α/β-Hydrolase Domain (ABHD) Inhibitors as New Potential Therapeutic Options against Lipid-Related Diseases

Abstract

Much of the experimental evidence in the literature has linked altered lipid metabolism to severe diseases such as cancer, obesity, cardiovascular pathologies, diabetes, and neurodegenerative diseases. Therefore, targeting key effectors of the dysregulated lipid metabolism may represent an effective strategy to counteract these pathological conditions. In this context, α/β-hydrolase domain (ABHD) enzymes represent an important and diversified family of proteins, which are involved in the complex environment of lipid signaling, metabolism, and regulation. Moreover, some members of the ABHD family play an important role in the endocannabinoid system, being designated to terminate the signaling of the key endocannabinoid regulator 2-arachidonoylglycerol. This Perspective summarizes the research progress in the development of ABHD inhibitors and modulators: design strategies, structure–activity relationships, action mechanisms, and biological studies of the main ABHD ligands will be highlighted.

An ER phospholipid hydrolase drives ER-associated mitochondrial constriction for fission and fusion

“…Phospholipid hydrolases are known to remove one acyl chain from phospholipids, whereas acyltransferase motifs can catalyze the opposite reaction of a phospholipid hydrolase: where a single-chain phospholipid reacts with an acyl-CoA (coenzyme A) to restore a dual-chain phospholipid ( Aguado and Campbell, 1998 ; Eberhardt et al, 1997 ; Lord et al, 2013 ; Zhao et al, 2008 ). The opposing predicted acyltransferase motif in ABHD16A, although biochemically uncharacterized, is present in many integral ER membrane proteins and other ABHD family proteins and has the potential to either add or alter acyl chains to lysophospholipids/phospholipids ( Bononi et al, 2021 ; Harayama et al, 2014 ; Hishikawa et al, 2014 ; Shindou et al, 2013 ; Zhao et al, 2008 ). Lipase-like motifs (GXSXXG) are predicted to have similarity to bacterial lipase motifs (GXSXG), although it is unknown whether ABHD16A’s lipase-like motifs, one near the acyltransferase motif, and one within the alpha/beta hydrolase domain, have lipase activity.…”

Research Advances Through Activity‐Based Lipid Hydrolase Profiling

“…[59] For another member of the intracellular lipolytic cascade, HSL, only nonspecific inhibitors could be identified via competitive ABPP, [60] and selective human ATGL inhibition has recently been achieved by NG-497, although via different means of discovery. [61] Many inhibitors of the ABHD protein family are summarized by Bononi et al, [62] several of which have been identified through ABPP. Recently, ABPP enabled the discovery of a new ABHD6 inhibitor that improves selectivity over MGL and FAAH.…”

“…Many inhibitors of the ABHD protein family are summarized by Bononi et al ., [62] several of which have been identified through ABPP. Recently, ABPP enabled the discovery of a new ABHD6 inhibitor that improves selectivity over MGL and FAAH [63] …”

Emerging Role of Phospholipids and Lysophospholipids for Improving Brain Docosahexaenoic Acid as Potential Preventive and Therapeutic Strategies for Neurological Diseases

“…These two ABHDs offer new perceptions into Lyso-PS signaling in the cerebellum, the most atrophic brain region in human polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) subjects [ 93 ]. These enzymes can have a potential therapeutic role in the altered lipid metabolism of Lyso-PS in several diseases such as cancer, diabetes, and neurodegenerative diseases [ 94 ].…”