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Title:Characterization of endocannabinoid and endovanilloid metabolism by cytochrome P450 epoxygenases
Author(s):Carnevale, Lauren N.
Director of Research:Nair, Satish
Doctoral Committee Chair(s):Nair, Satish
Doctoral Committee Member(s):Burke, Martin D; Nelson, Erik; Fratti, Rutilio
Department / Program:Biochemistry
Discipline:Biochemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):cytochrome p450, endocannabinoid
Abstract:The endocannabinoid system is composed of an expanding set of lipid signaling molecules, their biosynthetic and degradative enzymes, and the cannabinoid receptors 1 and 2 (CB1 and CB2). Anandamide (C20:4, N-acyl ethanolamine) was the first endogenous ligand to be identified. A range of ester and amide polyunsaturated fatty acid conjugates and cytochrome P450 epoxygenase derived metabolites were identified which retain activity at the receptors but have distinct biological activities. These ligands, receptors, and enzymes are collectively implicated in neuronal signaling, cardiovascular function, and the immune response. A comprehensive understanding of endocannabinoid signaling and receptor pharmacology is necessary to develop targeted therapeutics. Chapter 1 provides an introduction to the endocannabinoids, endovanilloids, and the cytochrome P450 epoxygenases. We discuss the kinetic and pharmacological characterization of the N-arachidonoyl neurotransmitter conjugates, as well as their epoxide metabolites, at CYP2J2, CB1, CB2, and the transient receptor potential vanilloid 1 channel. Then we examine virodhamine and demonstrate its inhibition of CYP2J2 in a human endothelial cell wound healing assay. Next, we investigate the effect of epoxide position on bioactivity and introduce a chemical approach to prevent isomerization of sn-2 monoacylglycerols. Chapter 2 outlines our current efforts towards the structural elucidation of lipid-associated proteins. Specifically, CYP2J2 Nanodiscs were prepared to study real-time protein dynamics using liquid phase transition electron microscopy and the expression was optimized for x-ray crystallographic studies on α/β-hydrolase domain 5 and adipose triglyceride lipase.
Issue Date:2020-11-20
Type:Thesis
URI:http://hdl.handle.net/2142/109582
Rights Information:Copyright 2020 Lauren Carnevale
Date Available in IDEALS:2021-03-05
Date Deposited:2020-12


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