Mammalian alpha beta hydrolase domain (ABHD) proteins: Lipid metabolizing enzymes at the interface of cell signaling and energy metabolism

Abstract

Dysregulation of lipid metabolism underlies many chronic diseases such as obesity, diabetes, cardiovascular disease, and cancer. Therefore, understanding enzymatic mechanisms controlling lipid synthesis and degradation is imperative for successful drug discovery for these human diseases. Genes encoding α/β hydrolase fold domain (ABHD) proteins are present in virtually all reported genomes, and conserved structural motifs shared by these proteins predict common roles in lipid synthesis and degradation. However, the physiological substrates and products for these lipid metabolizing enzymes and their broader role in metabolic pathways remain largely uncharacterized. Recently, mutations in several members of the ABHD protein family have been implicated in inherited inborn errors of lipid metabolism. Furthermore, studies in cell and animal models have revealed important roles for ABHD proteins in lipid metabolism, lipid signal transduction, and metabolic disease. The purpose of this review is to provide a comprehensive summary surrounding the current state of knowledge regarding mammalian ABHD protein family members. In particular, we will discuss how ABHD proteins are ideally suited to act at the interface of lipid metabolism and signal transduction. Although, the current state of knowledge regarding mammalian ABHD proteins is still in its infancy, this review highlights the potential for the ABHD enzymes as being attractive targets for novel therapies targeting metabolic disease.

Critical roles for α/β hydrolase domain 5 (ABHD5)/comparative gene identification-58 (CGI-58) at the lipid droplet interface and beyond

“…CGI-58 is a member of the alpha beta hydrolase domain-containing (ABHD) family of enzymes, many of which possess a classic lipase catalytic triad [104]. However CGI-58 lacks the predicted nucleophile serine within the lipase active site, and by all accounts has no intrinsic lipase activity towards TAG or many other glycerolipid and glycerophospholipid substrates [104].…”

The α/β Hydrolase CGI-58 and Peroxisomal Transport Protein PXA1 Coregulate Lipid Homeostasis and Signaling in Arabidopsis

“…The interaction of CGI-58 with PXA1 in plants raises the intriguing question of whether mammalian CGI-58, or perhaps one or more of the other 18 a/b hydrolase-like proteins in humans (Li et al, 2009;Lord et al, 2013), might similarly interact with peroxisomal, or perhaps mitochondrial, ABC-type transport proteins to help facilitate the breakdown and/or further metabolism of various lipid substrates. Although human CGI-58 has not been shown to physically associate with any of the peroxisomal ABC transporters, a large-scale affinity-capture study that employed the peroxisomal ABC half-transporter PMP70 as bait revealed an association with another a/b hydrolase-type protein named the mesoderm-specific transcript protein (Ewing et al, 2007).…”

Biochemical characterization of human alpha/beta hydrolase domain 6 as a therapeutic target

“…Although there is a large amount of variability in the primary sequences, all serine hydrolases with the alpha/beta hydrolase domain share a common secondary structure organization and similar subsequent tertiary structures. 8,49 The catalytic triad consists of serine, aspartic acid, and histidine, and their location is very well conserved on specific loops within the overall structure. In ABHD6 the catalytic triad is proposed to be Ser148, Asp278, and His306, with Ser148 confirmed by mutational analysis.…”

“…The serine hydrolase superfamily is one of the largest groups of structurally-related enzymes and is characterized by the presence of the alpha/beta hydrolase fold domain, which is 8 β-strands forming the core surrounded by helices and loops that connect the strands. 8 All enzymes that contain this fold have a highly conserved catalytic triad: serine, histidine, and aspartic acid. These residues can be found in ABHD6 at Ser142, as confirmed by mutational analysis 6 , His306, and Asp278.…”

“…4,8 To investigate the effect of the phospholipid bilayer and estimate the location of the lid domain of hABHD6, a molecular dynamics experiment was performed. The native substrate, 2-AG was docked into the binding site of the homology model of hABHD6 using the YASARA macro "AutoDock" 84 and the optimal position had a binding energy of 2.17 kcal/mol ( Figure 37A, Table 11).…”