Antioxidants

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12 pages, 1554 KiB

Open AccessArticle

Hypoxia Tolerance Declines with Age in the Absence of Methionine Sulfoxide Reductase (MSR) in Drosophila melanogaster

by Nirthieca Suthakaran, Sanjana Chandran, Michael Iacobelli and David Binninger

Antioxidants 2021, 10(7), 1135; https://doi.org/10.3390/antiox10071135 - 17 Jul 2021

Cited by 3 | Viewed by 2824

Unlike the mammalian brain, Drosophila melanogaster can tolerate several hours of hypoxia without any tissue injury by entering a protective coma known as spreading depression. However, when oxygen is reintroduced, there is an increased production of reactive oxygen species (ROS) that causes oxidative [...] Read more.

Unlike the mammalian brain, Drosophila melanogaster can tolerate several hours of hypoxia without any tissue injury by entering a protective coma known as spreading depression. However, when oxygen is reintroduced, there is an increased production of reactive oxygen species (ROS) that causes oxidative damage. Methionine sulfoxide reductase (MSR) acts to restore functionality to oxidized methionine residues. In the present study, we have characterized in vivo effects of MSR deficiency on hypoxia tolerance throughout the lifespan of Drosophila. Flies subjected to sudden hypoxia that lacked MSR activity exhibited a longer recovery time and a reduced ability to survive hypoxic/re-oxygenation stress as they approached senescence. However, when hypoxia was induced slowly, MSR deficient flies recovered significantly quicker throughout their entire adult lifespan. In addition, the wildtype and MSR deficient flies had nearly 100% survival rates throughout their lifespan. Neuroprotective signaling mediated by decreased apoptotic pathway activation, as well as gene reprogramming and metabolic downregulation are possible reasons for why MSR deficient flies have faster recovery time and a higher survival rate upon slow induction of spreading depression. Our data are the first to suggest important roles of MSR and longevity pathways in hypoxia tolerance exhibited by Drosophila. Full article

(This article belongs to the Special Issue Biological Significance of Methionine Oxidation and Reduction)

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14 pages, 2854 KiB

Open AccessArticle

Profiling Dopamine-Induced Oxidized Proteoforms of β-synuclein by Top-Down Mass Spectrometry

by Arianna Luise, Elena De Cecco, Erika Ponzini, Martina Sollazzo, PierLuigi Mauri, Frank Sobott, Giuseppe Legname, Rita Grandori and Carlo Santambrogio

Antioxidants 2021, 10(6), 893; https://doi.org/10.3390/antiox10060893 - 1 Jun 2021

Cited by 2 | Viewed by 2765

Abstract

The formation of multiple proteoforms by post-translational modifications (PTMs) enables a single protein to acquire distinct functional roles in its biological context. Oxidation of methionine residues (Met) is a common PTM, involved in physiological (e.g., signaling) and pathological (e.g., oxidative stress) states. This [...] Read more.

The formation of multiple proteoforms by post-translational modifications (PTMs) enables a single protein to acquire distinct functional roles in its biological context. Oxidation of methionine residues (Met) is a common PTM, involved in physiological (e.g., signaling) and pathological (e.g., oxidative stress) states. This PTM typically maps at multiple protein sites, generating a heterogeneous population of proteoforms with specific biophysical and biochemical properties. The identification and quantitation of the variety of oxidized proteoforms originated under a given condition is required to assess the exact molecular nature of the species responsible for the process under investigation. In this work, the binding and oxidation of human β-synuclein (BS) by dopamine (DA) has been explored. Native mass spectrometry (MS) has been employed to analyze the interaction of BS with DA. In a second step, top-down fragmentation of the intact protein from denaturing conditions has been performed to identify and quantify the distinct proteoforms generated by DA-induced oxidation. The analysis of isobaric proteoforms is approached by a combination of electron-transfer dissociation (ETD) at each extent of modification, quantitation of methionine-containing fragments and combinatorial analysis of the fragmentation products by multiple linear regression. This procedure represents a promising approach to systematic assessment of proteoforms variety and their relative abundance. The method can be adapted, in principle, to any protein containing any number of methionine residues, allowing for a full structural characterization of the protein oxidation states. Full article

(This article belongs to the Special Issue Biological Significance of Methionine Oxidation and Reduction)

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13 pages, 3615 KiB

Open AccessArticle

Structural Insights into a Bifunctional Peptide Methionine Sulfoxide Reductase MsrA/B Fusion Protein from Helicobacter pylori

by Sulhee Kim, Kitaik Lee, Sun-Ha Park, Geun-Hee Kwak, Min Seok Kim, Hwa-Young Kim and Kwang Yeon Hwang

Antioxidants 2021, 10(3), 389; https://doi.org/10.3390/antiox10030389 - 5 Mar 2021

Cited by 3 | Viewed by 2797

Abstract

Methionine sulfoxide reductase (Msr) is a family of enzymes that reduces oxidized methionine and plays an important role in the survival of bacteria under oxidative stress conditions. MsrA and MsrB exist in a fusion protein form (MsrAB) in some pathogenic bacteria, such as [...] Read more.

Methionine sulfoxide reductase (Msr) is a family of enzymes that reduces oxidized methionine and plays an important role in the survival of bacteria under oxidative stress conditions. MsrA and MsrB exist in a fusion protein form (MsrAB) in some pathogenic bacteria, such as Helicobacter pylori (Hp), Streptococcus pneumoniae, and Treponema denticola. To understand the fused form instead of the separated enzyme at the molecular level, we determined the crystal structure of HpMsrAB^C44S/C318S at 2.2 Å, which showed that a linker region (Hpiloop, 193–205) between two domains interacted with each HpMsrA or HpMsrB domain via three salt bridges (E193-K107, D197-R103, and K200-D339). Two acetate molecules in the active site pocket showed an sp² planar electron density map in the crystal structure, which interacted with the conserved residues in fusion MsrABs from the pathogen. Biochemical and kinetic analyses revealed that Hpiloop is required to increase the catalytic efficiency of HpMsrAB. Two salt bridge mutants (D193A and E199A) were located at the entrance or tailgate of Hpiloop. Therefore, the linker region of the MsrAB fusion enzyme plays a key role in the structural stability and catalytic efficiency and provides a better understanding of why MsrAB exists in a fused form. Full article

(This article belongs to the Special Issue Biological Significance of Methionine Oxidation and Reduction)

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18 pages, 1341 KiB

Open AccessArticle

Methionine Sulfoxide Reductase B Regulates the Activity of Ascorbate Peroxidase of Banana Fruit

by Lu Xiao, Guoxiang Jiang, Huiling Yan, Hongmei Lai, Xinguo Su, Yueming Jiang and Xuewu Duan

Antioxidants 2021, 10(2), 310; https://doi.org/10.3390/antiox10020310 - 18 Feb 2021

Cited by 21 | Viewed by 3712

Abstract

Ascorbate peroxidase (APX) is a key antioxidant enzyme that is involved in diverse developmental and physiological process and stress responses by scavenging H₂O₂ in plants. APX itself is also subjected to multiple posttranslational modifications (PTMs). However, redox-mediated PTM of APX [...] Read more.

Ascorbate peroxidase (APX) is a key antioxidant enzyme that is involved in diverse developmental and physiological process and stress responses by scavenging H₂O₂ in plants. APX itself is also subjected to multiple posttranslational modifications (PTMs). However, redox-mediated PTM of APX in plants remains poorly understood. Here, we identified and confirmed that MaAPX1 interacts with methionine sulfoxide reductase B2 (MsrB2) in bananas. Ectopic overexpression of MaAPX1 delays the detached leaf senescence induced by darkness in Arabidopsis. Sulfoxidation of MaAPX1, i.e., methionine oxidation, leads to loss of the activity, which is repaired partially by MaMsrB2. Moreover, mimicking sulfoxidation by mutating Met36 to Gln also decreases its activity in vitro and in vivo, whereas substitution of Met36 with Val36 to mimic the blocking of sulfoxidation has little effect on APX activity. Spectral analysis showed that mimicking sulfoxidation of Met36 hinders the formation of compound I, the first intermediate between APX and H₂O₂. Our findings demonstrate that the redox state of methionine in MaAPX1 is critical to its activity, and MaMsrB2 can regulate the redox state and activity of MaAPX1. Our results revealed a novel post-translational redox modification of APX. Full article

(This article belongs to the Special Issue Biological Significance of Methionine Oxidation and Reduction)

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21 pages, 12873 KiB

Open AccessArticle

Integration of MsrB1 and MsrB2 in the Redox Network during the Development of Orthodox and Recalcitrant Acer Seeds

by Ewelina Stolarska, Karolina Bilska, Natalia Wojciechowska, Agnieszka Bagniewska-Zadworna, Pascal Rey and Ewa M. Kalemba

Antioxidants 2020, 9(12), 1250; https://doi.org/10.3390/antiox9121250 - 9 Dec 2020

Cited by 7 | Viewed by 2264

Abstract

Two related tree species, Norway maple (Acer platanoides L.) and sycamore (Acer pseudoplatanus L.), produce desiccation-tolerant (orthodox) and desiccation-sensitive (recalcitrant) seeds, respectively. We compared the seeds of these two species to characterize the developmentally driven changes in the levels of peptide-bound [...] Read more.

Two related tree species, Norway maple (Acer platanoides L.) and sycamore (Acer pseudoplatanus L.), produce desiccation-tolerant (orthodox) and desiccation-sensitive (recalcitrant) seeds, respectively. We compared the seeds of these two species to characterize the developmentally driven changes in the levels of peptide-bound methionine sulfoxide (MetO) and the abundance of methionine sulfoxide reductases (Msrs) B1 and B2, with respect to the cellular redox environment. Protein oxidation at the Met level was dynamic only in Norway maple seeds, and the reduced MsrB2 form was detected only in this species. Cell redox status, characterized by the levels of reduced and oxidized ascorbate, glutathione, and nicotinamide adenine dinucleotide (NAD)/phosphate (NADP), was clearly more reduced in the Norway maple seeds than in the sycamore seeds. Clear correlations between MetO levels, changes in water content and redox status were reported in orthodox Acer seeds. The abundance of Msrs was correlated in both species with redox determinants, mainly ascorbate and glutathione. Our data suggest that MsrB2 is associated with the acquisition of desiccation tolerance and that ascorbate might be involved in the redox pathway enabling the regeneration of Msr via intermediates that are not known yet. Full article

(This article belongs to the Special Issue Biological Significance of Methionine Oxidation and Reduction)

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18 pages, 3306 KiB

Open AccessArticle

The Selenoprotein MsrB1 Instructs Dendritic Cells to Induce T-Helper 1 Immune Responses

by Ho-Jae Lee, Joon Seok Park, Hyun Jung Yoo, Hae Min Lee, Byung Cheon Lee and Ji Hyung Kim

Antioxidants 2020, 9(10), 1021; https://doi.org/10.3390/antiox9101021 - 20 Oct 2020

Cited by 15 | Viewed by 4329

Abstract

Immune activation associates with the intracellular generation of reactive oxygen species (ROS). To elicit effective immune responses, ROS levels must be balanced. Emerging evidence shows that ROS-mediated signal transduction can be regulated by selenoproteins such as methionine sulfoxide reductase B1 (MsrB1). However, how [...] Read more.

Immune activation associates with the intracellular generation of reactive oxygen species (ROS). To elicit effective immune responses, ROS levels must be balanced. Emerging evidence shows that ROS-mediated signal transduction can be regulated by selenoproteins such as methionine sulfoxide reductase B1 (MsrB1). However, how the selenoprotein shapes immunity remains poorly understood. Here, we demonstrated that MsrB1 plays a crucial role in the ability of dendritic cells (DCs) to provide the antigen presentation and costimulation that are needed for cluster of differentiation antigen four (CD4) T-cell priming in mice. We found that MsrB1 regulated signal transducer and activator of transcription-6 (STAT6) phosphorylation in DCs. Moreover, both in vitro and in vivo, MsrB1 potentiated the lipopolysaccharide (LPS)-induced Interleukin-12 (IL-12) production by DCs and drove T-helper 1 (Th1) differentiation after immunization. We propose that MsrB1 activates the STAT6 pathway in DCs, thereby inducing the DC maturation and IL-12 production that promotes Th1 differentiation. Additionally, we showed that MsrB1 promoted follicular helper T-cell (Tfh) differentiation when mice were immunized with sheep red blood cells. This study unveils as yet unappreciated roles of the MsrB1 selenoprotein in the innate control of adaptive immunity. Targeting MsrB1 may have therapeutic potential in terms of controlling immune reactions. Full article

(This article belongs to the Special Issue Biological Significance of Methionine Oxidation and Reduction)

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22 pages, 4735 KiB

Open AccessArticle

Susceptibility of Protein Methionine Oxidation in Response to Hydrogen Peroxide Treatment–Ex Vivo Versus In Vitro: A Computational Insight

by Juan C. Aledo and Pablo Aledo

Antioxidants 2020, 9(10), 987; https://doi.org/10.3390/antiox9100987 - 13 Oct 2020

Cited by 10 | Viewed by 3231

Abstract

Methionine oxidation plays a relevant role in cell signaling. Recently, we built a database containing thousands of proteins identified as sulfoxidation targets. Using this resource, we have now developed a computational approach aimed at characterizing the oxidation of human methionyl residues. We found [...] Read more.

Methionine oxidation plays a relevant role in cell signaling. Recently, we built a database containing thousands of proteins identified as sulfoxidation targets. Using this resource, we have now developed a computational approach aimed at characterizing the oxidation of human methionyl residues. We found that proteins oxidized in both cell-free preparations (in vitro) and inside living cells (ex vivo) were enriched in methionines and intrinsically disordered regions. However, proteins oxidized ex vivo tended to be larger and less abundant than those oxidized in vitro. Another distinctive feature was their subcellular localizations. Thus, nuclear and mitochondrial proteins were preferentially oxidized ex vivo but not in vitro. The nodes corresponding with ex vivo and in vitro oxidized proteins in a network based on gene ontology terms showed an assortative mixing suggesting that ex vivo oxidized proteins shared among them molecular functions and biological processes. This was further supported by the observation that proteins from the ex vivo set were co-regulated more often than expected by chance. We also investigated the sequence environment of oxidation sites. Glutamate and aspartate were overrepresented in these environments regardless the group. In contrast, tyrosine, tryptophan and histidine were clearly avoided but only in the environments of the ex vivo sites. A hypothetical mechanism of methionine oxidation accounts for these observations presented. Full article

(This article belongs to the Special Issue Biological Significance of Methionine Oxidation and Reduction)

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13 pages, 1505 KiB

Open AccessArticle

Reduction of Protein Bound Methionine Sulfoxide by a Periplasmic Dimethyl Sulfoxide Reductase

by Lionel Tarrago, Sandrine Grosse, David Lemaire, Laetitia Faure, Mathilde Tribout, Marina I. Siponen, Mila Kojadinovic-Sirinelli, David Pignol, Pascal Arnoux and Monique Sabaty

Antioxidants 2020, 9(7), 616; https://doi.org/10.3390/antiox9070616 - 14 Jul 2020

Cited by 10 | Viewed by 3737

Abstract

In proteins, methionine (Met) can be oxidized into Met sulfoxide (MetO). The ubiquitous methionine sulfoxide reductases (Msr) A and B are thiol-oxidoreductases reducing MetO. Reversible Met oxidation has a wide range of consequences, from protection against oxidative stress to fine-tuned regulation of protein [...] Read more.

In proteins, methionine (Met) can be oxidized into Met sulfoxide (MetO). The ubiquitous methionine sulfoxide reductases (Msr) A and B are thiol-oxidoreductases reducing MetO. Reversible Met oxidation has a wide range of consequences, from protection against oxidative stress to fine-tuned regulation of protein functions. Bacteria distinguish themselves by the production of molybdenum-containing enzymes reducing MetO, such as the periplasmic MsrP which protects proteins during acute oxidative stress. The versatile dimethyl sulfoxide (DMSO) reductases were shown to reduce the free amino acid MetO, but their ability to reduce MetO within proteins was never evaluated. Here, using model oxidized proteins and peptides, enzymatic and mass spectrometry approaches, we showed that the Rhodobacter sphaeroides periplasmic DorA-type DMSO reductase reduces protein bound MetO as efficiently as the free amino acid L-MetO and with catalytic values in the range of those described for the canonical Msrs. The identification of this fourth type of enzyme able to reduce MetO in proteins, conserved across proteobacteria and actinobacteria, suggests that organisms employ enzymatic systems yet undiscovered to regulate protein oxidation states. Full article

(This article belongs to the Special Issue Biological Significance of Methionine Oxidation and Reduction)

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