Interactions of hydrogen sulfide with myeloperoxidase

Abstract

BACKGROUND AND PURPOSEThe actions of hydrogen sulfide in human physiology have been extensively studied and, although it is an essential mediator of many biological functions, the underlying molecular mechanisms of its actions are ill-defined. To elucidate the roles of sulfide in inflammation, we have investigated its interactions with human myeloperoxidase (MPO), a major contributor to inflammatory oxidative stress. EXPERIMENTAL APPROACHThe interactions of sulfide and MPO were investigated using electron paramagnetic resonance, electronic circular dichroism, UV-vis and stopped-flow spectroscopies. KEY RESULTSWe found favourable reactions between sulfide and the native-ferric enzyme as well as the MPO redox intermediates, ferrous MPO, compound I and compound II. Sulfide was a potent reversible inhibitor of MPO enzymic activity with an IC50 of 1 µM. In addition, the measured second-order rate constants for the reactions of sulfide with compound I [k = (1.1 ± 0.06) × 10 6 M −1 s ] suggest that sulfide is a potential substrate for MPO in vivo. CONCLUSION AND IMPLICATIONSEndogenous levels of sulfide are likely to inhibit the activity of circulating and endothelium-bound MPO. The fully reversible inhibition suggests a mediatory role of sulfide on the oxidant-producing function of the enzyme. Furthermore, the efficient HOCl oxidation of sulfide to give polysulfides (recently recognized as important components of sulfide biology) together with MPO-catalysed sulfide oxidation and the lack of interaction between MPO and sulfide oxidation products, predict a modulatory role of MPO in sulfide signalling. LINKED ARTICLESThis article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx

Redox chemistry and chemical biology of H2S, hydropersulfides, and derived species: Implications of their possible biological activity and utility

“…Much more recently, it was shown that other ferric heme proteins can react directly with H 2 S to give an Fe III -SH complex with the same spectral changes observed in the initial study by Keilin [19,20]. One of the most studied of all H 2 S-heme protein interactions is that of H 2 S with a hemoglobin of the bivalve mollusc, Lucina pectinata , that inhabits H 2 S-rich environments [for example, 21-26].…”

“…The mechanism by which excess H 2 S facilitates reduction of the ferric-H 2 S complex (or ferric-HS − complex) is intriguing and has recently been demonstrated for myeloperoxidase (MPO) using spectroscopic measurements on the Fe II -sulfide complex, which was also independently synthesized by the reaction of reduced MPO with sulfide [20]. The sulfur-containing product of this reaction has been proposed to be dihydrogen persulfide (H 2 S 2 ) [26].…”

Biogenesis of reactive sulfur species for signaling by hydrogen sulfide oxidation pathways

“…The product of cytochrome c oxidase reduction under aerobic conditions has not been characterized but is predicted to be elemental sulfur 93,94 . Sulfide binds to the heme iron in myeloperoxidase 95 and lactoperoxidase 96 . Although it has been observed that re-formation of the iron–sulfide complex of myeloperoxidase from compound I is oxygen dependent, possible sulfide oxidation products were not characterized 95 .…”

Persulfidation (S-sulfhydration) and H2S

“…H 2 S also binds and reduces cytochrome c, a reaction that in the presence of oxygen leads to superoxide production (Wedmann et al 2014). In addition, Pálinkás et al (2014) have recently investigated interactions of H 2 S with human myeloperoxidase (MPO), a major contributor to inflammatory oxidative stress, to show that H 2 S inhibits the enzyme by reducing iron centre and by binding to the reduced Fe 2+ . It is still, however, unclear to which extent is the coordination and/or reduction of metal centres involved in signalling by H 2 S. Miljkovic et al (2013) demonstrated that metal centres in mitochondria are responsible for the H 2 S-stimulated haem centre-catalysed reduction of nitrite, a reaction which can explain the use of nitrite as an antidote for acute H 2 S poisoning.…”