Myeloperoxidase (MPO) is abundant hemoprotein present in neutrophils and monocytes which plays an essential role in immune surveillance and host defense mechanisms. It also is implicated in the pathogenesis of atherosclerosis and other inflammatory disorders. Upon phagocyte activation, MPO is secreted into both the extracellular milieu and the phagolysosome where it uses hydrogen peroxide (H2O2) produced during a respiratory burst as co-substrate. Activated intermediates, Compounds I and II, are sequentially formed which generate cytotoxic oxidants and diffusible radical species. Despite the potential significance of MPO to both human health and disease, little is known about the factors that influence MPO catalytic activity and function. In this proposal we focus on the potential role of nitric oxide (NO, nitrogen monoxide) and physiological reductants like ascorbate (Vitamin C) in the regulation of MPO activity, conformation and function. MPO and inducible nitric oxide synthase (NOS) are both stored and secreted in primary granules of activated leukocytes, and NO is known to react with the iron center of hemoproteins at near diffusion-controlled rates. However, the potential interactions between NO and the distal heme moiety of MPO are essentially unexplored. Similarly, ascorbate and other physiological reductants function in regulation the redox state of tissues. However, their role in modulating MPO catalysis through heme reduction has not been explored. The overall goal of this proposal is to identify the biochemical mechanisms through which NO and physiological reductants like ascorbate modulate MPO catalytic activity, conformation and function. We will examine the role of NO in modulating MPO activity and function and develop a comprehensive kinetic model for the interaction of nitrogen oxides with MPO. In parallel, we will examine the potential role of peroxidases in serving as a catalytic sink for NO, modulating its bioavailability and function. We will test the hypothesis that MPO-nitrosyl complexes serve as a novel mechanism for catalyzing formation of nitrosothiol adducts both in vitro and in vivo. Finally, we will explore the role of physiological reductants in reducing MPO-Fe(III) to the inactive form MPO- Fe(II), as well as characterize the role of heme reduction on MPO structure and function. Studies of MPO catalytic mechanisms and function are essential to a more fundamental understanding of the factors which govern MPO-dependent processes in human health and disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Physical Biochemistry Study Section (PB)
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Qasba, Pankaj
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Cleveland Clinic Lerner
United States
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Jeelani, Roohi; Maitra, Dhiman; Chatzicharalampous, Charalampos et al. (2018) Melatonin prevents hypochlorous acid-mediated cyanocobalamin destruction and cyanogen chloride generation. J Pineal Res 64:
Thakur, Mili; Shaeib, Faten; Khan, Sana N et al. (2017) Galactose and its Metabolites Deteriorate Metaphase II Mouse Oocyte Quality and Subsequent Embryo Development by Disrupting the Spindle Structure. Sci Rep 7:231
Jeelani, Roohi; Jahanbakhsh, Seyedehameneh; Kohan-Ghadr, Hamid-Reza et al. (2017) Mesna (2-mercaptoethane sodium sulfonate) functions as a regulator of myeloperoxidase. Free Radic Biol Med 110:54-62
Shaeib, Faten; Khan, Sana N; Thakur, Mili et al. (2016) The Impact of Myeloperoxidase and Activated Macrophages on Metaphase II Mouse Oocyte Quality. PLoS One 11:e0151160
Shaeib, Faten; Khan, Sana N; Ali, Iyad et al. (2016) The Defensive Role of Cumulus Cells Against Reactive Oxygen Species Insult in Metaphase II Mouse Oocytes. Reprod Sci 23:498-507
Shaeib, Faten; Khan, Sana N; Ali, Iyad et al. (2015) Melatonin prevents myeloperoxidase heme destruction and the generation of free iron mediated by self-generated hypochlorous acid. PLoS One 10:e0120737
Khan, Sana N; Shaeib, Faten; Najafi, Tohid et al. (2015) Diffused Intra-Oocyte Hydrogen Peroxide Activates Myeloperoxidase and Deteriorates Oocyte Quality. PLoS One 10:e0132388
Maitra, Dhiman; Ali, Iyad; Abdulridha, Rasha M et al. (2014) Kinetic studies on the reaction between dicyanocobinamide and hypochlorous acid. PLoS One 9:e110595
Goud, Pravin T; Goud, Anuradha P; Najafi, Tohid et al. (2014) Direct real-time measurement of intra-oocyte nitric oxide concentration in vivo. PLoS One 9:e98720
Abu-Soud, Husam M; Maitra, Dhiman; Shaeib, Faten et al. (2014) Disruption of heme-peptide covalent cross-linking in mammalian peroxidases by hypochlorous acid. J Inorg Biochem 140:245-54

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