Hemin-promoted peroxidation of red cell cytoskeletal proteins

Solar, Irit; Dulitzky, J.; Shaklai, Nurith

doi:10.1016/0003-9861(90)90615-6

Cited by 34 publications

(12 citation statements)

References 39 publications

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“…The protein may participate in transport, storage, or scavenging of heme, roles that have been suggested for intracellular heme-binding proteins (32)(33)(34). Ongoing studies aim to establish whether the physiological significance of the protein relates to these heme-binding properties or, alternatively, whether the role of the protein is to (i) bind fatty acids, (ii) catalyze heme-regulated reduction reactions, or (iii) protect cells from oxidative damage by catalyzing the reduction of the higher oxidation states of hemeproteins.…”

Section: Resultsmentioning

confidence: 99%

Characterization of NADPH-dependent methemoglobin reductase as a heme-binding protein present in erythrocytes and liver.

Xu¹,

Quandt²,

Hultquist³

1992

Proc. Natl. Acad. Sci. U.S.A.

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An NADPH-dependent reductase, first shown in the 1930s to catalyze the methylene blue-dependent reduction of methemoglobin in erythrocytes, has now been characterized as a high-affinity heme-binding protein and has been detected in liver. Highly purified bovine erythrocyte reductase binds protohemin to form a 1:1 complex with a Kd of 7 nM. Binding of protohemin completely inhibits reductase activity. Other tetrapyrroles and fatty acids also bind to the reductase and inhibit its activity. Protoporphyrin, hematoporphyrin, and coproporphyrin form 1:1 complexes withKd values ranging from 1 to 5 IzM. The inhibition constants for a number of saturated and unsaturated fatty acids range from 6 to 52 ,LM. A protein that is immunologically cross-reactive to the reductase has been detected in the cytosolic fractions of bovine and rat liver and of bovine, rat, rabbit, and human erythrocytes. By immunoblot analysis, the bovine liver and erythrocyte proteins appear identical in size, as do the rat liver and erythrocyte proteins. The concentration of the protein in bovine erythrocytes has been estimated by quantitative immunoblotting to be 10 juM. The detection of this protein in liver cells, the demonstration of its binding properties, and its weak reductase activity bring into question the long-held belief that this is uniquely an erythrocyte protein and that it functions as a reductase.Methylene blue stimulation of methemoglobin reduction in human erythrocytes was described 60 years ago by Warburg et al. (1), Steele and Spink (2), and Williams and Challis (3). Subsequent work by a number of investigators resulted in preparations of a cytosolic NADPH-dependent reductase that catalyzed the reduction of methylene blue and flavins and, in the presence of redox couplers, catalyzed the reduction of methemoglobin (4-9). Whereas this NADPHdependent reductase is believed to contribute very little to methemoglobin reduction under normal conditions (10), its catalysis of methemoglobin reduction in the presence of methylene blue or riboflavin is the basis for the use of these compounds as therapeutic agents in the treatment of congenital and toxic methemoglobinemia (11)(12)(13). The erythrocyte reductase has variously been referred to as NADPH dehydrogenase, diaphorase, methemoglobin reductase, and, most recently, flavin reductase.The reductase has been shown to bind small molecules. Isolation procedures generally yield two forms of the reductase, which exhibit very similar activities but different isoelectric points; one, but not the other, of these forms is reported to possess protein-bound NADP+ and a proteinbound yellow chromophore of unknown structure (7,8,(14)(15)(16). The isolation of the protein in the presence of flavin yields a flavoprotein (17). The protein isolated without the addition of flavin contains no flavin and yet exhibits full reductase activity.Recently (18) Bovine erythrocyte green heme-binding protein was purified as described (19). Antibodies to the green heme-binding protein were raised in young adult ...

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Section: Resultsmentioning

confidence: 99%

Characterization of NADPH-dependent methemoglobin reductase as a heme-binding protein present in erythrocytes and liver.

Xu¹,

Quandt²,

Hultquist³

1992

Proc. Natl. Acad. Sci. U.S.A.

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“…It is known that the influence of hemin on spectrin and protein 4.1 is significant while on actin - only minor23. Hemin could alter the conformation of protein 4.1 and weaken spectrin-protein 4.1 interaction and associations4.…”

Section: Discussionmentioning

confidence: 99%

Transformation of membrane nanosurface of red blood cells under hemin action

Козлова

Черныш

Moroz

et al. 2014

Sci Rep

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Hemin is the product of hemoglobin oxidation. Some diseases may lead to a formation of hemin. The accumulation of hemin causes destruction of red blood cells (RBC) membranes. In this study the process of development of topological defects of RBC membranes within the size range from nanoscale to microscale levels is shown. The formation of the grain-like structures in the membrane (“grains”) with typical sizes of 120–200 nm was experimentally shown. The process of formation of “grains” was dependent on the hemin concentration and incubation time. The possible mechanism of membrane nanostructure alterations is proposed. The kinetic equations of formation and transformation of small and medium topological defects were analyzed. This research can be used to study the cell intoxication and analyze the action of various agents on RBC membranes.

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“…Ironically, while heme is essential for many functions, the transitional nature of the coordinated iron renders it a significant pro-oxidant that can harm many cellular entities including DNA, proteins, cytoskeleton, and membranes (Maines and Kappas, 1975; Solar et al, 1990; Chiabrando et al, 2014). To prevent cellular damage and to control infections, mammals restrict the pool of free circulating hemoproteins through scavenger proteins such as serum albumin, hemopexin (for heme), and heptoglobin (for hemoglobin) (Solar et al, 1989; Krishnamurthy et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The crimson conundrum: heme toxicity and tolerance in GAS

Sachla

Breton

Akhter

et al. 2014

Front. Cell. Infect. Microbiol.

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The massive erythrocyte lysis caused by the Group A Streptococcus (GAS) suggests that the β-hemolytic pathogen is likely to encounter free heme during the course of infection. In this study, we investigated GAS mechanisms for heme sensing and tolerance. We compared the minimal inhibitory concentration of heme among several isolates and established that excess heme is bacteriostatic and exposure to sub-lethal concentrations of heme resulted in noticeable damage to membrane lipids and proteins. Pre-exposure of the bacteria to 0.1 μM heme shortened the extended lag period that is otherwise observed when naive cells are inoculated into heme-containing medium, implying that GAS is able to adapt. The global response to heme exposure was determined using microarray analysis revealing a significant transcriptome shift that included 79 up regulated and 84 down regulated genes. Among other changes, the induction of stress-related chaperones and proteases, including groEL/ES (8x), the stress regulators spxA2 (5x) and ctsR (3x), as well as redox active enzymes were prominent. The heme stimulon also encompassed a number of regulatory proteins and two-component systems that are important for virulence. A three-gene cluster that is homologous to the pefRCD system of the Group B Streptococcus was also induced by heme. PefR, a MarR-like regulator, specifically binds heme with stoichiometry of 1:2 and protoporphyrin IX (PPIX) with stoichiometry of 1:1, implicating it is one of the GAS mediators to heme response. In summary, here we provide evidence that heme induces a broad stress response in GAS, and that its success as a pathogen relies on mechanisms for heme sensing, detoxification, and repair.

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Hemin-promoted peroxidation of red cell cytoskeletal proteins

Cited by 34 publications

References 39 publications

Characterization of NADPH-dependent methemoglobin reductase as a heme-binding protein present in erythrocytes and liver.

Characterization of NADPH-dependent methemoglobin reductase as a heme-binding protein present in erythrocytes and liver.

Transformation of membrane nanosurface of red blood cells under hemin action

The crimson conundrum: heme toxicity and tolerance in GAS

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