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Article ; Online: Hemoglobin can Act as a (Pseudo)-Peroxidase in Vivo. What is the Evidence?

Abdu I. Alayash / Michael T. Wilson

Frontiers in Molecular Biosciences, Vol

2022 Volume 9

Keywords	hemoglobin ; ferryl hemoglobin ; pseudoperoxidase ; blood substitutes ; fenton reagent ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Hemoglobin-Based Blood Substitutes and the Treatment of Sickle Cell Disease

Abdu I. Alayash

Biomolecules, Vol 7, Iss 1, p

More Harm than Help?

2017 Volume 2

Abstract: Intense efforts have been made by both industry and academia over the last three decades to produce viable hemoglobin (Hb)-based oxygen carriers (HBOCs), also known as “blood substitutes”. Human trials conducted so far by several manufactures in a ... ...

Abstract	Intense efforts have been made by both industry and academia over the last three decades to produce viable hemoglobin (Hb)-based oxygen carriers (HBOCs), also known as “blood substitutes”. Human trials conducted so far by several manufactures in a variety of clinical indications, including trauma, and elective surgeries have failed and no product has gained the Food and Drug Administration approval for human use. Safety concerns due to frequent incidences of hemodynamic, cardiac events, and even death led to the termination of some of these trials. Several second generation HBOC products that have been chemically and/or genetically modified (or in some cases ligated with carbon monoxide (CO)) found a new clinical application in conditions as complex as sickle cell disease (SCD). By virtue of higher oxygen affinity (P50) (R-state), and smaller size, HBOCs may be able to reach the microvasculature unload of oxygen to reverse the cycles of sickling/unsickling of the deoxy-sickle cell Hb (HbS) (T-state), thus preventing vaso-occlusion, a central event in SCD pathophysiology. However, biochemically, it is thought that outside the red blood cell (due to frequent hemolysis), free HbS or infused HBOCs are capable of interfering with a number of oxidative and signaling pathways and may, thus, negate any benefit that HBOCs may provide. This review discusses the advantages and disadvantages of using HBOCs in SCD.
Keywords	hemoglobin ; blood substitutes ; sickle cell disease ; heme oxidation ; Biology (General) ; QH301-705.5 ; Science ; Q ; Microbiology ; QR1-502
Subject code	610
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Providence Mutation (βK82D) in Human Hemoglobin Substantially Reduces βCysteine 93 Oxidation and Oxidative Stress in Endothelial Cells

Sirsendu Jana / Michael Brad Strader / Abdu I. Alayash

International Journal of Molecular Sciences, Vol 21, Iss 9453, p

2020 Volume 9453

Abstract: The highly toxic oxidative transformation of hemoglobin (Hb) to the ferryl state (HbFe 4+ ) is known to occur in both in vitro and in vivo settings. We recently constructed oxidatively stable human Hbs, based on the Hb Providence (βK82D) mutation in ... ...

Abstract	The highly toxic oxidative transformation of hemoglobin (Hb) to the ferryl state (HbFe 4+ ) is known to occur in both in vitro and in vivo settings. We recently constructed oxidatively stable human Hbs, based on the Hb Providence (βK82D) mutation in sickle cell Hb (βE6V/βK82D) and in a recombinant crosslinked Hb (rHb0.1/βK82D). Using High Resolution Accurate Mass (HRAM) mass spectrometry, we first quantified the degree of irreversible oxidation of βCys93 in these proteins, induced by hydrogen peroxide (H 2 O 2 ), and compared it to their respective controls (HbA and HbS). Both Hbs containing the βK82D mutation showed considerably less cysteic acid formation, a byproduct of cysteine irreversible oxidation. Next, we performed a novel study aimed at exploring the impact of introducing βK82D containing Hbs on vascular endothelial redox homeostasis and energy metabolism. Incubation of the mutants carrying βK82D with endothelial cells resulted in altered bioenergetic function, by improving basal cellular glycolysis and glycolytic capacity. Treatment of cells with Hb variants containing βK82D resulted in lower heme oxygenase-1 and ferritin expressions, compared to native Hbs. We conclude that the presence of βK82D confers oxidative stability to Hb and adds significant resistance to oxidative toxicity. Therefore, we propose that βK82D is a potential gene-editing target in the treatment of sickle cell disease and in the design of safe and effective oxygen therapeutics.
Keywords	hemoglobin providence ; βCys93 oxidation ; pulmonary endothelium ; glycolysis ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Effects of α subunit substitutions on the oxidation of βCys93 and the stability of sickle cell hemoglobin

Wayne Hicks / Fantao Meng / Tigist Kassa / Abdu I. Alayash

Redox Report, Vol 25, Iss 1, Pp 95-

2020 Volume 103

Abstract: The β subunit substitutions, F41Y and K82D, in sickle cell hemoglobin (Hb) (βE6 V) provides significant resistance to oxidative stress by shielding βCys93 from the oxidizing ferryl heme. We evaluated the oxidative resistance of βCys93 to hydrogen ... ...

Abstract	The β subunit substitutions, F41Y and K82D, in sickle cell hemoglobin (Hb) (βE6 V) provides significant resistance to oxidative stress by shielding βCys93 from the oxidizing ferryl heme. We evaluated the oxidative resistance of βCys93 to hydrogen peroxide (H2O2) in α subunit mutations in βE6 V (at both the putative and lateral contact regions) that included (1) αH20Q/βE6 V; (2) αH50Q/βE6 V; (3) αH20Q/H50Q/βE6 V; (4) αH20R/βE6 V; and (5) αH20R/H50Q/βE6 V. Estimation by mass spectrometry of irreversible oxidation of βCys93 to cysteic acid (CA) was unchanged or moderately increased in the single mutants harboring a H20Q or H50Q substitution when compared to control (βE6 V). The introduction of Arg (R) singularly or in combination with Q enhanced the pseudoperoxidative cycle by slightly decreasing the ferryl in favor of ferrous and ferric species after treatment with H2O2. Higher rates for heme loss from the ferric forms of the Q species to the receptor high affinity recombinant apomyglobin were observed in contrast to the R mutants and control. Because of their improved solubility, a combination of Q and R substitutions together with mutations carrying redox active variants (F41Y/K82D) may provide dual antioxidant and antisickling targets in the design of gene therapy-based candidates.
Keywords	sickle cell hemoglobin mutants ; oxidation ; βcys93 ; Pathology ; RB1-214 ; Biology (General) ; QH301-705.5
Subject code	500
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Taylor & Francis Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Caffeic acid

Tigist Kassa / James G. Whalin / Mark P. Richards / Abdu I. Alayash

FEBS Open Bio, Vol 11, Iss 12, Pp 3293-

an antioxidant with novel antisickling properties

2021 Volume 3303

Abstract: It is well documented that caffeic acid (3,4‐dihydroxycinnamic acid) (CA) interacts with and inhibits the oxidative reactions of myoglobin (Mb) and hemoglobin (Hb), and this interaction underlies its antioxidative action in meat. Sickle cell hemoglobin ( ... ...

Abstract	It is well documented that caffeic acid (3,4‐dihydroxycinnamic acid) (CA) interacts with and inhibits the oxidative reactions of myoglobin (Mb) and hemoglobin (Hb), and this interaction underlies its antioxidative action in meat. Sickle cell hemoglobin (HbS) is known for its tendency to oxidize more readily than normal HbA in the presence of hydrogen peroxide (H2O2), which leads to a more persistent and highly oxidizing ferryl Hb (HbFe4+). We have investigated the effects of CA on HbS oxidation intermediates, specifically on the ferric/ferryl forms. At a low concentration of H2O2 (0.5‐fold over heme), we observed a fivefold reduction in the amount of HbFe4+ accumulated in a mixture of ferric and H2O2 solution. Higher levels of H2O2 (onefold and twofold over heme) led to a lesser threefold and twofold reduction in the content of HbFe4+, respectively, possibly due to the saturation of the binding sites on the Hb molecule. The most intriguing finding was that when 5‐molar excess CA over heme was used, and a considerable increase in the delay time of HbS polymerization to approximately 200 s was observed. This delay in polymerization of HbS is theoretically sufficient to avoid microcapillary blockage and prevent vasoconstrictions in vivo. Mass spectrometry analysis indicated that CA was more extensively covalently bonded to βCys93 than to βCys112 and αCys104. The dual antioxidant and antisickling properties of CA may be explored further to maximize its therapeutic potential in SCD.
Keywords	antioxidants ; caffeic acid ; ferryl hemoglobin ; sickle cell disease ; Biology (General) ; QH301-705.5
Subject code	500
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
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Article ; Online: HIF-1α-Dependent Metabolic Reprogramming, Oxidative Stress, and Bioenergetic Dysfunction in SARS-CoV-2-Infected Hamsters

Sirsendu Jana / Michael R. Heaven / Charles B. Stauft / Tony T. Wang / Matthew C. Williams / Felice D’Agnillo / Abdu I. Alayash

International Journal of Molecular Sciences, Vol 24, Iss 1, p

2022 Volume 558

Abstract: The mechanistic interplay between SARS-CoV-2 infection, inflammation, and oxygen homeostasis is not well defined. Here, we show that the hypoxia-inducible factor (HIF-1α) transcriptional pathway is activated, perhaps due to a lack of oxygen or an ... ...

Abstract	The mechanistic interplay between SARS-CoV-2 infection, inflammation, and oxygen homeostasis is not well defined. Here, we show that the hypoxia-inducible factor (HIF-1α) transcriptional pathway is activated, perhaps due to a lack of oxygen or an accumulation of mitochondrial reactive oxygen species (ROS) in the lungs of adult Syrian hamsters infected with SARS-CoV-2. Prominent nuclear localization of HIF-1α and increased expression of HIF-1α target proteins, including glucose transporter 1 (Glut1), lactate dehydrogenase (LDH), and pyruvate dehydrogenase kinase-1 (PDK1), were observed in areas of lung consolidation filled with infiltrating monocytes/macrophages. Upregulation of these HIF-1α target proteins was accompanied by a rise in glycolysis as measured by extracellular acidification rate (ECAR) in lung homogenates. A concomitant reduction in mitochondrial respiration was also observed as indicated by a partial loss of oxygen consumption rates (OCR) in isolated mitochondrial fractions of SARS-CoV-2-infected hamster lungs. Proteomic analysis further revealed specific deficits in the mitochondrial ATP synthase (Atp5a1) within complex V and in the ATP/ADP translocase (Slc25a4). The activation of HIF-1α in inflammatory macrophages may also drive proinflammatory cytokine production and complement activation and oxidative stress in infected lungs. Together, these findings support a role for HIF-1α as a central mediator of the metabolic reprogramming, inflammation, and bioenergetic dysfunction associated with SARS-CoV-2 infection.
Keywords	COVID-19 disease ; bioenergetics ; hamster ; hypoxia ; proteomics ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Determination of extinction coefficients of human hemoglobin in various redox states

Meng, Fantao / Abdu I. Alayash

Analytical biochemistry. 2017 Mar. 15, v. 521

2017

Abstract: The role of hemoglobin (Hb) redox forms in tissue and organ toxicities remain ambiguous despite the well-documented contribution of Hb redox reactivity to cellular and subcellular oxidative changes. Moreover, several recent studies, in which Hb toxicity ... ...

Abstract	The role of hemoglobin (Hb) redox forms in tissue and organ toxicities remain ambiguous despite the well-documented contribution of Hb redox reactivity to cellular and subcellular oxidative changes. Moreover, several recent studies, in which Hb toxicity were investigated, have shown conflicting outcomes. Uncertainties over the potential role of these species may in part be due to the protein preparation method of choice, the use of published extinction coefficients and the lack of suitable controls for Hb oxidation and heme loss. Highly purified and well characterized redox forms of human Hb were used in this study and the extinction coefficients of each Hb species (ferrous/oxy, ferric/met and ferryl) were determined. A new set of equations were established to improve accuracy in determining the transient ferryl Hb species. Additionally, heme concentrations in solutions and in human plasma were determined using a novel reversed phase HPLC method in conjugation with our photometric measurements. The use of more accurate redox-specific extinction coefficients and method calculations will be an invaluable tool for both inÂ vitro and inÂ vivo experiments aimed at determining the role of Hb-mediated vascular pathology in hemolytic anemias and when Hb is used as oxygen therapeutics.
Keywords	absorption ; equations ; heme ; hemoglobin ; hemolytic anemia ; humans ; in vivo studies ; oxidation ; oxygen ; reversed-phase high performance liquid chromatography ; therapeutics ; toxicity ; uncertainty
Language	English
Dates of publication	2017-0315
Size	p. 11-19.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1110-1
ISSN	1096-0309 ; 0003-2697
ISSN (online)	1096-0309
ISSN	0003-2697
DOI	10.1016/j.ab.2017.01.002
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Post-translational modification as a response to cellular stress induced by hemoglobin oxidation in sickle cell disease

Michael Brad Strader / Sirsendu Jana / Fantao Meng / Michael R. Heaven / Arun S. Shet / Swee Lay Thein / Abdu I. Alayash

Scientific Reports, Vol 10, Iss 1, Pp 1-

2020 Volume 14

Abstract: Abstract Intracellular oxidative stress and oxidative modification of sickle hemoglobin (HbS) play a role in sickle cell disease (SCD) pathogenesis. Recently, we reported that Hb-dependent oxidative stress induced post-translational modifications (PTMs) ... ...

Abstract	Abstract Intracellular oxidative stress and oxidative modification of sickle hemoglobin (HbS) play a role in sickle cell disease (SCD) pathogenesis. Recently, we reported that Hb-dependent oxidative stress induced post-translational modifications (PTMs) of Hb and red blood cell (RBC) membrane proteins of transgenic SCD mice. To identify the mechanistic basis of these protein modifications, we followed in vitro oxidative changes occurring in intracellular Hb obtained from RBCs and RBC-derived microparticles (MPs) from the blood of 23 SCD patients (HbSS) of which 11 were on, and 12, off hydroxyurea (HU) treatment, and 5 ethnic matched controls. We used mass spectrometry-based proteomics to characterize these oxidative PTMs on a cross-sectional group of these patients (n = 4) and a separate subgroup of patients (n = 2) studied prior to initiation and during HU treatment. Collectively, these data indicated that band-3 and its interaction network involved in MPs formation exhibited more protein phosphorylation and ubiquitination in SCD patients than in controls. HU treatment reversed these oxidative PTMs back to level observed in controls. These PTMs were also confirmed using orthogonal immunoprecipitation experiments. Moreover, we observed specific markers reflective of oxidative stress, including irreversible oxidation of βCys93 and ubiquitination of Hb βLys145 (and βLys96). Overall, these studies strongly suggest that extensive erythrocyte membrane protein phosphorylation and ubiquitination are involved in SCD pathogenesis and provide further insight into the multifaceted effects of HU treatment.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
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Article ; Online: Site-directed mutagenesis of cysteine residues alters oxidative stability of fetal hemoglobin

Karin Kettisen / Michael Brad Strader / Francine Wood / Abdu I. Alayash / Leif Bülow

Redox Biology, Vol 19, Iss , Pp 218-

2018 Volume 225

Abstract: Redox active cysteine residues including βCys93 are part of hemoglobin's “oxidation hotspot”. Irreversible oxidation of βCys93 ultimately leads to the collapse of the hemoglobin structure and release of heme. Human fetal hemoglobin (HbF), similarly to ... ...

Abstract	Redox active cysteine residues including βCys93 are part of hemoglobin's “oxidation hotspot”. Irreversible oxidation of βCys93 ultimately leads to the collapse of the hemoglobin structure and release of heme. Human fetal hemoglobin (HbF), similarly to the adult hemoglobin (HbA), carries redox active γCys93 in the vicinity of the heme pocket. Site-directed mutagenesis has been used in this study to examine the impact of removal and/or addition of cysteine residues in HbF. The redox activities of the recombinant mutants were examined by determining the spontaneous autoxidation rate, the hydrogen peroxide induced ferric to ferryl oxidation rate, and irreversible oxidation of cysteine by quantitative mass spectrometry. We found that substitution of γCys93Ala resulted in oxidative instability characterized by increased oxidation rates. Moreover, the addition of a cysteine residue at α19 on the exposed surface of the α-chain altered the regular electron transfer pathway within the protein by forming an alternative oxidative site. This may also create an accessible site for di-sulfide bonding between Hb subunits. Engineering of cysteine residues at suitable locations may be useful as a tool for managing oxidation in a protein, and for Hb, a way to stave off oxidation reactions resulting in a protein structural collapse. Keywords: Fetal hemoglobin, Site-directed mutagenesis, Cysteine, Oxidation, Hydrogen peroxide, Protein electron transfer
Keywords	Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2018-10-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Haptoglobin preferentially binds β but not α subunits cross-linked hemoglobin tetramers with minimal effects on ligand and redox reactions.

Yiping Jia / Francine Wood / Paul W Buehler / Abdu I Alayash

PLoS ONE, Vol 8, Iss 3, p e

2013 Volume 59841

Abstract: Human hemoglobin (Hb) and haptoglobin (Hp) exhibit an extremely high affinity for each other, and the dissociation of Hb tetramers into dimers is generally believed to be a prerequisite for complex formation. We have investigated Hp interactions with ... ...

Abstract	Human hemoglobin (Hb) and haptoglobin (Hp) exhibit an extremely high affinity for each other, and the dissociation of Hb tetramers into dimers is generally believed to be a prerequisite for complex formation. We have investigated Hp interactions with native Hb, αα, and ββ cross-linked Hb (ααXLHb and ββXLHb, respectively), and rapid kinetics of Hb ligand binding as well as the redox reactivity in the presence of and absence of Hp. The quaternary conformation of ββ subunit cross-linking results in a higher binding affinity than that of αα subunit cross-linked Hb. However, ββ cross-linked Hb exhibits a four fold slower association rate constant than the reaction rate of unmodified Hb with Hp. The Hp contact regions in the Hb dimer interfaces appear to be more readily exposed in ββXLHb than ααXLHb. In addition, apart from the functional changes caused by chemical modifications, Hp binding does not induce appreciable effects on the ligand binding and redox reactions of ββXLHb. Our findings may therefore be relevant to the design of safer Hb-based oxygen therapeutics by utilizing this preferential binding of ββXLHb to Hp. This may ultimately provide a safe oxidative inactivation and clearance pathway for chemically modified Hbs in circulation.
Keywords	Medicine ; R ; Science ; Q
Subject code	500
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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