Fast product release requires active-site water dynamics in carbonic anhydrase

Jin Kyun Kim, Seon Woo Lim, Hannah Jeong, Cheol Lee, Seoyoon Kim, Dong Woo Son, Rajeev Kumar, Jacob T. Andring, Carrie Lomelino, Jennifer L. Wierman, Aina E. Cohen, Tae Joo Shin, Cheol-Min Ghim, Robert McKenna, Byung Hoon Jo, Duyoung Min, Jeong-Mo Choi and Chae Un Kim ()
Additional contact information
Jin Kyun Kim: Ulsan National Institute of Science and Technology (UNIST)
Seon Woo Lim: Ulsan National Institute of Science and Technology (UNIST)
Hannah Jeong: Ulsan National Institute of Science and Technology (UNIST)
Cheol Lee: Ulsan National Institute of Science and Technology (UNIST)
Seoyoon Kim: Ulsan National Institute of Science and Technology (UNIST)
Dong Woo Son: Gyeongsang National University
Rajeev Kumar: Pusan National University
Jacob T. Andring: University of Florida
Carrie Lomelino: University of Florida
Jennifer L. Wierman: Ithaca
Aina E. Cohen: Menlo Park
Tae Joo Shin: Ulsan National Institute of Science and Technology (UNIST)
Cheol-Min Ghim: Ulsan National Institute of Science and Technology (UNIST)
Robert McKenna: University of Florida
Byung Hoon Jo: Gyeongsang National University
Duyoung Min: Ulsan National Institute of Science and Technology (UNIST)
Jeong-Mo Choi: Pusan National University
Chae Un Kim: Ulsan National Institute of Science and Technology (UNIST)

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Water plays an essential role in enzyme structure, stability, and the substantial rate enhancement of enzyme catalysis. However, direct observations linking enzyme catalysis and active-site water dynamics pose a significant challenge due to experimental difficulties. By integrating an ultraviolet (UV) photolysis technique with temperature-controlled X-ray crystallography, we track the catalytic pathway of carbonic anhydrase II (CAII) at 1.2 Å resolution. This approach enables us to construct molecular movies of CAII catalysis, encompassing substrate (CO2) binding, conversion from substrate to product (bicarbonate), and product release. In the catalytic pathway, we identify an unexpected configuration in product binding and correlate it with sub-nanosecond rearrangement of active-site water. Based on these experimental observations, we propose a comprehensive mechanism of CAII and describe the detailed structure and dynamics of active-site water in CAII. Our findings suggest that CAII has evolved to utilize the structure and fast dynamics of the active-site waters for its diffusion-limited catalytic efficiency.

Date: 2025
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DOI: 10.1038/s41467-025-59645-x

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