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New chemical tools to illuminate N-acylphosphatidylethanolamine biosynthesis
Wendel, T.J. 2023
New chemical tools to illuminate N-acylphosphatidylethanolamine biosynthesis
Doctoral Thesis
some documents under embargo until 2024-09-23
2024-09-23T00:00:00Z; 2024-09-23T00:00:00Z; 2024-09-23T00:00:00Z; 2024-09-23T00:00:00Z; 2024-09-23T00:00:00Z; 2024-09-23T00:00:00Z; 2024-09-23T00:00:00Z
This thesis describes the development and optimization of the first molecular tools to study the enzyme PLA2G4E. After remaining elusive for many years, in 2016, this enzyme was discovered to be... Show moreThis thesis describes the development and optimization of the first molecular tools to study the enzyme PLA2G4E. After remaining elusive for many years, in 2016, this enzyme was discovered to be responsible for the calcium-dependent formation of N-acylphosphatidylethanolamines (NAPEs) in cells. NAPEs are low-abundant lipid species that play roles in membrane stabilization, cell signaling and homeostasis. They are well-known as precursors to the signaling lipids of the N-acylethanolamine (NAE) class, but their own biological functions remain relatively poorly understood. To find inhibitors of PLA2G4E, a focused compound library was screened in a newly developed activity-based protein profiling (ABPP) assay. Hits were identified and optimized by building structure-activity relationships (SARs) through organic synthesis and activity assays. WEN091 was identified as potent inhibitor of PLA2G4E that was able to reduce cellular NAPE levels. Cellular target engagement was confirmed by use of a tailored activity-based probe. Using these molecular tools, the relevance of NAPEs and PLA2G4E in cellular processes and disease may be elucidated. Show less
Activity-based protein profiling of diacylglycerol lipases
Baggelaar, M.P. 2017
Activity-based protein profiling of diacylglycerol lipases
Doctoral Thesis
open access
2018-09-06T00:00:00Z; 2018-09-06T00:00:00Z; 2018-09-06T00:00:00Z; 2018-09-06T00:00:00Z
Diacylglycerol lipase (DAGL)-α and -β are enzymes responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol. Selective and reversible inhibitors are required to study the... Show moreDiacylglycerol lipase (DAGL)-α and -β are enzymes responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol. Selective and reversible inhibitors are required to study the function of DAGLs in neuronal cells in an acute and temporal fashion. The work described in this thesis has led to the identification of an activity-based probe (ABP) for DAGL-α. This ABP was instrumental for the identification of a new class of highly selective DAGL inhibitors. These novel inhibitors can be used to investigate the role of the diacylglycerol lipases in metabolic syndrome and neurodegenerative diseases such a Parkinson’s disease, Alzheimer’s disease and Multiple Sclerosis. Show less