Histidine oxidation in lytic polysaccharide monooxygenase

IF 2.7 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Magne Torbjörnsson, Marlisa M. Hagemann, Ulf Ryde, Erik Donovan Hedegård
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引用次数: 5

Abstract

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.

Graphical abstract

Abstract Image

多糖单加氧酶中组氨酸的氧化
水解多糖单加氧酶(LPMOs)包含一个铜酶超家族,通过氧化破坏连接糖单元的糖苷键来促进多糖的解聚合。LPMOs用于纤维素解聚的工业用途已经开始,但仍远未达到其全部潜力。一个问题是,LPMOs自氧化,从而失活。这种自氧化的机制尚不清楚,但与铜原子配位的组氨酸残基是最容易受到影响的。一个不寻常的甲基修饰NE2原子在一个配位组氨酸残基已被提出具有保护作用。此外,底物结合也被认为可以减少氧化损伤。在这里,我们首次用量子和分子力学(QM/MM)相结合的计算来研究组氨酸氧化的机制,在之前的研究中,中间产物被证明是由过氧化物和还原的LPMO反应形成的。我们发现含有[Cu-O]+片段的中间体足以氧化两个组氨酸残基上最近的C-H键,但His-1的NE2原子的甲基化增加了该反应的反应屏障。底物进一步增加了活化势垒。我们还研究了具有去质子化酪氨酸自由基的[Cu-OH]2+中间体。该中间体先前被认为具有保护作用,我们也发现它比相应的a [Cu-O]+中间体具有更高的势垒。图形抽象
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来源期刊
JBIC Journal of Biological Inorganic Chemistry
JBIC Journal of Biological Inorganic Chemistry 化学-生化与分子生物学
CiteScore
5.90
自引率
3.30%
发文量
49
审稿时长
3 months
期刊介绍: Biological inorganic chemistry is a growing field of science that embraces the principles of biology and inorganic chemistry and impacts other fields ranging from medicine to the environment. JBIC (Journal of Biological Inorganic Chemistry) seeks to promote this field internationally. The Journal is primarily concerned with advances in understanding the role of metal ions within a biological matrix—be it a protein, DNA/RNA, or a cell, as well as appropriate model studies. Manuscripts describing high-quality original research on the above topics in English are invited for submission to this Journal. The Journal publishes original articles, minireviews, and commentaries on debated issues.
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