Title :

Finding homes to orphan enzymes

Abstract :

My graduate research in the Raushel lab at TAMU focused on the functional annotation of orphan bacterial enzymes and biological pathways. During my graduate studies, I realized the gigantic problem of misannotation of enzymes or lack of thereof in the post-genomic era. Following completion of my graduate studies, I decided to apply my background in biochemistry and mechanistic enzymology, to functionally annotate orphan enzymes in mammalian diseases, and pathophysiology in the Cravatt Lab at TSRI. Here, using a combination of activity based protein profiling, chemoproteomics, and lipidomics, I have identified and functionally characterized an as of yet uncharacterized serine hydrolase enzyme ABHD16A (also BAT5) as the major phosphatidylserine (PS) lipase in mammalian cells and tissues and as the enzyme responsible for biosynthesizing immunomodulatorylyso-PSs in vivo. I validated this annotation of ABHD16A using pharmacological studies performed with first generation small molecule inhibitors of ABHD16A, and from genetic data obtained from ABHD16A-directed shRNA probes, and ABHD16A–/– mice. This functional validation of ABHD16A has potential therapeutic implications in the neurological disorder PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, cataract) and other immunological disorders involving deregulated lyso-PS signaling.