title: Homolytic Cleavage of Both Heme-Bound Hydrogen Peroxide and Hydrogen Sulfide Leads to the Formation of Sulfheme.
abstract: Many heme-containing proteins with a histidine in the distal E7 (HisE7) position can form sulfheme in the presence of hydrogen sulfide (H2S) 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 H2S to enter the solvent-excluded active site through a hydrophobic channel to ultimately form a hydrogen bond with H2O2 bound to Fe(III). Proton transfer from H2O2 to His64 to form compound (Cpd) 0, followed by hydrogen transfer from H2S to the Fe(III)-H2O2 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 to 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 NB-Fe(III) bonds compared with other pyrrole nitrogen-Fe(III) bonds, which would lead to decreased oxygen binding. Overall, 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 H2S on cell signaling and reactivity.
authors.affiliation: Chemistry Department, University of Puerto Rico , Mayagüez Campus, Mayagüez 00681, Puerto Rico.
authors.forename: Hector D
authors.initials: HD
authors.lastname: Arbelo-Lopez
authors.affiliation: Center for Computational Research, University of Buffalo , Buffalo, New York 14203, United States.
authors.forename: Nikolay A
authors.initials: NA
authors.lastname: Simakov
authors.affiliation: UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37831-6309, United States.|Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee , Knoxville, Tennessee 37996, United States.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Smith
authors.affiliation: Chemistry Department, University of Puerto Rico , Mayagüez Campus, Mayagüez 00681, Puerto Rico.
authors.forename: Juan
authors.initials: J
authors.lastname: Lopez-Garriga
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee , Knoxville, Tennessee 37996, United States.
authors.forename: Troy
authors.initials: T
authors.lastname: Wymore
mesh_terms: D000818:Animals; D049872:Bivalvia / Q000378:metabolism; D020134:Catalytic Domain; D006418:Heme / Q000031:analogs & derivatives* / Q000737:chemistry*; D006454:Hemoglobins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006860:Hydrogen Bonding; D006861:Hydrogen Peroxide / Q000737:chemistry*; D006862:Hydrogen Sulfide / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D011524:Protoporphyrins / Q000737:chemistry / Q000378:metabolism; D011789:Quantum Theory
chemical_list: D006454:Hemoglobins; D011524:Protoporphyrins; C052173:sulfheme; D006418:Heme; C026236:hemoglobin I, non-mammalian; D006861:Hydrogen Peroxide; C028025:protoporphyrin IX; D006862:Hydrogen Sulfide