Redox robustness drives LPMO evolution

Iván Ayuso-Fernández, Tom Z. Emrich-Mills, Ole Golten, Zarah Forsberg, Kelsi R. Hall, László G. Nagy, Morten Sørlie, Åsmund Kjendseth Røhr, Vincent G. H. Eijsink
2025 · doi:10.1101/2025.06.16.659879
preprint OA: closed
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Abstract

Enzymes known as lytic polysaccharide monooxygenases (LPMOs) are exceptionally powerful small redox enzymes that master the controlled generation and productive use of potentially damaging hydroxyl radicals in what is essentially a H 2 O 2 -driven peroxygenase reaction. We have used ancestral sequence reconstruction and enzyme resurrection to unravel evolutionary steps leading to this unprecedented catalytic power. Real-time monitoring of copper re-oxidation and amino acid radical formation showed evolutionary improvement of both the capacity to avoid futile turnover of H 2 O 2 and the ability to scavenge damaging radicals resulting from such turnover through a hole hopping pathway. These results show how selective pressure imposed by the need for generating a highly oxidizing intermediate shapes metalloenzymes, involving large parts of the enzyme, well beyond the catalytic center.

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[{'doi': None, 'name': 'European Research Council', 'awards': ['856446']}, {'doi': None, 'name': 'The Research Council of Norway', 'awards': ['301022']}, {'doi': None, 'name': 'The Research Council of Norway', 'awards': ['245828']}]

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