Histidine oxidation in lytic polysaccharide monooxygenase
Magne Torbjörnsson1, Marlisa M Hagemann2, Ulf Ryde3
1Department of Theoretical Chemistry, Lund University, Chemical Centre, P. O. Box 124, 221 00, Lund, Sweden.
Summary
Lytic polysaccharide monooxygenases (LPMOs) deactivate through self-oxidation. Methylation of histidine residues and substrate binding increase reaction barriers, potentially protecting these crucial copper enzymes during industrial applications.
Area of Science:
- Biochemistry
- Enzymology
Background:
- Lytic polysaccharide monooxygenases (LPMOs) are copper enzymes vital for polysaccharide depolymerization.
- Industrial applications of LPMOs are limited by enzyme self-oxidation and deactivation.
- The mechanism of LPMO self-oxidation, particularly involving histidine residues, remains unclear.
Purpose of the Study:
- To elucidate the mechanism of histidine oxidation in LPMOs.
- To investigate the protective role of histidine methylation and substrate binding against self-oxidation.
- To computationally evaluate proposed protective intermediates in LPMO deactivation.
Main Methods:
- Combined quantum mechanics/molecular mechanics (QM/MM) calculations were employed.
- The study focused on intermediates formed from reduced LPMOs reacting with peroxide.
- Reaction pathways and activation barriers for histidine oxidation were analyzed.
Main Results:
- A [Cu-O]+ intermediate can oxidize histidine C-H bonds.
- Methylation of histidine NE2 increases the oxidation reaction barrier.
- Substrate binding further elevates the activation barrier for histidine oxidation.
- A [Cu-OH]2+ intermediate with a tyrosine radical shows higher barriers than the [Cu-O]+ intermediate.
Conclusions:
- Histidine oxidation is a key deactivation pathway for LPMOs.
- Histidine methylation and substrate binding offer protective mechanisms by increasing reaction barriers.
- Computational insights provide a basis for engineering more stable and industrially relevant LPMOs.
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