Abstract
Lactoperoxidase (LPO) is the major consumer of hydrogen peroxide (H2O2) in the airways through its ability to oxidize thiocyanate (SCN−) to produce hypothiocyanous acid, an antimicrobial agent. In nasal inflammatory diseases, such as cystic fibrosis, both LPO and myeloperoxidase (MPO), another mammalian peroxidase secreted by neutrophils, are known to co-localize. The aim of this study was to assess the interaction of LPO and hypochlorous acid (HOCl), the final product of MPO. Our rapid kinetic measurements revealed that HOCl binds rapidly and reversibly to LPO-Fe(III) to form the LPO-Fe(III)-OCl complex, which in turn decayed irreversibly to LPO Compound II through the formation of Compound I. The decay rate constant of Compound II decreased with increasing HOCl concentration with an inflection point at 100 µM HOCl, after which the decay rate increased. This point of inflection is the critical concentration of HOCl beyond which HOCl switches its role, from mediating destabilization of LPO Compound II to LPO heme destruction. Lactoperoxidase heme destruction was associated with protein aggregation, free iron release, and formation of a number of fluorescent heme degradation products. Similar results were obtained when LPO-Fe(II)-O2, Compound III, was exposed to HOCl. Heme destruction can be partially or completely prevented in the presence of SCN−. On the basis of the present results we concluded that a complex bi-directional relationship exists between LPO activity and HOCl levels at sites of inflammation; LPO serve as a catalytic sink for HOCl, while HOCl serves to modulate LPO catalytic activity, bioavailability, and function.
Highlights
Myeloperoxidase (MPO) and lactoperoxidase (LPO) are homologous members of the mammalian peroxidase superfamily which include eosinophil peroxidase and thyroid peroxidase
As hypochlorous acid (HOCl) is thought to oxidize the heme moiety of LPO, we examined whether these spectral transformations that are apparent from our UV–visible spectral analysis may represent the oxidation, free iron release, and subsequently protein aggregation
H2O2 and protect the airway epithelium from its toxicity [38,42]. This is especially important in the airways, where catalase is present in the peroxisomal system, but not secreted in the luminal fluid [43], thereby making mammalian peroxidases the main H2O2 scavengers
Summary
Myeloperoxidase (MPO) and lactoperoxidase (LPO) are homologous members of the mammalian peroxidase superfamily which include eosinophil peroxidase and thyroid peroxidase. These enzymes share an overall 60–70% amino acid sequence homology [1,2,3]. LPO is a monomeric protein with a single polypeptide chain of 78.5 kDa, and uses the pseudo halide, thiocyanate (SCN2) as a preferred substrate to generate hypothiocyanous acid (HOSCN) [6,7]. MPO is a 150– 165 kDa, homodimer, each subunit comprising of a pair of light and heavy chains, and uses chloride (Cl2) as the preferred substrate to generate hypochlorous acid (HOCl) [2,3,8].
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