Chemical catalyst-promoted photooxygenation of amyloid proteins

Sohma, Youhei; Sawazaki, Taka; Kanai, Motomu

doi:10.1039/d1ob01677f

Cited by 13 publications

(9 citation statements)

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“…Photooxygenation of histidine in undruggable protein targets, specifically amyloids, has been realized by our group – [26 –28] . Amyloids are insoluble fibrillar structures that arise from the abnormal aggregation of proteins or peptides.…”

Section: Application Of Histidine Photooxygenationmentioning

confidence: 99%

Histidine Photooxygenation Chemistry: Mechanistic Evidence and Elucidation

Matsukawa,

Yamane,

Kanai

2023

The Chemical Record

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Histidine photooxygenation has been the subject of extensive investigation for many years. The intricate nature of histidine distinguishes it from other amino acids, as its side chain readily undergoes changes in charge state and tautomerization in response to pH, and the polarity of the imidazole ring inverts upon oxidation. This complexity gives rise to a diverse range of oxidation products and mechanisms, posing challenges in their interpretation. This review aims to provide a thorough overview of the chemistry involved in histidine photooxygenation, encompassing a comprehensive analysis of resulting products, mechanisms engaged in their formation, and analytical techniques that have contributed to their identification. Additionally, it explores a wide range of applications stemming from this transformation, offering valuable insights into its practical implications in fields such as materials science, biomedical research, and drug development. By bridging the existing gap in literature, this review serves as a resource for understanding the intricacies of histidine photooxygenation and its diverse ramifications.

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Section: Application Of Histidine Photooxygenationmentioning

confidence: 99%

Histidine Photooxygenation Chemistry: Mechanistic Evidence and Elucidation

Matsukawa,

Yamane,

Kanai

2023

The Chemical Record

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“…Aggregated Aβ as well as tau contains the cross-β-sheet structure and is called amyloid. Targeting the cross-β-sheet structure characteristic of amyloids, we developed Aβ amyloid-selective photo-oxygenation catalysts 1–4 (Figure a). − Only when interacting with the cross-β-sheet structure do these catalysts get activated and act as photosensitizers to generate singlet oxygen ( 1 O 2 ) under light irradiation. Due both to the switch function of the catalysts and the short-lived nature of 1 O 2 , photo-oxygenation proceeds selectively with amyloids. – Specifically, histidine (His) and methionine (Met) were the main oxygenation sites using catalysts 1–4 . , The covalent incorporation of hydrophilic oxygen atoms into the amyloid decreased its aggregative property and facilitated phagocytotic degradation of Aβ amyloid by microglia cells in mice brains …”

Section: Introductionmentioning

confidence: 99%

Quantitative Assays for Catalytic Photo-Oxygenation of Alzheimer Disease-Related Tau Proteins

Umeda

Sawazaki

Furuta

et al. 2023

ACS Chem. Neurosci.

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Catalytic photo-oxygenation of tau amyloid is a potential therapeutic approach to tauopathies, including Alzheimer disease (AD). However, tau is a complex target containing great molecular size and heterogeneous isoforms/proteoforms. Although catalytic photo-oxygenation has been confirmed when using catalyst 1 and recombinant tau pretreated with heparin, its effects on tau from human patients have not yet been clarified. In this study, focusing on the histidine residues being oxygenated, we have constructed two assay systems capable of quantitatively evaluating the catalytic activity when used on human patient tau: (1) fluorescence labeling at oxygenated histidine sites and (2) LC–MS/MS analysis of histidine-containing fragments. Using these assays, we identified 2 as a promising catalyst for oxygenation of human tau. In addition, our results suggest that aggregated tau induced by heparin is different from actual AD patient tau in developing effective photo-oxygenation catalysts.

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“… 25 − 27 In recent years, a number of studies have investigated the potential of PDT for treating AD by specifically targeting the Aβ peptide. 28 , 29 A range of photosensitizers have been tested, and these studies have shown that photo-oxidation of monomeric (or soluble) Aβ can inhibit the peptide’s aggregation and that photo-oxidation of fibrillar Aβ can cause fibril fragmentation and disintegration in vitro. 18 , 30 − 38 Encouragingly, Aβ aggregate degradation induced by photo-oxidation has also been found to attenuate aggregate toxicity 39 and reduce aggregate levels in the brains of AD mouse models.…”

Section: Introductionmentioning

confidence: 99%

“…Among the many approaches that have been studied, photodynamic therapy (PDT) has drawn the attention of researchers − because it is spatiotemporally controllable and minimally invasive. , PDT has been used to treat diseases since the 1960s and is currently being used to treat many types of skin, lung, and esophageal cancers or pre-cancers . PDT requires a photosensitizer to produce singlet oxygens, which lead to the generation of reactive oxygen species (ROS) that subsequently oxidize cellular components, including cell membranes and organelles, and induce apoptosis, which destroys diseased tissues. − In recent years, a number of studies have investigated the potential of PDT for treating AD by specifically targeting the Aβ peptide. , A range of photosensitizers have been tested, and these studies have shown that photo-oxidation of monomeric (or soluble) Aβ can inhibit the peptide’s aggregation and that photo-oxidation of fibrillar Aβ can cause fibril fragmentation and disintegration in vitro. ,− Encouragingly, Aβ aggregate degradation induced by photo-oxidation has also been found to attenuate aggregate toxicity and reduce aggregate levels in the brains of AD mouse models . In transgenic AD models of Caenorhabditis elegans, photo-oxidation of Aβ fibrils has been found to reduce Aβ neurotoxicity and extend the longevity of C.…”

Section: Introductionmentioning

confidence: 99%

Partial Destabilization of Amyloid-β Protofibril by Methionine Photo-Oxidation: A Molecular Dynamic Simulation Study

Maghsoodi

Martin

2023

ACS Omega

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Selective photosensitized oxidation of amyloid protein aggregates is being investigated as a possible therapeutic strategy for treating Alzheimer’s disease (AD). Photo-oxidation has been shown to degrade amyloid-β (Aβ) aggregates and ameliorate aggregate toxicity in vitro and reduce aggregate levels in the brains of AD animal models. To shed light on the mechanism by which photo-oxidation induces fibril destabilization, we carried out an all-atom molecular dynamics (MD) simulation to examine the effect of methionine (Met35) oxidation on the conformation and stability of a β-sheet-rich Aβ9–40 protofibril. Analyses of up to 1 μs simulations showed that the oxidation of the Met35 residues, which resulted in the addition of hydrophilic oxygens in the fibril core, reduced the overall conformational stability of the protofibril. Specifically, Met35 disrupted the hydrophobic interface that stabilizes the stacking of the two hexamers that comprise the protofibril. The oxidized protofibril is more solvent exposed and exhibits more backbone flexibility. However, the protofibril retained the underlying U-shaped architecture of each peptide upon oxidation, and although some loss of β-sheets occurred, a significant portion remained. Our simulation results are thus consistent with our experimental observation that photo-oxidation of Aβ40 fibril resulted in the dis-agglomeration and fragmentation of Aβ fibrils but did not cause complete disruption of the fibrillar morphology or β-sheet structures. The partial destabilization of Aβ aggregates supports the further development of photosensitized platforms for the targeting and clearing of Aβ aggregates as a therapeutic strategy for treating AD.

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Chemical catalyst-promoted photooxygenation of amyloid proteins

Abstract: Misfolded proteins produce aberrant fibrillar aggregates, called amyloid, that contain cross-beta-sheet higher order structures. The species generated in the aggregation processes (i.e., oligomers, protofibrils, and fibrils) are cytotoxic and can...

Cited by 13 publications

References 58 publications

Histidine Photooxygenation Chemistry: Mechanistic Evidence and Elucidation

Histidine Photooxygenation Chemistry: Mechanistic Evidence and Elucidation

Quantitative Assays for Catalytic Photo-Oxygenation of Alzheimer Disease-Related Tau Proteins

Partial Destabilization of Amyloid-β Protofibril by Methionine Photo-Oxidation: A Molecular Dynamic Simulation Study

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