Responses of normal and sickle cell hemoglobin to S-nitroscysteine: implications for therapeutic applications of NO in treatment of sickle cell disease

Bonaventura, Celia; Godette, G; Ferruzzi, G; Tesh, Shirley; Stevens, Robert; Henkens, Robert W.

doi:10.1016/s0301-4622(02)00092-3

Cited by 15 publications

(13 citation statements)

References 37 publications

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“…In previous work where only NEM modification of β93 residues was observed, the level of modification was usually 50% or less [15,16]. In the current work, ESI-MS data are indicative of greater than 85% modification of the β93 residues.…”

Section: Nem Modification Of β93 Cys Promotes Hb S Fiber Formationsupporting

confidence: 47%

“…In the current work, ESI-MS data are indicative of greater than 85% modification of the β93 residues. In the earlier studies with low levels of β93 Cys modification [15,16], we speculate that the inhibitory effect detected for modification at the cis position dominates over the enhancement effect at the trans position.…”

Section: Nem Modification Of β93 Cys Promotes Hb S Fiber Formationmentioning

confidence: 74%

“…Previous work had suggested that the other Cys residues should not be modified by the relatively mild reaction conditions used in this study [15,29,37,[51][52][53]. The peak areas of the α140 and β112 S-H absorption bands, as determined from the fitting of the data, were compared and the ratio was found to be similar for Hb A and NEM-L Hb A (Fig.…”

Section: Ft-ir Spectroscopymentioning

confidence: 88%

“…A variety of different methods, including FT-IR spectroscopy, ESI-MS and tandem MS, indicate NEM modification occurs at both β93 and α104 Cys residues and that the α104 residue is moderately reactive under relatively standard conditions [37]. Previously, modifications at Hb Cys residues other than β93 were only observed at high concentrations of modifying reagent [14,15,31]. Benesch and co-workers [31] observed that titration with an 100-fold molar excess of PMB results in the observation of 7.5 reactive -SH groups per mole of Hb, while lower PMB concentrations yield a value of 2.4 reactive -SH groups per mole of Hb.…”

Section: The α104 Cys Residue Is Modified By Nemmentioning

confidence: 99%

“…Other investigators have determined that limited exposure of deoxy Hb to NO leads to nitrosylation of β-subunit hemes and subsequent oxygenation leads to the formation of SNO-Hb [12]. Formation of SNO-Hb primarily occurs when NO binds to the β93 Cys residues [13][14][15] and the S-nitroso form of hemoglobin has been observed to exhibit increased O 2 affinity [16]. A recent model for NO action, proposed by Stamler and co-workers [17,18] suggests that Hb quaternary state, and thus O 2 affinity, is mediated by the allosteric transfer of NO from the heme irons to the β93 Cys residues.…”

Section: Introductionmentioning

confidence: 99%

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The role of β93 Cys in the inhibition of Hb S fiber formation

Knee

Roden

Flory

et al. 2007

Biophysical Chemistry

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Recent studies have suggested that nitric oxide (NO) binding to hemoglobin (Hb) may lead to the inhibition of sickle cell fiber formation and the dissolution of sickle cell fibers. NO can react with Hb in at least 3 ways: 1) formation of Hb(II)NO, 2) formation of methemoglobin, and 3) formation of S-nitrosohemoglobin, through nitrosylation of the β93 Cys residue. In this study, the role of β93 Cys in the mechanism of sickle cell fiber inhibition is investigated through chemical modification with N-ethylmaleimide. UV resonance Raman, FT-IR and electrospray ionization mass spectroscopic methods in conjunction with equilibrium solubility and kinetic studies are used to characterize the effect of β93 Cys modification on Hb S fiber formation. Both FT-IR spectroscopy and electrospray mass spectrometry results demonstrate that modification can occur at both the β93 and α104 Cys residues under relatively mild reaction conditions. Equilibrium solubility measurements reveal that singlymodified Hb at the β93 position leads to increased amounts of fiber formation relative to unmodified or doubly-modified Hb S. Kinetic studies confirm that modification of only the β93 residue leads to a faster onset of polymerization. UV resonance Raman results indicate that modification of the α104 residue in addition to the β93 residue significantly perturbs the α 1 β 2 interface, while modification of only β93 does not. These results in conjunction with the equilibrium solubility and kinetic measurements are suggestive that modification of the α104 Cys residue and not the β93 Cys residue leads to T-state destabilization and inhibition of fiber formation. These findings have implications for understanding the mechanism of NO binding to Hb and NO inhibition of Hb S fiber formation.

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Section: Nem Modification Of β93 Cys Promotes Hb S Fiber Formationsupporting

confidence: 47%

Section: Nem Modification Of β93 Cys Promotes Hb S Fiber Formationmentioning

confidence: 74%

Section: Ft-ir Spectroscopymentioning

confidence: 88%

Section: The α104 Cys Residue Is Modified By Nemmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The role of β93 Cys in the inhibition of Hb S fiber formation

Knee

Roden

Flory

et al. 2007

Biophysical Chemistry

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Protein oxidation at the air-lung interface

2003

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Whilst performing its normal functions the lung is required to deal with a range of toxic insults. Whether these are infectious agents, allergens or air pollutants they subject the lung to a range of direct and indirect oxidative stresses. In many instances these challenges lead to oxidative alterations of peptides and proteins within the lung. Measurement of protein oxidation products permits the degree of oxidative stress to be assessed and indicates that endogenous antioxidant defences are overwhelmed. The range of protein oxidation products observed is diverse and the nature and extent of specific oxidation products may inform us about the nature of the damaging ROS and NOS. Recently, there has been a significant shift away from the measurement of these oxidation products simply to establish the presence of oxidative stress, to a focus on identifying specific proteins sensitive to oxidation and establishing the functional consequences of these modifications. In addition the identification of specific enzyme systems to repair these oxidative modifications has lead to the belief that protein function may be regulated through these oxidation reactions. In this review we focus primarily on the soluble protein components of within the surface liquid layer in the lung and the consequence of their undue oxidation.

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