Metal-catalyzed Oxidation Research Articles

Catalytic Enantioselective Hydroxylation of Tertiary Propargylic C(sp3)-H Bonds in Acyclic Systems: a Kinetic Resolution Study.

Direct site-selective and enantioselective oxyfunctionalization of C(sp3)-H bonds to form alcohols with a general scope, with predictable selectivities, and in preparatively useful yields represents a paradigm shift in the standard logic of synthetic organic chemistry. However, the knowledge of either enzymatic or nonenzymatic asymmetric hydroxylation of tertiary C-H bonds for enantioenriched tertiary alcohol synthesis is sorely lacking. Here, we report a practical manganese-catalyzed enantio-differentiating hydroxylation of tertiary propargylic C-H bonds in acyclic systems, producing a wide range of structurally diverse enantioenriched tertiary propargyl alcohols in high efficiency with extremely efficient chemo- and enantio-discrimination. Other features include the use of C-H substrates as the limiting reagent, noteworthy functional group compatibility, great synthetic utilities, and scalability. The findings serve as a blueprint for the development of metal-catalyzed asymmetric oxidation of challenging substrates.

Synergistic doping and de-doping of Co3O4 catalyst for effortless formaldehyde oxidation

The pursuit of high-performance non-precious metal catalysts for Volatile Organic Compounds (VOCs) abatement is paramount in meeting stringent environmental regulations. In this study, we present a groundbreaking approach by crafting a highly defective Co3O4 catalyst through a strategic process involving Mg doping and subsequent partial de-doping. The catalyst exhibited an exceptional activity in the oxidation of formaldehyde (HCHO), achieving a remarkable conversion rate of 2.92 μmol·m−2·h−1, which is 3.1 times that of the pristine Co3O4 at 100 °C and an HCHO space velocity of 75,000 mL·g−1·h−1. Our methodology involves a dual-action process of doping and de-doping, orchestrating the introduction of significant structural and surface defects. These include surface cracks, lattice distortions, cationic vacancies, oxygen vacancies, lower metal coordination, and more. This orchestrated creation of defects serves to amplify the generation of active oxygen sites, thereby enhancing the intrinsic oxidative ability of the catalyst. The net result is a lowered activation energy barrier for HCHO, further contributing to the catalyst performance enhancement. This study not only establishes a new benchmark for Co3O4 catalysis but also provides insightful paradigms for the role of defects engineering in promoting non-noble metal-catalyzed volatile organic compounds oxidation.

Towards the development of a safe, metal-catalyzed aerobic oxidation of 2-acetyl thiophene

Thiophene-2-carbonyl chloride (TCC) is a key raw material in the manufacture of active ingredients for agriculture. A new 3-step process for preparing TCC from commercial thiophene was recently developed that featured a metal-catalyzed aerobic oxidation of 2-acetylthiopehene (AcT). That process utilized pure oxygen in a flammable solvent, acetic acid, at elevated temperatures, which represented a hazardous condition by operating above the limiting oxygen concentration for the solvent and at a temperature above the flashpoint for the solvent. More recently, the same oxidation reaction has been achieved in an autoclave using diluted oxygen. Described in this Letter are details of our progress towards the identification of safe operating conditions for the aerobic oxidation of AcT.

Design of 3D-Printed Heterogeneous Reactor Systems To Overcome Incompatibility Hurdles when Combining Metal and Enzyme Catalysis in a One-Pot Process.

Combining chemo- and biocatalysis enables the design of novel economic and sustainable one-pot processes for the preparation of industrial chemicals, preferably proceeding in water. While a range of proofs-of-concept for the compatibility of such catalysts from these two different "worlds of catalysis" have recently been demonstrated, merging noncompatible chemo- and biocatalysts for joint applications within one reactor remained a challenge. A conceptual solution is compartmentalization of the catalytic moieties by heterogenization of critical catalyst components, thus "shielding" them from the complementary noncompatible catalyst, substrate or reagent. Exemplified for a one-pot process consisting of a metal-catalyzed Wacker oxidation and enzymatic reduction as noncompatible individual reactions steps, we demonstrate that making use of 3D printing of heterogeneous materials containing Cu as a critical metal component can overcome such incompatibility hurdles. The application of a 3D-printed Cu-ceramic device as metal catalyst component allows an efficient combination with the enzyme and the desired two-step transformation of styrene into the chiral alcohol product with high overall conversion and excellent enantioselectivity. This compartmentalization concept based on 3D printing of heterogenized metal catalysts represents a scalable methodology and opens up numerous perspectives to be used as a general tool also for other related chemoenzymatic research challenges.

Development of a high throughput oxidation profiling strategy for monoclonal antibody products

Oxidation is one of the most common degradation pathways of biopharmaceutics, potentially leading to altered product stability, pharmacokinetics, reduced biological activity and/or an increased immunogenicity. However, it is often insufficiently assessed in early development stages, leaving potential molecule liabilities undiscovered. Aim of the present work was the development of a high throughput oxidation profiling strategy, applicable throughout various stages of biopharmaceutical development. The study demonstrates that the combination of multiple stress assays, including peroxide-based, visible light, and metal-catalyzed oxidation (MCO), enables a comprehensive understanding of a mAb's oxidation susceptibility. The most effective parameters to evaluate oxidation in a high-throughput screening workflow are aggregation, tryptophan oxidation and changes in the hydrophobicity profile of the Fc and Fab subunit measured via Size Exclusion Chromatography, Intrinsic Tryptophan Fluorescence Emission spectroscopy and Reversed-Phase Chromatography subunit analysis, respectively. This oxidation profiling approach is valuable tool to systematically characterize the oxidation susceptibility under relevant conditions, time effective and with minimal sample consumption.

Molecular characterization, cytoprotective, DNA protective, and immunological assessment of peroxiredoxin-1 (Prdx1) from yellowtail clownfish (Amphiprion clarkii)

Peroxiredoxin-1 (Prdx1) is a thiol-specific antioxidant enzyme that detoxifies reactive oxygen species (ROS) and regulates the redox status of cells. In this study, the Prdx1 cDNA sequence was isolated from the pre-established Amphiprion clarkii (A. clarkii) (AcPrdx1) transcriptome database and characterized structurally and functionally. The AcPrdx1 coding sequence comprises 597 bp and encodes 198 amino acids with a molecular weight of 22.1 kDa and a predicted theoretical isoelectric point of 6.3. AcPrdx1 is localized and functionally available in the cytoplasm and nucleus of cells. The TXN domain of AcPrdx1 comprises two peroxiredoxin signature VCP motifs, which contain catalytic peroxidatic (Cp-C52) and resolving cysteine (CR-C173) residues. The constructed phylogenetic tree and sequence alignment revealed that AcPrdx1 is evolutionarily conserved, and its most closely related counterpart is Amphiprion ocellaris. Under normal physiological conditions, AcPrdx1 was ubiquitously detected in all tissues examined, with the most robust expression in the spleen. Furthermore, AcPrdx1 transcripts were significantly upregulated in the spleen, head kidney, and blood after immune stimulation by polyinosinic:polycytidylic acid (poly (I:C)), lipopolysaccharide (LPS), and Vibrio harveyi injection. Recombinant AcPrdx1 (rAcPrdx1) demonstrated antioxidant and DNA protective properties in a concentration-dependent manner, as evidenced by insulin disulfide reduction, peroxidase activity, and metal-catalyzed oxidation (MCO) assays, whereas cells transfected with pcDNA3.1(+)/AcPrdx1 showed significant cytoprotective function under oxidative and nitrosative stress. Overexpression of AcPrdx1 in fathead minnow (FHM) cells led to a lower viral copy number following viral hemorrhagic septicemia virus (VHSV) infection, along with upregulation of several antiviral genes. Collectively, this study provides insights into the function of AcPrdx1 in defense against oxidative stressors and its role in the immune response against pathogenic infections in A. clarkii.

Screening for Metal-Chelating Activity in Potato Protein Hydrolysates Using Surface Plasmon Resonance and Peptidomics.

Metal-catalyzed lipid oxidation is a major factor in food waste, as it reduces shelf life. Addressing this issue, our study investigates the potential of hydrolysates derived from potato protein, a by-product of potato starch production, as metal-chelating antioxidants. Through sequential enzymatic hydrolysis using alcalase or trypsin combined with Flavourzyme, we produced various hydrolysates, which were then fractionated using ultrafiltration. Using a combination of peptidomics and bioinformatics, we predicted the presence of metal-chelating and free radical-scavenging peptides across all hydrolysate fractions, with a trend indicating a higher content of antioxidant peptides in lower molecular weight fractions. To validate these predictions, we utilized surface plasmon resonance (SPR) and a 9-day emulsion storage experiment. While SPR demonstrated potential in identifying antioxidant activity, it faced challenges in differentiating between hydrolysate fractions due to significant standard errors. In the storage experiment, all hydrolysates showed lipid oxidation inhibition, though not as effectively as ethylenediaminetetraacetic acid (EDTA). Remarkably, one fraction (AF13) was not significantly different (p < 0.05) from EDTA in suppressing hexanal formation. These results highlight SPR and peptidomics/bioinformatics as promising yet limited methods for antioxidant screening. Importantly, this study reveals the potential of potato protein hydrolysates as antioxidants in food products, warranting further research.

A Toxoplasma gondii thioredoxin with cell adhesion and antioxidant function.

Toxoplasma gondii (T. gondii) is a widespread, zoonotic protozoan intracellular parasite with a complex life cycle, which can cause toxoplasmosis, a potentially serious disease. During the invasion process, T. gondii proteins first bind to the relevant host cell receptors, such as glycosaminoglycan molecule (GAG-binding motif), which is one of the main receptors for parasites or virus to infect host cells. However, research on TGME49_216510 (T. gondii Trx21), a protein from Toxoplasma gondii, is limited. Bioinformatics analysis of the Trx21 protein was performed firstly. And specific primers were then designed using the conserved domain and GAG-binding motif to amplify, express, and purify a fragment of the Trx21 protein. The purified Trx21-GST protein was used for antioxidant and cell adhesion experiments. Simultaneously, mice were immunized with Trx21-His to generate specific polyclonal antibodies for subcellular localization analysis. The Trx21 protein, consisting of 774 amino acids, included a transmembrane region, three GAG-binding motifs, and a Thioredoxin-like domain. The recombinant Trx21-His protein had a molecular mass of about 31 kDa, while the Trx21-GST protein had a molecular mass of about 55 kDa, which was analyzed by SDS-PAGE and Western blot. Subcellular localization analysis by IFA revealed that Trx21 is predominantly distributed in the cytoplasm of T. gondii. Furthermore, Trx21 exhibited a protective effect on supercoiled DNA against metal-catalyzed oxidation (MCO) and demonstrated adhesion abilities to Vero cells. These results indicate that Trx21 plays an important role in host cell interaction and oxidative damage.

Peroxiredoxin-2 gene in Antheraea pernyi modulates immune functions and protect DNA damage

Peroxiredoxins have been shown to protect insects from oxidative damage and to play a role in the immune system. In the present study, we cloned and characterized the Antheraea pernyi peroxiredoxin 2 (ApPrx-2) gene, then assessed its functional roles. The ApPrx-2 gene has a 687 bp open reading frame that encodes a protein with 288 amino acid residues. Quantitative real-time PCR analysis revealed that the mRNA levels of ApPrx-2 were highest in the hemocytes. Immune challenge assay revealed that ApPrx-2 transcription could be induced after microbial challenge. A DNA cleavage assay employing recombinant ApPrx-2 protein and a metal-catalyzed oxidation system showed that rApPrx-2 protein could protect supercoiled DNA against oxidative stress. The protein antioxidant activity of rApPrx-2 was examined, and it was found that rApPrx-2 exhibited a high level of antioxidant activity by removing H2O2. In addition, ApPrx-2 knockdown larvae had higher H2O2 levels and a lower survival rate when compared to controls. Interestingly, the antibacterial activity was significantly higher in ApPrx-2 depleted larvae compared with control. Overall, our findings indicate that ApPrx-2 may be involved in a range of physiological functions of A. pernyi, as it protects supercoiled DNA from oxidative stress and regulates antibacterial activity.

Structural rearrangement of elastin under oxidative stress

Reactive oxygen species (ROS) are key elements in several physiological processes. A high level of ROS leads to oxidative stress that damages biomolecules and is linked to many diseases like type-2 diabetes, cancer, inflammation, and many more. Here, our in-vitro study aimed to gauge the effect of ROS on the structural rearrangement of elastin through metal-catalyzed oxidation (MCO) at physiological temperature through laser light scattering, UV–vis, FTIR, and FESEM imaging. Light scattering data show a decrease in the hydrodynamic radius of elastin upon oxidation for the first hour. The rate of size reduction of ROS-treated elastin and the rate for self-assembly of bare elastin in the first two hours is found to be almost the same. However, the rate of association of ROS-treated is one order slower than the bare elastin after one hour. UV–vis absorption shows a blue shift accompanied by increased absorption, followed by a redshift and broadening of peak. FTIR data reveal changes in the secondary structures for both bare and oxidized elastin with time. While bare elastin coacervation increases unordered structure, the corresponding case of oxidized elastin saw a rise in β-sheet. FESEM images show the morphological changes occurring with time. Thus, we conclude that oxidative stress leads to structural rearrangement of the protein through interaction with the polar and hydrophobic domains, followed by aggregation. This study might be helpful for therapeutics focusing on preventing elastin degradation against aging.

Catalytic Asymmetric Oxidation of Amines to Hydroxylamines.

Chiral hydroxylamines are increasingly common structural elements in pharmaceuticals and agrochemicals, but their asymmetric synthesis remains challenging. Although enantioselective oxidation is the most straightforward method to prepare chiral oxides with a higher oxidation state, asymmetric and even nonasymmetric amine oxidation to hydroxylamines has been poorly addressed. We report a titanium-catalyzed asymmetric oxidation of racemic amines providing a broad range of structurally diverse chiral hydroxylamines with excellent chemo- and enantioselectivity. Notably, hydroxylamines bearing diverse substituent patterns on the stereocenters, including α,α-ester-alkyl, α,α-amide-alkyl, α,α-aryl-alkyl, α,α-alkynyl-alkyl, and α,α-dialkyl, are well tolerated with good functional group compatibility. Catalyst turnover numbers up to 5000 and selectivity factors up to 278 are observed. This finding offers a democratized platform to chiral hydroxylamines as design elements for drug discovery and provides insights into metal-catalyzed asymmetric oxidation of challenging substrates.

Periodate-Mediated Aerobic Oxidation of Sulfides over a Bifunctional Porphyrin-polyoxometalate Catalyst: Photosensitized Singlet Oxygen Oxidation of Iodate to Periodate.

Regeneration of terminal oxidants by molecular oxygen in metal-catalyzed oxidations of organic substrates has the advantage of avoiding the use of stoichiometric amounts of hazardous and/or expensive reagents to meet (some of) the green chemistry requirements. In the present study, photosensitized singlet oxygen oxidation of iodate to periodate has been used to regenerate the oxidant in polyoxometalate (POM)-catalyzed oxidation of sulfides to sulfoxides with periodate in water. To the best of our knowledge, it is the first report on singlet oxygen oxidation of iodate to periodate. In order to determine the contribution of photooxidation and oxidation pathways in the formation of sulfoxide, the oxidation of diphenyl sulfide with a very low reactivity toward aerobic photooxidation was studied; a sevenfold increase in the conversion of the sulfide to the diphenyl sulfoxide was observed for the reaction conducted in the presence of H2TMPyP-PW12O40/IO3-/O2/hν compared to that in the presence of H2TMPyP-PW12O40/O2/hν. Also, under the same conditions, a ca. 1.5-fold increase was observed in the case of methyl phenyl sulfide, which shows high reactivity toward both the oxidation and photooxidation reactions. A porphyrin-POM nanocomposite formed by the electrostatic immobilization of meso-tetra(N-methylpyridinium-4-yl)porphyrin (H2TMPyP) on PW12O40 was employed for the one-pot oxidation and photooxidation reactions. Field-emission scanning electron microscopy (FESEM), X-ray diffraction (XRD), diffuse-reflectance UV-vis spectroscopy, thermal gravimetric analysis, and Fourier transform infrared were used to characterize the formation of the hybrid compound. An average particle size of 42 nm was estimated for H2TMPyP-PW12O40 from XRD peak broadening using the Scherrer equation. Also, FESEM images showed the formation of nearly spherical nanoparticles with a size of ca. 200 nm. The redshift of the Soret band of H2TMPyP upon immobilization on POM was attributed to strong N-H···O hydrogen-bond interactions between POM and porphyrin.

Synthesis of Novel C 2 Bishydroxamic Acid Ligands and their Application in Asymmetric Epoxidation Reactions

AbstractAsymmetric oxidation reactions have significantly benefited from bishydroxamic Brønsted acid ligands, and they can proceed with remarkable stereoselectivity. Designing and synthesizing these ligands are essential for achieving high enantioselectivity in metal-catalyzed oxidation reactions. This paper presents a straightforward method for synthesizing novel phenyl-ring-centric bishydroxamic acids (BHA). A preliminary analysis of Ti-BHA-catalyzed reactions resulted in asymmetric epoxides with an exceptional enantiomeric excess (&gt;99% ee). At the same time, ongoing experiments aim to improve the reaction conversion for enhanced overall efficiency.

Primary Processes of Free Radical Formation in Pharmaceutical Formulations of Therapeutic Proteins.

Oxidation represents a major pathway for the chemical degradation of pharmaceutical formulations. Few specific details are available on the mechanisms that trigger oxidation reactions in these formulations, specifically with respect to the formation of free radicals. Hence, these mechanisms must be formulated based on information on impurities and stress factors resulting from manufacturing, transportation and storage. In more detail, this article focusses on autoxidation, metal-catalyzed oxidation, photo-degradation and radicals generated from cavitation as a result of mechanical stress. Emphasis is placed on probable rather than theoretically possible pathways.

Iron Availability Influences Protein Carbonylation in Arabidopsis thaliana Plants.

Protein carbonylation is an irreversible form of post-translational modification triggered by reactive oxygen species in animal and plant cells. It occurs either through the metal-catalyzed oxidation of Lys, Arg, Pro, and Thr side chains or the addition of α, β-unsaturated aldehydes and ketones to the side chains of Cys, Lys, and His. Recent genetic studies concerning plants pointed to an implication of protein carbonylation in gene regulation through phytohormones. However, for protein carbonylation to stand out as a signal transduction mechanism, such as phosphorylation and ubiquitination, it must be controlled in time and space by a still unknown trigger. In this study, we tested the hypothesis that the profile and extent of protein carbonylation are influenced by iron homeostasis in vivo. For this, we compared the profile and the contents of the carbonylated proteins in the Arabidopsis thaliana wild-type and mutant-deficient in three ferritin genes under normal and stress conditions. Additionally, we examined the proteins specifically carbonylated in wild-type seedlings exposed to iron-deficient conditions. Our results indicated that proteins were differentially carbonylated between the wild type and the triple ferritin mutant Fer1-3-4 in the leaves, stems, and flowers under normal growth conditions. The profile of the carbonylated proteins was also different between the wild type and the ferritin triple mutant exposed to heat stress, thus pointing to the influence of iron on the carbonylation of proteins. Consistent with this, the exposure of the seedlings to iron deficiency and iron excess greatly influenced the carbonylation of certain proteins involved in intracellular signal transduction, translation, and iron deficiency response. Overall, the study underlined the importance of iron homeostasis in the occurrence of protein carbonylation in vivo.

Effect of the metal ion-induced carbonylation modification of mitochondrial membrane channel protein VDAC on cell vitality, seedling growth and seed aging.

Seeds are the most important carrier of germplasm preservation. However, an irreversible decrease in vigor can occur after the maturation of seeds, denoted as seed aging. Mitochondrion is a crucial organelle in initiation programmed cell death during seed aging. However, the underlying mechanism remains unclear. Our previous proteome study found that 13 mitochondria proteins underwent carbonylation modification during the aging of Ulmus pumila L. (Up) seeds. This study detected metal binding proteins through immobilized metal affinity chromatography (IMAC), indicating that metal binding proteins in mitochondria are the main targets of carbonization during seed aging. Biochemistry, molecular and cellular biology methods were adopted to detect metal-protein binding, protein modification and subcellular localization. Yeast and Arabidopsis were used to investigate the biological functions in vivo. In IMAC assay, 12 proteins were identified as Fe2+/Cu2+/Zn2+ binding proteins, including mitochondrial voltage dependent anion channels (VDAC). UpVDAC showed binding abilities to all the three metal ions. His204Ala (H204A) and H219A mutated UpVDAC proteins lost their metal binding ability, and became insensitive to metal-catalyzed oxidation (MCO) induced carbonylation. The overexpression of wild-type UpVDAC made yeast cells more sensitive to oxidative stress, retarded the growth of Arabidopsis seedlings and accelerated the seed aging, while overexpression of mutated UpVDAC weakened these effects of VDAC. These results reveal the relationship between the metal binding ability and carbonylation modification, as well as the probable function of VDAC in regulating cell vitality, seedling growth and seed aging.

Oxidation of Phospholipids by OH Radical Coordinated to Copper Amyloid-β Peptide—A Density Functional Theory Modeling

Oxidative stress and metal dyshomeostasis are considered crucial factors in the pathogenesis of Alzheimer’s disease (AD). Indeed, transition metal ions such as Cu(II) can generate reactive oxygen species (ROS) via O2 Fenton-like reduction, catalyzed by Cu(II) coordinated to the amyloid-beta (Aβ) peptide. Despite intensive efforts, the mechanisms of ROS-induced molecular damage remain poorly understood. In the present paper, we investigate, on the basis of Density Functional Theory (DFT) computations, a possible mechanism of the OH radical propagation toward membrane phospholipid polar head and fatty acid chains starting from the end-product of the OH radical generation by Cu(II)-Aβ. Using phosphatidylcholine as a model of a single unit inside a membrane, we evaluated the thermochemistry of the OH propagation with the oxidation of a C-H bond and the formation of the radical moiety. The DFT results show that Cu(II)-Aβ-OH can oxidize only sn-2 C-H bonds of the polar head and can easily oxidize the C-H bond adjacent to the carbon–carbon double bond in a mono or bis unsaturated fatty acid chain. These results are discussed on the basis of the recent literature on in vitro Aβ metal-catalyzed oxidation and on the possible implications in the AD oxidative stress mechanism.

Recent Progress in Metal‐Catalyzed Selective Oxidation of 5‐Hydroxymethylfurfural into Furan‐Based Value‐Added Chemicals

5-hydroxymethylfurfural (HMF), one of the most significant biomass-derived renewable resources, has been widely utilized to create furan-based value-added chemicals such as 2,5-diformylfuran (DFF), 5-hydroxymethyl-2-furancarboxylic acid (HMFCA), 5-formyl-2-furancarboxylic acid (FFCA), and 2,5-furan dicarboxylic acid (FDCA). Indeed, DFF, HMFCA and FFCA are key intermediate products during the oxidation of HMF to FDCA. Herein, this review aims to demonstrate the recent advances in metal-catalyzed oxidation of HMF into FDCA via two different reaction routes (HMF-DFF-FFCA-FDCA and HMF-HMFCA-FFCA-FDCA). All the four furan-based compounds are comprehensively discussed by the selective oxidation of HMF. Additionally, various metal catalysts, reaction conditions, and reaction mechanisms used to obtain the four different products are systematically reviewed. It is anticipated that this review will provide related researchers with new perspectives and speed up the development of this field.

In-Depth Characterization of Acidic Variants Induced by Metal-Catalyzed Oxidation in a Recombinant Monoclonal Antibody.

Characterization of antibody charge heterogeneity is an important task for antibody drug development. Recently, a correlation between acidic charge heterogeneity and metal-catalyzed oxidation has been observed for antibody drugs. However, to date, the acidic variants induced by metal-catalyzed oxidation have not been elucidated. In addition, it is challenging to satisfactorily explain the induced acidic charge heterogeneity, as the existing analytical workflows, which relied on either untargeted or targeted peptide mapping analysis, could lead to incomplete identification of the acidic variants. In this work, we present a new characterization workflow by combining untargeted and targeted analyses to thoroughly identify and characterize the induced acidic variants in a highly oxidized IgG1 antibody. As a part of this workflow, a tryptic peptide mapping method was also developed for accurate determination of the relative extent of site-specific carbonylation, where a new hydrazone reduction procedure was established to minimize under-quantitation artifacts caused by incomplete reduction of hydrazones during sample preparation. In summary, we identified 28 site-specific oxidation products, which are located on 26 residues and of 11 different modification types, as the sources of the induced acidic charge heterogeneity. Many of the oxidation products were reported for the first time in antibody drugs. More importantly, this study provides new insights to understanding acidic charge heterogeneity of antibody drugs in the biotechnology industry. Additionally, the characterization workflow presented in this study can be applied as a platform approach in the biotechnology industry to better address the need for in-depth characterization of antibody charge variants.

Metal-induced oxidative stress and human plasma protein oxidation after SARS-CoV-2 infection

Pathogenesis of COVID-19 by SARS-CoV-2 resulted in a global pandemic and public health emergency in 2020. Viral infection can induce oxidative stress through reactive oxygen species (ROS). Inflammation and environmental stress are major sources of oxidative stress after infection. Micronutrients such as iron, copper, zinc, and manganese play various roles in human tissues and their imbalance in blood can impact immune responses against pathogens including SARS CoV-2. We hypothesized that alteration of free metal ions during infection and metal-catalyzed oxidation plays a critical role towards pathogenesis after infection. We analyzed convalescent and hospitalized COVID-19 patient plasma using orthogonal analytical techniques to determine redox active metal concentrations, overall protein oxidation, oxidative modifications, and protein levels via proteomics to understand the consequences of metal-induced oxidative stress in COVID-19 plasma proteins. Metal analysis using ICP-MS showed significantly greater concentrations of copper in COVID-19 plasma compared to healthy controls. We demonstrate significantly greater total protein carbonylation, other oxidative modifications, and deamidation of plasma proteins in COVID-19 plasma compared to healthy controls. Proteomics analysis showed that levels of redox active proteins including hemoglobulin were elevated in COVID-19 plasma. Molecular modeling concurred with potential interactions between iron binding proteins and SARS CoV-2 surface proteins. Overall, increased levels of redox active metals and protein oxidation indicate that oxidative stress-induced protein oxidation in COVID-19 may be a consequence of the interactions of SARS-CoV-2 proteins with host cell metal binding proteins resulting in altered cellular homeostasis.