Evolutionary divergence and functions of the human acyl-CoA thioesterase gene ( ACOT ) family
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Evolutionary divergence and functions of the human acyl-CoA thioesterase gene (ACOT) family Chad Brocker,1 Christopher Carpenter,1 Daniel W. Nebert2* and Vasilis Vasiliou1* 1
Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA 2 Department of Environmental Health and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA *Correspondence to: E-mail: [email protected]; [email protected] Date received (in revised form): 25th July 2010
Abstract 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 a/b-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, acylCoA 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. Keywords: ACOT, acyl-CoA, thioesterase, hydrolase, gene family, evolution, human genome
Introduction Acyl-CoA thioesterases (ACOTs) represent a group of enzymes that metabolise acyl-CoA esters to their corresponding non-esterified fatty acid and coenzyme A (CoASH). In addition to ‘acyl-CoA thioesterases’, these enzymes also have been described as ‘acyl-CoA hydrolases’, ‘acyl-CoA thioester hydrolases’ and ‘deacylases’. The reaction catalysed by ACOT enzymes is very important during fatty acid metabolism. As such, ACOT genes are found throughout prokaryotic and eukaryotic organisms. In mammals, acyl-CoA
thioesterase expression is widespread and activity is detectable within many tissues and cell types. ACOT activity helps to regulate cellular pools, as well as proper ratios, of activated fatty acyl-CoAs (acyl-CoA esters), free fatty acids (non-esterified fatty acids) and CoASH. These enzymes are found within a number of subcellular locations, including peroxisomes, mitochon
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