Peroxynitrite-Mediated Heme Oxidation and Protein Modification of Native and Chemically Modified Hemoglobins

Alayash, Abdu I.; Ryan, B. A. Brockner; Cashon, Robert E.

doi:10.1006/abbi.1997.0449

Cited by 84 publications

(50 citation statements)

References 25 publications

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“…Interestingly, a further increase of the concentration of BAY 58-2667 up to 100 M rendered the enzyme heme deficient even in its ferrous state. Oxidation of the heme by the sGC inhibitor ODQ is known to change the secondary structure of sGC (40,41) and weaken the binding of the heme moiety (5) as described for other heme proteins such as myoglobin (42)(43)(44). Therefore, the ferric heme could be displaced at lower concentrations of BAY 58-2667, whereas for the displacement of the tightly bound ferrous heme higher concentrations of BAY 58-2667 were needed.…”

Section: Discussionmentioning

confidence: 99%

Identification of Residues Crucially Involved in the Binding of the Heme Moiety of Soluble Guanylate Cyclase

Schmidt

Schramm

Schröder

et al. 2004

Journal of Biological Chemistry

155

153

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Soluble guanylate cyclase (sGC), a heterodimeric hemeprotein, is the only receptor for the biological messenger nitric oxide (NO) identified to date and is intimately involved in various signal transduction pathways. By using the recently discovered NO-and hemeindependent sGC activator BAY 58-2667 and a novel cGMP reporter cell, we could distinguish between hemecontaining and heme-free sGC in an intact cellular system. Using these novel tools, we identified the invariant amino acids tyrosine 135 and arginine 139 of the ␤ 1 -subunit as crucially important for both the binding of the heme moiety and the activation of sGC by BAY 58-2667. The heme is displaced by BAY 58-2667 due to a competition between the carboxylic groups of this compound and the heme propionic acids for the identified residues tyrosine 135 and arginine 139. This displacement results in the release of the axial heme ligand histidine 105 and to the observed activation of sGC. Based on these findings we postulate a signal transmission triad composed of histidine 105, tyrosine 135, and arginine 139 responsible for the enzyme activation by this compound and probably also for transducing changes in heme status and porphyrin geometry upon NO binding into alterations of sGC catalytic activity.

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Section: Discussionmentioning

confidence: 99%

Identification of Residues Crucially Involved in the Binding of the Heme Moiety of Soluble Guanylate Cyclase

Schmidt

Schramm

Schröder

et al. 2004

Journal of Biological Chemistry

155

153

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“…If peroxynitrite oxidizes oxyHb by a two-electron oxidation process, nitrite and molecular oxygen should be produced in addition to ferrylHb (Equation Neither nitrite nor molecular oxygen yields have been assessed yet, so the mechanism proposed in Equation 1 cannot be confirmed with the available data. Other authors have previously proposed that reaction of oxyHb with peroxynitrite leads to a rapid one-electron oxidation of the heme iron to the ferric form (11). The latter (11) reported the appearance of a ferryl-like spectrum toward the end of the reaction period that was proposed to have been caused by concomitant peroxide production as a result of the presence of nitrite in the peroxynitrite preparations.…”

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confidence: 99%

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confidence: 99%

“…Other authors have previously proposed that reaction of oxyHb with peroxynitrite leads to a rapid one-electron oxidation of the heme iron to the ferric form (11). The latter (11) reported the appearance of a ferryl-like spectrum toward the end of the reaction period that was proposed to have been caused by concomitant peroxide production as a result of the presence of nitrite in the peroxynitrite preparations.Considering that the observed final product of the reaction is metHb (6,8,9,11) and that the ferryl intermediate is transient and detected at low yields, other reaction mechanisms could be * This work was supported by grants from Consejo Nacional de Investigación Científica y Tecnológica (to N. R.), Comisión Sectorial de Investigación Científica and Third World Academy of Science (to A. D.), The Howard Hughes Medical Institute (to R. R.), and Fundação de Amparo à Pesquisa do Estado de Sã o Paulo (FAPESP) (to O. A.).…”

mentioning

confidence: 99%

“…Considering that the observed final product of the reaction is metHb (6,8,9,11) and that the ferryl intermediate is transient and detected at low yields, other reaction mechanisms could be * This work was supported by grants from Consejo Nacional de Investigación Científica y Tecnológica (to N. R.), Comisión Sectorial de Investigación Científica and Third World Academy of Science (to A. D.), The Howard Hughes Medical Institute (to R. R.), and Fundação de Amparo à Pesquisa do Estado de Sã o Paulo (FAPESP) (to O. A.).…”

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Reaction of Human Hemoglobin with Peroxynitrite

Romero

Radí

Linares

et al. 2003

Journal of Biological Chemistry

120

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Peroxynitrite, a strong oxidant formed intravascularly in vivo, can diffuse onto erythrocytes and be largely consumed via a fast reaction (2 ؋ 10 4 M ؊1 s ؊1 ) with oxyhemoglobin. The reaction mechanism of peroxynitrite with oxyhemoglobin that results in the formation of methemoglobin remains to be elucidated. In this work, we studied the reaction under biologically relevant conditions using millimolar oxyhemoglobin concentrations and a stoichiometric excess of oxyhemoglobin over peroxynitrite. The results support a reaction mechanism that involves the net one-electron oxidation of the ferrous heme, isomerization of peroxynitrite to nitrate, and production of superoxide radical and hydrogen peroxide. Homolytic cleavage of peroxynitrite within the heme iron allows the formation of ferrylhemoglobin in ϳ10% yields, which can decay to methemoglobin at the expense of reducing equivalents of the globin moiety. Indeed, spin-trapping studies using 2-methyl-2-nitroso propane and 5,5 dimethyl-1-pyrroline-N-oxide (DMPO) demonstrated the formation of tyrosyl-and cysteinyl-derived radicals. DMPO also inhibited covalently linked dimerization products and led to the formation of DMPO-hemoglobin adducts. Hemoglobin nitration was not observed unless an excess of peroxynitrite over oxyhemoglobin was used, in agreement with a marginal formation of nitrogen dioxide. The results obtained support a role of oxyhemoglobin as a relevant intravascular sink of peroxynitrite.Peroxynitrite, 1 a strong oxidant formed intravascularly in vivo by the diffusion-limited reaction between nitric oxide ( ⅐ NO) and superoxide (O 2 . ) radicals (1-5), rapidly oxidizes human oxyhemoglobin (oxyHb) 2 (k 2 ϭ 2 ϫ 10 4 M Ϫ1 s Ϫ1 at 37°C and pH 7.4 (6,7)) to yield methemoglobin (metHb) as the final product. Peroxynitrite can behave as either a one-or two-electron oxidant during its direct reaction with transition metal centers; therefore, it is not apparent how metHb is formed. Recently, an initial two-electron oxidation process has been proposed leading to the formation of a high oxidation state intermediate, ferrylhemoglobin (ferrylHb) (8, 9). However, the ferrylHb intermediate detected during reaction of oxyHb with peroxynitrite has a very short half-life (i.e. milliseconds), and it can only be clearly observed when trapped with sodium sulfide (8, 9). Even under excess of sodium sulfide, the yields of sulfo-hemoglobin obtained were low (ϳ 10 -15% of metHb yield). This contrasts with the two-electron oxidation product obtained with oxyHb under excess of hydrogen peroxide (H 2 O 2 ), which yields a relatively stable ferrylHb intermediate (i.e. minutes) that can be observed directly by spectrophotometric techniques (10). If peroxynitrite oxidizes oxyHb by a two-electron oxidation process, nitrite and molecular oxygen should be produced in addition to ferrylHb (Equation 1):Neither nitrite nor molecular oxygen yields have been assessed yet, so the mechanism proposed in Equation 1 cannot be confirmed with the available data. Other authors have previously prop...

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Reactive Inorganic Oxy‐Species of C, N, S, and P

Sharma¹

2012

Oxidation of Amino Acids, Peptides, and Proteins

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Peroxynitrite-Mediated Heme Oxidation and Protein Modification of Native and Chemically Modified Hemoglobins

Cited by 84 publications

References 25 publications

Identification of Residues Crucially Involved in the Binding of the Heme Moiety of Soluble Guanylate Cyclase

Identification of Residues Crucially Involved in the Binding of the Heme Moiety of Soluble Guanylate Cyclase

Reaction of Human Hemoglobin with Peroxynitrite

Reactive Inorganic Oxy‐Species of C, N, S, and P

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