Cytosolic ACOTs hydrolyse MCFA-CoA, LCFA-CoA

Stable Identifier
R-HSA-5690043
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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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, Lehtiƶ, 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
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Title
acyl-CoA hydrolase activity of Cytosolic ACOTs, THEM4 [cytosol]
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