Homolytic Cleavage of Both Heme-Bound Hydrogen Peroxide and Hydrogen Sulfide Leads to the Formation of Sulfheme

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• 作者：Hector D. Arbelo-Lopez ; Nikolay A. Simakov ; Jeremy C. Smith ; Juan Lopez-Garriga ; Troy Wymore
• 刊名：Journal of Physical Chemistry B
• 出版年：2016
• 出版时间：August 4, 2016
• 年：2016
• 卷：120
• 期：30
• 页码：7319-7331
• 全文大小：853K
• 年卷期：0
• ISSN：1520-5207

文摘

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 N_B–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.