Reactome | Cytosolic ACOTs hydrolyse MCFA-CoA, LCFA-CoA

Cytosolic ACOTs hydrolyse MCFA-CoA, LCFA-CoA

Stable Identifier

R-HSA-5690043

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol

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Cytosolic ACOTs hydrolyse MCFA-CoA, LCFA-CoA

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The maintenance/regulation of cellular levels of free fatty acids and fatty acyl-CoAs (the activated form of free fatty acids) is extremely important, as imbalances in lipid metabolism can have serious consequences for human health. Free fatty acids can act as detergents to disrupt membranes so their generation is normally tightly regulated to states where they will be rapidly consumed or sequestered. Acyl-coenzyme A thioesterases (ACOTs) hydrolyse the thioester bond in medium- to long-chain fatty acyl-CoAs (of C12-C18 lengths) (MCFA-CoA, LCFA-CoA) to their free fatty acids (MCFA, LCFA) (Cohen 2013, Hunt et al. 2012, Kirkby et al. 2010). ACOTs that function in the cytosol are ACOT1 (Hunt et al. 2005), ACOT11 (Adams et al. 2001), ACOT12 trimer (Swarbrick et al. 2014), ACOT13 tetramer (Cao et al. 2009, Cheng et al. 2006), ACOT7 hexamer (Hunt et al. 2005b) and ACOT7L dimer (Jiang et al. 2006).

Recent mouse studies reveals a key regulatory role for PCTP in lipid and glucose metabolism. Phosphatidylcholine transfer protein (PCTP aka STARD2) is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain superfamily, a functionally diverse group of proteins that share a unique structural motif for binding lipids. PCTP appears to limit access of fatty acids to mitochondria by binding to (Ersoy et al. 2013) and stimulating the activity of acyl-coenzyme A thioesterase 13 (ACOT13, aka Acyl-CoA thioesterase 13, THEM2), an enzyme that catalyses the hydrolysis of acyl-CoAs to their free fatty acids (Kawano et al. 2014). Ultimately, insulin signaling is downregulated (Kang et al. 2010).

Literature References

PubMed ID	Title	Journal	Year
23901139	Phosphatidylcholine transfer protein interacts with thioesterase superfamily member 2 to attenuate insulin signaling Ersoy, BA, Tarun, A, D'Aquino, K, Hancer, NJ, Ukomadu, C, White, MF, Michel, T, Manning, BD, Cohen, DE	Sci Signal	2013
16423998	A functional variant in the transcriptional regulatory region of gene LOC344967 cosegregates with disease phenotype in familial nasopharyngeal carcinoma Jiang, RC, Qin, HD, Zeng, MS, Huang, W, Feng, BJ, Zhang, F, Chen, HK, Jia, WH, Chen, LZ, Feng, QS, Zhang, RH, Yu, XJ, Zheng, MZ, Zeng, YX	Cancer Res.	2006
16934754	Crystal structure of human thioesterase superfamily member 2 Cheng, Z, Song, F, Shan, X, Wei, Z, Wang, Y, Dunaway-Mariano, D, Gong, W	Biochem. Biophys. Res. Commun.	2006
11696000	BFIT, a unique acyl-CoA thioesterase induced in thermogenic brown adipose tissue: cloning, organization of the human gene and assessment of a potential link to obesity Adams, SH, Chui, C, Schilbach, SL, Yu, XX, Goddard, AD, Grimaldi, JC, Lee, J, Dowd, P, Colman, S, Lewin, DA	Biochem. J.	2001
19170545	The mechanisms of human hotdog-fold thioesterase 2 (hTHEM2) substrate recognition and catalysis illuminated by a structure and function based analysis Cao, J, Xu, H, Zhao, H, Gong, W, Dunaway-Mariano, D	Biochemistry	2009
22465940	The emerging role of acyl-CoA thioesterases and acyltransferases in regulating peroxisomal lipid metabolism Hunt, MC, Siponen, MI, Alexson, SE	Biochim. Biophys. Acta	2012
23700546	New players on the metabolic stage: How do you like Them Acots? Cohen, DE	Adipocyte	2013
24732803	Thioesterase superfamily member 2 (Them2) and phosphatidylcholine transfer protein (PC-TP) interact to promote fatty acid oxidation and control glucose utilization Kawano, Y, Ersoy, BA, Li, Y, Nishiumi, S, Yoshida, M, Cohen, DE	Mol. Cell. Biol.	2014
25002576	Structural basis for regulation of the human acetyl-CoA thioesterase 12 and interactions with the steroidogenic acute regulatory protein-related lipid transfer (START) domain Swarbrick, CM, Roman, N, Cowieson, N, Patterson, EI, Nanson, J, Siponen, MI, Berglund, H, Lehtiö, L, Forwood, JK	J. Biol. Chem.	2014
15638818	Identification of fatty acid oxidation disorder patients with lowered acyl-CoA thioesterase activity in human skin fibroblasts Hunt, MC, Ruiter, J, Mooyer, P, van Roermond, CW, Ofman, R, Ijlst, L, Wanders, RJ	Eur. J. Clin. Invest.	2005
20470824	Functional and structural properties of mammalian acyl-coenzyme A thioesterases Kirkby, B, Roman, N, Kobe, B, Kellie, S, Forwood, JK	Prog. Lipid Res.	2010
16940157	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 Hunt, MC, Rautanen, A, Westin, MA, Svensson, LT, Alexson, SE	FASEB J.	2006
20338778	PC-TP/StARD2: Of membranes and metabolism Kang, HW, Wei, J, Cohen, DE	Trends Endocrinol. Metab.	2010