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Abstract
Diacylglycerol acyltransferases (DGATs) have a crucial role in the biosynthesis of triacylglycerol (TG), the major storage form of metabolic energy in eukaryotic organisms. Even though DGAT2, one of two distinct DGATs, has a vital role in TG biosynthesis, little is known about the regulation of DGAT2 activity. In this study, we examined the role of cysteine and its oxidation in the enzymatic activity of human DGAT2 in vitro. Human DGAT2 activity was considerably inhibited not only by thiol-modifying reagents (NEM and IA) but also by ROS-related chemicals (H2O2 and β-lapachone), while human DGAT1 and GPAT1 were little affected. Particularly, ROS-related chemicals concomitantly induced intermolecular disulfide crosslinking of human DGAT2. Both the oxidative inactivation and disulfide crosslinking were almost completely reversed by the treatment with DTT, a disulfide-reducing agent. These results clearly demonstrated the significant role of ROS-induced intermolecular crosslinking in the inactivation of human DGAT2 and also suggested DGAT2 as a redox-sensitive regulator in TG biosynthesis.
Highlights
Triacylglycerols (TGs), a most abundant dietary neutral lipid, are the major molecules of energy storage in most eukaryotic organisms
We examined the role of cysteine residues and their oxidation in the activity of human Diacylglycerol acyltransferases (DGATs) and found that DGAT2 activity is highly susceptible to cysteine modification unlike other tested enzymes acting in TG biosynthetic pathway
Membrane extract isolated from DGAT1- or DGAT2-overexpressing Sf9 insect cells was used as the enzyme sources
Summary
Triacylglycerols (TGs), a most abundant dietary neutral lipid, are the major molecules of energy storage in most eukaryotic organisms. The excessive accumulation of TGs in tissues is one of the main causes of metabolic diseases such as obesity, fatty liver, hyperlipidemia, type II diabetes and cardiovascular diseases [1,2,3]. With the worldwide increase in the prevalence of these metabolic diseases, it would be of great importance to better understand the process of TG biosynthesis and the molecular mechanism of enzymes in this pathway. Inhibition of DGAT2 activity by ROS decision to publish, or preparation of the manuscript
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