ELUCIDATION OF 15-LIPOXYGENASE-2 AND PEBP1 INTERACTIONS IMPLICATED IN ACUTE RENAL FAILURE

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Katherine Ray (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: 15-Lipoxygenase-2 (15-LOX-2) is one of six human lipoxygenase enzymes that catalyze the peroxidation of fatty acids and are involved in many different cell signaling pathways related to development , homeostasis , and even disease. 15-LOX-2 enzyme has recently been implicated in the ferroptosis pathway , or iron dependent programmed cell death , that is linked to acute renal failure. It is hypothesized that this occurs when phosphatidylethanolamine binding protein 1 (PEBP1) associates with 15-LOX-2 at the cellular membrane , leading to an allosteric change 15-LOX-2's structure. This interaction has been proposed to alter 15-LOX-2's substrate affinity from free fatty acids to phospholipids (primarily derived from phosphatidylethanolamine , PE , acquired from the membrane) , resulting in the generation of hp-ETE-PE's that feed into ferroptosis pathways when they are not adequately reduced by glutathione peroxidase IV complex. Despite this emerging model , there is no biochemical evidence for the PEBP1/15-LOX-2 interaction or allosteric regulation. Resolving this interaction is important towards developing methodologies for small molecule intervention approaches , such as employing recently discovered selective inhibitor of 15-LOX-2. For this thesis , interactions between 15-LOX-2 , PEBP1 , and the cell membrane are investigated using 10 nm lipid nanodiscs as a model of the phospholipid bilayer. Fast protein liquid chromatography (FPLC) and SDS-PAGE show binding of the 15-LOX-2 to the first generation nanodisc prep.

Additional Information

Publication

Thesis

Language: English

Date: 2019

Keywords

15-lipoxygenase-2, pebp1, ferroptosis

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