Employing AC and DC Electrolysis to Modulate Electroenzymatic Pathways for Efficient and Stereoselective H-D Exchange

Author

• Wassim El Housseini
• Rokas Gerulskis
• Nibedita Behera
• Huaijun Guan
• Rohit G. Jadhav
• Zachary A. Nguyen
• Egor Baiarashov
• Michael A. Pence
• Vamshi Krishna Kamaja
• Trevor Larkin
• Long Luo
• Shelley D. Minteer, Missouri University of Science and TechnologyFollow

Abstract

Stereoselective hydrogen isotope exchange (HIE) at chiral centers is an increasingly important strategy for preparing labeled molecules, yet its practical implementation depends on reliable control of nicotinamide cofactor regeneration. Here we introduce a redox-programmable electroenzymatic platform for stereoselective HIE based on electrode-controlled manipulation of the nicotinamide cofactor state. A wired ferredoxin–NADP⁺ reductase (FNR) electrode enables reversible electrochemical interconversion of NADP⁺ and its deuterated reduced form (NADPD) directly from D2O. Coupling this cofactor cycling with enantioselective alcohol dehydrogenases (ADHs) establishes a reversible alcohol–ketone redox manifold that drives efficient and stereoselective H-D exchange at chiral alcohols. Stereochemical outcomes are programmed by the combined choice of paired electrolysis mode and enzyme configuration: direct-current electrolysis enables stereochemical editing with stereocomplementary ADHs, whereas alternating-current electrolysis supports rapid bidirectional cycling with a single ADH to achieve stereoretentive labeling. This strategy affords near-quantitative deuterium incorporation with high enantiopurity across a broad range of secondary alcohols.

Recommended Citation

W. El Housseini and R. Gerulskis and N. Behera and H. Guan and R. G. Jadhav and Z. A. Nguyen and E. Baiarashov and M. A. Pence and V. K. Kamaja and T. Larkin and L. Luo and S. D. Minteer, "Employing AC and DC Electrolysis to Modulate Electroenzymatic Pathways for Efficient and Stereoselective H-D Exchange," Journal of the American Chemical Society, vol. 148, no. 22, pp. 22641 - 22652, American Chemical Society, Jun 2026.

The definitive version is available at https://doi.org/10.1021/jacs.6c02284

Department(s)

Chemistry

Publication Status

Open Access

International Standard Serial Number (ISSN)

1520-5126; 0002-7863

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2026 American Chemical Society, All rights reserved.

Publication Date

10 Jun 2026

PubMed ID

42207689