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Human Acyl-Coenzyme A Thioesterase 4

PDB Code 3K2I Target Class Lipid signalling Target ACOT4 Alias ACOT4, PTE-Ib, PTE1B, PTE2B Disease Area/Function metabolism Date Deposited Sep 30 2009 Authors Siponen, M.I., Arrowsmith, C.H. Berglund, H. Bountra, C. Collins, R. Edwards, A.M. Flodin, S. Flores, A. Graslund, S. Hammarstrom, M. Johansson, A. Johansson, I. Kallas, A. Karlberg, T. Kraulis, P. Kotenyova, T. Kotzsch, A. Markova, N. Moche, M. Nielsen, T.K. Nordlund, P. Nyman, T. Persson, C. Roos, A.K. Schutz, P. Svensson, L. Thorsell, A.G. Tresaugues, L. Van Den Berg, S. Wahlberg, E. Weigelt, J. Welin, M. Wisniewska, M. Schuler, H.

About this structure

Acyl-coenzyme A thioesterases are a group of enzymes that catalyze the hydrolysis of acyl-CoAs to the free fatty acid and coenzyme A (CoASH), providing the potential to regulate intracellular levels of acyl-CoAs (refs 1-2), free fatty acids and CoASH. This family of enzymes is subdivided into 2 classes; Type I and Type II ACOTs. While Type II ACOTs are common to most living organisms, Type I ACOTs have only been found in animals. Four Type I ACOTs are encoded in the human genome (ACOT1, ACOT2, ACOT4, and ACOT6) and have been found in the cytosol, peroxisomes and mitochondria (ref 2). ACOT4 is the only peroxisomal Type I ACOT, the other confirmed peroxisomal enzyme being ACOT8 (a Type II enzyme) (ref 3).

Structural characterization of ACOT4 revealed the same overall structural characteristics as the recently determined Type I mitochondrial enzyme ACOT2 (PDB ID= 3HLK) (ref 4). The structure consists of a N-terminal and a C-terminal domain, with the N-terminal containing a seven-stranded β-sandwich and the C-terminal domain having the characteristic α/β hydrolase fold of this family’s Type I enzymes. The catalytic triad of the enzyme consisting of Ser232, Asp328, and His360 is located in the in the C-terminal domain at the edge of a large cavity extending between both domains.

References

  1. A revised nomenclature for mammalian acyl-CoA thioesterases/hydrolases. (2005) Hunt MC, Yamada J, Maltais LJ, Wright MW, Podesta EJ, Alexson SE. J Lipid Res. 46(9):2029-32. PubMed 16103133
  2. Novel functions of acyl-CoA thioesterases and acyltransferases as auxiliary enzymes in peroxisomal lipid metabolism. (2008) Hunt MC, Alexson SE. Prog Lipid Res. 47(6):405-21 PubMed 18538142
  3. Analysis of the mouse and human acyl-CoA thioesterase (ACOT) gene clusters shows that convergent, functional evolution results in a reduced number of human peroxisomal ACOTs. (2006) Hunt MC, Rautanen A, Westin MA, Svensson LT, Alexson SE. FASEB J. 20(11):1855-64 PubMed 16940157
  4. Crystal structure of human mitochondrial acyl-CoA thioesterase (ACOT2). (2009) Mandel CR, Tweel B, Tong L. Biochem Biophys Res Commun. 385(4):630-3 PubMed 19497300