Abstract
Alterations in lipid metabolism have been progressively documented as a characteristic property of cancer cells. Though, human ABHD2 gene was found to be highly expressed in breast and lung cancers, its biochemical functionality is yet uncharacterized. In the present study we report, human ABHD2 as triacylglycerol (TAG) lipase along with ester hydrolysing capacity. Sequence analysis of ABHD2 revealed the presence of conserved motifs G205XS207XG209 and H120XXXXD125. Phylogenetic analysis showed homology to known lipases, Drosophila melanogaster CG3488. To evaluate the biochemical role, recombinant ABHD2 was expressed in Saccharomyces cerevisiae using pYES2/CT vector and His-tag purified protein showed TAG lipase activity. Ester hydrolase activity was confirmed with pNP acetate, butyrate and palmitate substrates respectively. Further, the ABHD2 homology model was built and the modelled protein was analysed based on the RMSD and root mean square fluctuation (RMSF) of the 100 ns simulation trajectory. Docking the acetate, butyrate and palmitate ligands with the model confirmed covalent binding of ligands with the Ser207 of the GXSXG motif. The model was validated with a mutant ABHD2 developed with alanine in place of Ser207 and the docking studies revealed loss of interaction between selected ligands and the mutant protein active site. Based on the above results, human ABHD2 was identified as a novel TAG lipase and ester hydrolase.
Highlights
Lipases in addition to being essential enzymes necessary for the supply of energy play a major role in lipid signalling and metabolism
We report the triacylglycerol (TAG) lipase and ester hydrolase activities of human α β hydrolase2 (ABHD2)
The multiple data sets obtained from breast cancer in comparison with normal cells indicated high expression of human ABHD2 gene in breast and lung cancers [33,34,35]
Summary
Lipases in addition to being essential enzymes necessary for the supply of energy play a major role in lipid signalling and metabolism. The mammalian α β hydrolase domain (ABHD) containing proteins have emerged as novel potential regulators of lipid metabolism and in signal transduction [1]. The human ABHD family contains 21 proteins and is part of a superfamily possessing an α β hydrolase fold [1,2]. Hydrolase activity of ABHD is attributed to the catalytic triad composed of serine-acid-histidine residues located in loop regions. The majority of the human ABHD proteins possess another conserved motif HXXXXD where X is any amino acid residue and the motif was attributed to acyltransferase activity [4]
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