In vivo metabolite profiling as a means to identify uncharacterized lipase function: Recent success stories within the alpha beta hydrolase domain (ABHD) enzyme family

Abstract

Genome sequencing efforts have identified many uncharacterized lipase/esterase enzymes that have potential to be drug targets for metabolic diseases such as obesity, diabetes, and atherosclerosis. However, sequence information and associated structural predictions provide only a loose framework for linking enzyme function to disease risk. We are now confronted with the challenge of functionally annotating a large number of uncharacterized lipases, with the goal of generating new therapies for metabolic diseases. This daunting challenge involves not gathering sequence-driven predictions, but more importantly structural, biochemical (substrates and products), and physiological data. At the center of such drug discovery efforts is the accurate identification of physiologically relevant substrates and products of individual lipases, and determining whether newly identified substrates/products can modulate disease in appropriate preclinical animal model systems. This review describes the importance of coupling in vivo metabolite profiling to in vitro enzymology as a powerful means to assign lipase function in disease specific contexts using animal models. In particular, we highlight recent examples using this multidisciplinary approach to functionally annotate genes within the α/β hydrolase fold domain (ABHD) family of enzymes. These new discoveries within the ABHD enzyme family serve as powerful examples of linking novel lipase function to human disease.

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus

“…These results were consistent with our eQTL studies and support the hypothesis that increased ABHD8 expression is associated with an increased cancer risk. ABHD8 is a poorly studied lipase 38 . The Achilles heel project identified ABHD8 as a lineage-specific cancer cell vulnerability in OC cell lines 39 and a recent study identified ABHD8 as a potential OC susceptibility gene though its participation in a homeobox transcription factor-centred gene network associated with serous OC risk 40 .…”

An in vivo multiplexed small-molecule screening platform

“…Our proof-of-principle application identified the lipase ABHD6 as a regulator of metastatic seeding of PDAC. In the nervous system, ABHD6 modulates endocannabinoid signaling, however, ABHD6 is expressed in many cell types where it has different lipid substrates 35,37,38 . A similar enzyme, MAGL, contributes to a pathogenic lipid signature in cancer 39,40 and high ABHD6 expression correlates with increased metastatic ability in some cancer 41 .…”

ROG1 encodes a monoacylglycerol lipase in Saccharomyces cerevisiae

“…Rog1p has the lipase catalytic domain and it belongs to the alpha/beta-hydrolase (ABH) family [SGD,17]. ABH domain-containing proteins have lipid-related functions in the mammalian system [19]. To study its biochemical function, the ROG1 gene was cloned, overexpressed ( Fig.…”