Histidine oxidation in lytic polysaccharide monooxygenase

Magne Torbjörnsson, Marlisa M. Hagemann, Ulf Ryde*, Erik Donovan Hedegård*


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The lytic polysaccharide monooxygenases (LPMOs) comprise a super-family of copper enzymes that boost the depolymerisation of polysaccharides by oxidatively disrupting the glycosidic bonds connecting the sugar units. Industrial use of LPMOs for cellulose depolymerisation has already begun but is still far from reaching its full potential. One issue is that the LPMOs self-oxidise and thereby deactivate. The mechanism of this self-oxidation is unknown, but histidine residues coordinating to the copper atom are the most susceptible. An unusual methyl modification of the NE2 atom in one of the coordinating histidine residues has been proposed to have a protective role. Furthermore, substrate binding is also known to reduce oxidative damage. We here for the first time investigate the mechanism of histidine oxidation with combined quantum and molecular mechanical (QM/MM) calculations, with outset in intermediates previously shown to form from a reaction with peroxide and a reduced LPMO. We show that an intermediate with a [Cu-O] + moiety is sufficiently potent to oxidise the nearest C-H bond on both histidine residues, but methylation of the NE2 atom of His-1 increases the reaction barrier of this reaction. The substrate further increases the activation barrier. We also investigate a [Cu-OH] 2+ intermediate with a deprotonated tyrosine radical. This intermediate was previously proposed to have a protective role, and we also find it to have higher barriers than the corresponding a [Cu-O] + intermediate.

TidsskriftJournal of Biological Inorganic Chemistry
Udgave nummer3
Sider (fra-til)317-328
StatusUdgivet - apr. 2023

Bibliografisk note

Funding Information:
This investigation has been supported by Grants from the Swedish research council (projects 2018-05003 and 2019-04205), The Villum Foundation, Young Investigator Program (Grant no. 29412), and Independent Research Fund Denmark (Grants no. 0252-00002B and 10.46540/2064-00002B). The computations were performed on computer resources provided by the Swedish National Infrastructure for Computing (SNIC) at Lunarc at Lund University, NSC at Linköping University and HPC2N at Umeå University, partially funded by the Swedish Research Council (Grant 2018-05973).

Publisher Copyright:
© 2023, The Author(s).


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