ferryl species
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2014 ◽  
Vol 70 (a1) ◽  
pp. C310-C310
Author(s):  
Jayashree Soman ◽  
Michael Strader ◽  
Wayne Hicks ◽  
Tigist Kassa ◽  
Eileen Singleton ◽  
...  

The mutants HbA Bristol-Alesha (βV(E11)67M) and HbF Toms River (γV(E11)67M) [1,2] are examples of a `silent' posttranslational modification in which the side chain of the substituted amino acid is chemically modified (Met→Asp) resulting in a disparity between the DNA and protein sequences. In both cases the patients' hemolysate contained both V67M and V67D isoforms. But in the analogous α subunit mutant, Hb Evans αV(E11)62M, the conversion to Asp was not identified and DNA sequencing confirmed the Met replacement [3]. Our crystal structures of the three (ferrous) CO-bound recombinant V(E11)M mutants show the MetE11 side chain in similar conformations. But the air-oxidized β mutant crystals clearly showed a `bifurcated' and smaller electron density pattern for the E11 side chain, indicating the appearance of Asp. Also, the ligand electron-density at the iron atom in the oxidized β subunit appears to be an oxoferryl Fe4+=O rather than a Fe3+OH2 ferric complex. In contrast, there was little change in the electron density for αMetE11 in oxidized αV62M crystals. The ligand in the ferric α subunit is clearly a coordinated water molecule. But again, a ferryl Fe4+=O complex appears to occur in the wild-type β subunit. This strongly suggest that β subunits have a greater propensity to form highly reactive ferryl species, and that the ferryl species play a role in the Met→Asp conversion. Our autoxidation and proteomics studies showed that although all three recombinant VE11M mutants had similar, high rates of autooxidation and a strong H2O2 dose dependence on sulfoxide and sulfone formation, no Asp formation was detected in α subunits whereas MetE11 is converted to Asp to levels as high as 15% in vitro in β and γ subunits. We propose that the Met→Asp conversion specifically involves H2O2 mediated oxidation of the ferrous heme to an oxoferryl state, and because the transient ferryl intermediates are much less stable in the α subunits, there is no oxidative conversion.


2012 ◽  
Vol 109 (36) ◽  
pp. 14326-14331 ◽  
Author(s):  
M. Srnec ◽  
S. D. Wong ◽  
J. England ◽  
L. Que ◽  
E. I. Solomon

2007 ◽  
Vol 403 (3) ◽  
pp. 391-395 ◽  
Author(s):  
Radu Silaghi-Dumitrescu ◽  
Brandon J. Reeder ◽  
Peter Nicholls ◽  
Chris E. Cooper ◽  
Michael T. Wilson

Ferryl (Fe(IV)=O) species are involved in key enzymatic processes with direct biomedical relevance; among others, the uncontrolled reactivities of ferryl Mb (myoglobin) and Hb (haemoglobin) have been reported to be central to the pathology of rhabdomyolysis and subarachnoid haemorrhage. Rapid-scan stopped-flow methods have been used to monitor the spectra of the ferryl species in Mb and Hb as a function of pH. The ferryl forms of both proteins display an optical transition with pK∼4.7, and this is assigned to protonation of the ferryl species itself. We also demonstrate for the first time a direct correlation between Hb/Mb ferryl reactivity and ferryl protonation status, simultaneously informing on chemical mechanism and toxicity and with broader biochemical implications.


2006 ◽  
Vol 128 (18) ◽  
pp. 6147-6153 ◽  
Author(s):  
Kari L. Stone ◽  
Lee M. Hoffart ◽  
Rachel K. Behan ◽  
Carsten Krebs ◽  
Michael T. Green
Keyword(s):  

2006 ◽  
Vol 11 (3) ◽  
pp. 334-342 ◽  
Author(s):  
Walleska De Jesús-Bonilla ◽  
Anthony Cruz ◽  
Ariel Lewis ◽  
José Cerda ◽  
Daniel E. Bacelo ◽  
...  

Author(s):  
K.S Hewitson ◽  
N Granatino ◽  
R.W.D Welford ◽  
M.A McDonough ◽  
C.J Schofield

The 2-oxoglutarate (2OG) and ferrous iron dependent oxygenases are a superfamily of enzymes that catalyse a wide range of reactions including hydroxylations, desaturations and oxidative ring closures. Recently, it has been discovered that they act as sensors in the hypoxic response in humans and other animals. Substrate oxidation is coupled to conversion of 2OG to succinate and carbon dioxide. Kinetic, spectroscopic and structural studies are consistent with a consensus mechanism in which ordered binding of (co)substrates enables control of reactive intermediates. Binding of the substrate to the active site triggers the enzyme for ligation of dioxygen to the metal. Oxidative decarboxylation of 2OG then generates the ferryl species thought to mediate substrate oxidation. Structural studies reveal a conserved double-stranded β-helix core responsible for binding the iron, via a 2His-1carboxylate motif and the 2OG side chain. The rigidity of this core contrasts with the conformational flexibility of surrounding regions that are involved in binding the substrate. Here we discuss the roles of 2OG oxygenases in terms of the generic structural and mechanistic features that render the 2OG oxygenases suited for their functions.


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