Critical role of myeloperoxidase-derived oxidants in the oxidation of the redox sensor glycerhaldehyde-3-phosphate deshydrogenase in activated macrophages: Implications at sites of inflammation

GOMEZ MEJIBA, SE; RAMIREZ, DC

INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2018

0141-8130

Herein we examined a novel free radical mechanism that causes oxidation, inactivation and aggregation of the redox sensor?glyceraldehydes-3-phosphate deshydrogenase (GAPDH) in RAW264.7 cells that have been activated with lipopolysaccharide (LPS). In this model, GAPDH is oxidized by myeloperoxidase (MPO)-derived hypochlorous acid (HOCl) resulting in its radicalization, oxidation, inactivation and aggregation with consequent accumulation of lactate and death of the macrophage. A number of reactive oxygen species are formed during macrophage activation by LPS that can oxidize changing structure and function of GAPDH. However, due to the close spatial and physical proximity between MPO and GAPDH, HOCl is the main species that triggers radicalization of GAPDH that ultimately results in enzyme aggregation and inactivation in cells primed with LPS. Lysine residues are the primary radicalization sites formed upon reaction of HOCl with the enzyme. Herein we provide robust evidence that HOCl-produced by MPO in close proximity (spatial and physical) can cause radicalization, inactivation and aggregation of GAPDH in stressed cells as a first approach to study the role of radicalization of specific proteins in cell fate and phenotypic variations under stress conditions, such as neurodegeneration and other chronic inflammatory diseases.