Evolutionary divergence and functions of the human acyl-CoA thioesterase gene (ACOT) family

Chad Brocker, Christopher Carpenter, Daniel W Nebert, Vasilis Vasiliou

The acyl-CoA thioesterase gene (ACOT ) family encodes enzymes that catalyse the hydrolysis of acyl-CoA thioester compounds, also known as activated fatty acids, to their corresponding non-esterified (free) fatty acid and coenzyme A (CoASH). These enzymes play a very important role in lipid metabolism by maintaining cellular levels and proper ratios of free and activated fatty acids, as well as CoASH. Within the acyl-CoA family there are two distinct subgroups, type I and type II. Despite catalysing the same reaction, the two groups are not structurally similar and do not share sequence homology, strongly suggesting convergent evolution. This suggestion is further supported if one compares the human with the mouse and rat ACOT gene families. To date, four human type I ACOTs have been identified which belong to the α/β-hydrolase fold enzyme superfamily. Type II ACOTs fall into the 'hot dog' fold superfamily. There are currently six human type II genes; however, two homologous proteins, thioesterase superfamily members 4 (THEM4) and 5 (THEM5) share common type II structural features and, in the case of THEM4, acyl-CoA thioesterase activity--suggesting that the family may be larger than previously realised. Although recent studies have greatly expanded the current understanding of these proteins and their physiological importance, there are a number of members whose functions are relatively unexplored and which warrant further investigation.