Substrate-Engaged Formation of Reactive Oxygen Intermediates in Metalloenzymes: Mechanisms and Implications for Biocatalysis
4 affiliations
- 1Shandong University , , No. 72 Binhai Road , ,
- 2Chang’an University , , ,
- 3Xiamen University , , ,
- 4Qingdao Marine Science and Technology Center , , ,
Abstract
Reactive oxygen intermediates in metalloenzymes are generally viewed as products of metal-centered O2 or H2O2 activation that are tuned by the surrounding protein environment. Increasing mechanistic evidence, however, shows that substrates can actively participate in the generation and evolution of these oxidants. In this Perspective, we discuss a substrate-engaged framework for reactive oxygen intermediate formation in metalloenzymes. Two major modes of substrate participation are emphasized. In H2O2-dependent heme enzymes, substrates can functionally replace or complement distal acid–base residues by providing transferable protons, organizing hydrogen-bond networks, and/or enabling proton-coupled electron transfer, thereby promoting productive O–O bond cleavage and ferryl/Compound I formation. In O2-activating heme and non-heme iron enzymes, substrates or substrate-derived intermediates can contribute electron density or reducing equivalents to metal–O2 adducts, generate radical-coupled intermediates, and guide metal–oxygen species into catalytically competent geometries. These examples indicate that substrate recognition, oxygen activation, and substrate oxidation are often coupled within a single catalytic manifold. This substrate-engaged view complements the traditional metal-centered paradigm and provides mechanistic principles for discovering and designing oxidative biocatalytic reactions in which substrates help generate, control, and productively consume reactive oxygen intermediates.
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BibTeX
@article{peng2026substrateengaged,
title = {{Substrate-Engaged Formation of Reactive Oxygen Intermediates in Metalloenzymes: Mechanisms and Implications for Biocatalysis}},
author = {Wei Peng and Yuanyuan Jiang and Yulu Liu and Xing Zhang and Zhicong He and Mingzhao Zhu and Binju Wang and Shengying Li},
journal = {JACS Au},
year = {2026},
month = oct,
doi = {10.1021/jacsau.6c01247},
url = {https://pubs.acs.org/jaaucr/article/doi/10.1021/jacsau.6c01247/5448902/Substrate-Engaged-Formation-of-Reactive-Oxygen},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Substrate-Engaged Formation of Reactive Oxygen Intermediates in Metalloenzymes: Mechanisms and Implications for Biocatalysis
AU - Wei Peng
AU - Yuanyuan Jiang
AU - Yulu Liu
AU - Xing Zhang
AU - Zhicong He
AU - Mingzhao Zhu
AU - Binju Wang
AU - Shengying Li
PY - 2026
DA - 2026/10/12
JO - JACS Au
DO - 10.1021/jacsau.6c01247
UR - https://pubs.acs.org/jaaucr/article/doi/10.1021/jacsau.6c01247/5448902/Substrate-Engaged-Formation-of-Reactive-Oxygen
AB - Reactive oxygen intermediates in metalloenzymes are generally viewed as products of metal-centered O2 or H2O2 activation that are tuned by the surrounding protein environment. Increasing mechanistic evidence, however, shows that substrates can actively participate in the generation and evolution of these oxidants. In this Perspective, we discuss a substrate-engaged framework for reactive oxygen intermediate formation in metalloenzymes. Two major modes of substrate participation are emphasized. In H2O2-dependent heme enzymes, substrates can functionally replace or complement distal acid–base residues by providing transferable protons, organizing hydrogen-bond networks, and/or enabling proton-coupled electron transfer, thereby promoting productive O–O bond cleavage and ferryl/Compound I formation. In O2-activating heme and non-heme iron enzymes, substrates or substrate-derived intermediates can contribute electron density or reducing equivalents to metal–O2 adducts, generate radical-coupled intermediates, and guide metal–oxygen species into catalytically competent geometries. These examples indicate that substrate recognition, oxygen activation, and substrate oxidation are often coupled within a single catalytic manifold. This substrate-engaged view complements the traditional metal-centered paradigm and provides mechanistic principles for discovering and designing oxidative biocatalytic reactions in which substrates help generate, control, and productively consume reactive oxygen intermediates.
SN - 2691-3704
ER -