P51 Activation of hydrogen sulfide by heme-superoxide limits triggering heme proteins oxidative products

Abstract

Hydrogen sulfide (H2S) has been regarded as a poisonous gas with a wide spectrum of cytotoxic effects. However, a new controversial role is emerging for H2S in the chemistry of biological systems. It has been found that H2S is synthesized endogenously in mammalian tissues and that it functions as a neuromodulator, and a smooth muscle relaxant [1] . However, the reaction of H2S with Hb and Mb, in the presence of H2O2or O2, results in covalent modification of the heme pyrrole ring bearing the 4-vinyl group, generating the so-called sulfmyoglobin and sulfhemoglobin derivatives. These sulfheme derivatives have lower O2 affinity affecting the heme protein functionality, resulting in a rare blood disease called sulfhemoglobinemia. For the formation of the sulfheme complex, the presence of a heme-ferryl and RSH species are needed, in addition to the adequate oriented histidine in the heme distal site [2] , [3] . However, the structural transient species are not known. Analysis of the sulfheme complex to further comprehend the mechanism and action mode of H2S in the human body, as well as in other organisms is essential. Therefore, it is important to define the relationship between H2S and hemeproteins since these proteins are prime targets. Here, we focus on determining the key intermediates controlling the appropriate interactions that lead to the formation of the sulfheme protein. To accomplish this aim, EPR analysis on Myoglobin (Mb) in the presence of H2S and H2O2 or O2 was performed. The data showed bands associated with ferric low spin species. Thus, the results indicate that the final sulfheme complex is a six coordinated low spin specie. Also, the data showed the development of bands associated characteristic thiol radical bands around 2.051 g and 2.032 g values. Interestingly, the formation of the thiol radicals was not observed upon the reaction of Mb with H2S, in the absence of O2 or H2O2. These data suggests that a thiol radical is a key intermediate in the mechanism that leads to the sulfMb complex formation. As a consequence, the results produced insight into the chemistry of H2S with hemeproteins where H2S reacts as an anti-oxidant, limiting the availability of the heme ferryls species to react with nearby amino acids. Therefore, the evidence shows that a single Histidine E7 amino acid controls the selective toxicity and reactivity of H2S with different hemoglobins, limiting ROS activity with heme proteins.