as future smart reagents in chemistry Shaik, Sason; Mandal, Debasish; Ramanan, Rajeev Nature Chemistry, Vol. 8, Issue 12 https://doi.org/10.1038/nchem.2651	journal	November 2016
Directing isomerization reactions of cumulenes with electric fields Zang, Yaping; Zou, Qi; Fu, Tianren Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-12487-w	journal	October 2019
Evolution of dynamical networks enhances catalysis in a designer enzyme Bunzel, H. Adrian; Anderson, J. L. Ross; Hilvert, Donald Nature Chemistry, Vol. 13, Issue 10 https://doi.org/10.1038/s41557-021-00763-6	journal	August 2021
A two-directional vibrational probe reveals different electric field orientations in solution and an enzyme active site Zheng, Chu; Mao, Yuezhi; Kozuch, Jacek Nature Chemistry, Vol. 14, Issue 8 https://doi.org/10.1038/s41557-022-00937-w	journal	May 2022
De novo protein design by deep network hallucination Anishchenko, Ivan; Pellock, Samuel J.; Chidyausiku, Tamuka M. Nature, Vol. 600, Issue 7889 https://doi.org/10.1038/s41586-021-04184-w	journal	December 2021
The road to fully programmable protein catalysis Lovelock, Sarah L.; Crawshaw, Rebecca; Basler, Sophie Nature, Vol. 606, Issue 7912 https://doi.org/10.1038/s41586-022-04456-z	journal	June 2022
Computational optimization of electric fields for better catalysis design Welborn, Valerie Vaissier; Ruiz Pestana, Luis; Head-Gordon, Teresa Nature Catalysis, Vol. 1, Issue 9 https://doi.org/10.1038/s41929-018-0109-2	journal	September 2018
Ligand-field theory Griffith, J. S.; Orgel, L. E. Quarterly Reviews, Chemical Society, Vol. 11, Issue 4 https://doi.org/10.1039/qr9571100381	journal	January 1957
Crystal structures of the active site in specifically metal-depleted and cobalt-substituted horse liver alcohol dehydrogenase derivatives. Schneider, G.; Eklund, H.; Cedergren-Zeppezauer, E. Proceedings of the National Academy of Sciences, Vol. 80, Issue 17 https://doi.org/10.1073/pnas.80.17.5289	journal	September 1983
Refined crystal structure of liver alcohol dehydrogenase–NADH complex at 1.8 Å resolution Al-Karadaghi, S.; Cedergren-Zeppezauer, E. S.; Hovmöller, S. Acta Crystallographica Section D Biological Crystallography, Vol. 50, Issue 6 https://doi.org/10.1107/S0907444994005263	journal	November 1994
Three-dimensional structures of the three human class I alcohol dehydrogenases Niederhut, M. S. Protein Science, Vol. 10, Issue 4 https://doi.org/10.1110/ps.45001	journal	April 2001
Active-Site-Specific Reconstituted Cobalt(II) Horse-Liver Alcohol Dehydrogenase. Changes of the Spectra of the Substrate trans-4-(N,N-Dimethylamino)-cinnamaldehyde and of the Catalytic Cobalt Ion upon Ternary Complex Formation with NADH and 1,4,5,6-Tetrahydronkotinamide-Adenine Dinucleotide Dietrich, Helmut; Maret, Wolfgang; Wallen, Leif European Journal of Biochemistry, Vol. 100, Issue 1 https://doi.org/10.1111/j.1432-1033.1979.tb02057.x	journal	October 1979
Substrate specificity and stereoselectivity of horse liver alcohol dehydrogenase Adolph, Hans W.; Maurer, Patrik; Schneider‐BernlÖHr, Helga European Journal of Biochemistry, Vol. 201, Issue 3 https://doi.org/10.1111/j.1432-1033.1991.tb16322.x	journal	November 1991
Extreme electric fields power catalysis in the active site of ketosteroid isomerase Fried, Stephen D.; Bagchi, Sayan; Boxer, Steven G. Science, Vol. 346, Issue 6216 https://doi.org/10.1126/science.1259802	journal	December 2014
A proficient enzyme Radzicka, A.; Wolfenden, R. Science, Vol. 267, Issue 5194 https://doi.org/10.1126/science.7809611	journal	January 1995
How directed evolution reshapes the energy landscape in an enzyme to boost catalysis Otten, Renee; Pádua, Ricardo A. P.; Bunzel, H. Adrian Science, Vol. 370, Issue 6523 https://doi.org/10.1126/science.abd3623	journal	December 2020
Scaffolding protein functional sites using deep learning Wang, Jue; Lisanza, Sidney; Juergens, David Science, Vol. 377, Issue 6604 https://doi.org/10.1126/science.abn2100	journal	July 2022
Electric Fields and Enzyme Catalysis Fried, Stephen D.; Boxer, Steven G. Annual Review of Biochemistry, Vol. 86, Issue 1 https://doi.org/10.1146/annurev-biochem-061516-044432	journal	June 2017

Similar Records

Removal of the Side Chain at the Active-Site Serine by a Glycine Substitution Increases the Stability of a Wide Range of Serine β-Lactamases by Relieving Steric Strain

Journal Article · Tue Apr 12 00:00:00 EDT 2016 · Biochemistry · OSTI ID:1379327

Regulation of enzymes of serine and one-carbon metabolism by testosterone in rat prostate, liver, and kidney

Journal Article · Wed Oct 01 00:00:00 EDT 1975 · Endocrinology; (United States) · OSTI ID:7332104

Roles of cysteinyl residues of phosphoribulokinase as examined by site-directed mutagenesis

Journal Article · Wed Jun 05 00:00:00 EDT 1991 · Journal of Biological Chemistry; (United States) · OSTI ID:5366625

Related Subjects

59 BASIC BIOLOGICAL SCIENCES

Enhanced active-site electric field accelerates enzyme catalysis

Citation Formats

References (45)

Similar Records

Related Subjects