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Human Acyl-coenzyme A thioesterase 12

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PDB Code 3B7K Target Class Lipid signalling Target ACOT12 Alias ACOT12, Cach, CACH-1, MGC105114, STARD15, THEAL Disease Area/Function Date Deposited Oct 31 2007 Authors LEHTIO, L., BUSAM, R., ARROWSMITH, C., COLLINS, R., DAHLGREN, L.G., EDWARDS, A., FLODIN, S., FLORES, A., GRASLUND, S., HAMMARSTROM, M., HALLBERG, B.M., HERMAN, M.D., JOHANSSON, I., KALLAS, A., KARLBERG, T., KOTENYOVA, T., MOCHE, M., NORDLUND, P., NYMAN, T., PERSSON, C., SAGEMARK, J., SUNDSTROM, M., THORSELL, A.G., TRESAUGUES, L., VAN DEN BERG, S., WEIGELT, J., WELIN, M., BERGLUND, H.,

About this structure

Acyl-CoA thioesterases (ACOT) are enzymes that hydrolyze acyl-CoAs to free fatty acid and coenzyme A . It is believed that ACOTs regulate intracellular levels of these molecules. The cytosolic or extra-mitochondrial acyl-CoA thioesterase 12 (ACOT12, CACH, or STARD15 [1]) hydrolyzes acetyl-CoA to acetate and CoA. Recent studies indicate that ACOT12 plays a vital role in fat metabolism by supplying cytosolic free CoA necessary for both fatty acid synthesis and oxidation [2].

ACOT12 was first detected in rat liver [3]. A high level of sequence similarity exists between rodents and humans. In addition they share a typical housekeeping promoter, which implies that the protein is generally essential. Despite the housekeeping promoter, tissue specific expression might be controlled by recently identified cis-acting elements [2].

ACOT12 consists of 555 amino acids. The protein has three domains consisting of two thioesterase domains in tandem and a C-terminal START domain. We have determined the structure of the thioesterase domains in complex with CoA to 2.7 Å. The product, CoA, is bound between the two thioesterase domains of the same polypeptide. Both domains display the expected hotdog fold [4] of other thioesterase domains but is unique in that the model describes two domains in tandem. They are tightly packed in the crystal as arranged as a trimer of dimers, which Is likely the the biologically relevant oligomer.

References

  1. Hunt, M.C., Yamada, J., Maltais, L.J., Wright, M.W., Podesta, EJ.. & Alexson, S.E. (2006) A revised nomenclature for mammalian acyl-CoA thioesterases/hydrolases. J. Lipid Res. 46:2029-32
  2. Suematsu, N. & Isohashi, F. (2006) Molecular cloning and functional expression of human cytosolic acetyl-CoA hydrolase. Acta Biochim. Pol. 53:553-61.
  3. Prass, R.L., Isohashi, F. & Utter, M.F. (1980) Purification and characterization of an extramitochondrial acetyl coenzyme A hydrolase from rat liver. J. Biol. Chem. 255:5215-23.
  4. Dillon, S.C. & Bateman, A. (2004) The Hotdog fold: wrapping up a superfamily of thioesterases and dehydratases. BMC Bioinformatics. 5:109.