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Title: Homolytic cleavage of both heme-bound hydrogen peroxide and hydrogen sulfide leads to the formation of sulfheme

Many heme-containing proteins with a histidine in the distal E7 (HisE7) position can form sulfheme in the presence of hydrogen sulfide (H 2S) and a reactive oxygen species such as hydrogen peroxide. For reasons unknown, sulfheme derivatives are formed specifically on solvent-excluded heme pyrrole B. Sulfhemes severely decrease the oxygen-binding affinity in hemoglobin (Hb) and myoglobin (Mb). Here, use of hybrid quantum mechanical/molecular mechanical methods has permitted characterization of the entire process of sulfheme formation in the HisE7 mutant of hemoglobin I (HbI) from Lucina pectinata. This process includes a mechanism for H 2S to enter the solvent-excluded active site through a hydrophobic channel to ultimately form a hydrogen bond with H 2O 2 bound to Fe(III). Proton transfer from H 2O 2 to His64 to form compound (Cpd) 0, followed by hydrogen transfer from H 2S to the Fe(III) H 2O 2 complex, results in homolytic cleavage of the O–O and S–H bonds to form a reactive thiyl radical (HS*), ferryl heme Cpd II, and a water molecule. Subsequently, the addition of HS to Cpd II, followed by three proton transfer reactions, results in the formation of a three-membered ring ferric sulfheme that avoids migration of the radical tomore » the protein matrix, in contrast to that in other peroxidative reactions. The transformation of this three-membered episulfide ring structure to the five-membered thiochlorin ring structure occurs through a significant potential energy barrier, although both structures are nearly isoenergetic. Both three- and five-membered ring structures reveal longer N B–Fe(III) bonds compared with other pyrrole nitrogen–Fe(III) bonds, which would lead to decreased oxygen binding. Altogether, these results are in agreement with a wide range of experimental data and provide fertile ground for further investigations of sulfheme formation in other heme proteins and additional effects of H 2S on cell signaling and reactivity.« less
Authors:
 [1] ;  [2] ;  [3] ;  [1] ;  [4]
  1. Univ. of Puerto Rico, Mayaguez (Puerto Rico)
  2. Univ. of Buffalo, Buffalo, NY (United States)
  3. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
  4. Univ. of Tennessee, Knoxville, TN (United States)
Publication Date:
OSTI Identifier:
1327756
Grant/Contract Number:
AC05-00OR22725
Type:
Accepted Manuscript
Journal Name:
Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry
Additional Journal Information:
Journal Volume: 120; Journal Issue: 30; Journal ID: ISSN 1520-6106
Publisher:
American Chemical Society
Research Org:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY