A cytokine-based designer enzyme with an abiological multinuclear metal center exhibits intrinsic and extrinsic catalysis

Akiko Ueno, Fumiko Takida, Tomoki Kita, Takuro Ishii, Tomoki Himiyama (), Takuya Mabuchi () and Yasunori Okamoto ()
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Akiko Ueno: Tohoku University
Fumiko Takida: Tohoku University
Tomoki Kita: Tohoku University
Takuro Ishii: Tohoku University
Tomoki Himiyama: National Institute of Advanced Industrial Science and Technology
Takuya Mabuchi: Tohoku University
Yasunori Okamoto: Tohoku University

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract A designer enzyme consisting of an abiological molecule incorporated into a natural protein has been developed as an exceptionally chemoselective catalyst, highlighting that the internal space of proteins is highly beneficial for enhancing catalytic performance. However, other features of proteins have received less attention in designer enzymes, for e.g., their use as ligands to construct abiological (multinuclear) metal centers and their intrinsic functions that have often been traded off for a new function. Here, grafting a synthetic trinuclear zinc complex inside a human cytokine macrophage migration inhibitory factor (MIF) scaffold using solely amino-acid side chains leads to a designer multi-metalloenzyme with extrinsic and intrinsic functions. The crystal structure of the designer tri-zinc enzyme verifies the accuracy of our design process based on geometry optimizations and quantum-chemical calculations. The extrinsic catalytic performance of this designer enzyme is of the highest class and comparable to that of previously reported designer zinc hydrolases. Importantly, an intrinsic function of MIF, i.e., its tautomerase activity, is maintained in this designer tri-zinc enzyme. Considering that cytokines are originally expressed in response to in vivo events, this cytokine-based designer metalloenzyme holds promising potential as a synthetic biological tool for the self-adaptive regulation of life phenomena.

Date: 2025
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DOI: 10.1038/s41467-025-61909-5

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