| Structural highlights
Function
[THEM4_HUMAN] Has acyl-CoA thioesterase activity towards medium and long-chain (C14 to C18) fatty acyl-CoA substrates, and probably plays an role in mitochondrial fatty acid metabolism. Plays a role in the apoptotic process, possibly via its regulation of AKT1 activity. According to PubMed:11598301, inhibits AKT1 phosphorylation and activity. According to PubMed:17615157, enhances AKT1 activity by favoring its phosphorylation and translocation to plasma membrane.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Acyl coenzyme A (acyl-CoA) thioesterases hydrolyze thioester bonds in acyl-CoA metabolites. The majority of mammalian thioesterases are alpha/beta-hydrolases and have been studied extensively. A second class of Hotdog-fold enzymes has been less well described. Here, we present a structural and functional analysis of a new mammalian mitochondrial thioesterase, Them5. Them5 and its paralog, Them4, adopt the classical Hotdog-fold structure and form homodimers in crystals. In vitro, Them5 shows strong thioesterase activity with long-chain acyl-CoAs. Loss of Them5 specifically alters the remodeling process of the mitochondrial phospholipid cardiolipin. Them5(-/-) mice show deregulation of lipid metabolism and the development of fatty liver, exacerbated by a high-fat diet. Consequently, mitochondrial morphology is affected, and functions such as respiration and beta-oxidation are impaired. The novel mitochondrial acyl-CoA thioesterase Them5 has a critical and specific role in the cardiolipin remodeling process, connecting it to the development of fatty liver and related conditions.
Acyl coenzyme a thioesterase them5/acot15 is involved in cardiolipin remodeling and Fatty liver development.,Zhuravleva E, Gut H, Hynx D, Marcellin D, Bleck CK, Genoud C, Cron P, Keusch JJ, Dummler B, Esposti MD, Hemmings BA Mol Cell Biol. 2012 Jul;32(14):2685-97. Epub 2012 May 14. PMID:22586271[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Maira SM, Galetic I, Brazil DP, Kaech S, Ingley E, Thelen M, Hemmings BA. Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane. Science. 2001 Oct 12;294(5541):374-80. PMID:11598301 doi:http://dx.doi.org/10.1126/science.1062030
- ↑ Ono H, Sakoda H, Fujishiro M, Anai M, Kushiyama A, Fukushima Y, Katagiri H, Ogihara T, Oka Y, Kamata H, Horike N, Uchijima Y, Kurihara H, Asano T. Carboxy-terminal modulator protein induces Akt phosphorylation and activation, thereby enhancing antiapoptotic, glycogen synthetic, and glucose uptake pathways. Am J Physiol Cell Physiol. 2007 Nov;293(5):C1576-85. Epub 2007 Jul 5. PMID:17615157 doi:http://dx.doi.org/10.1152/ajpcell.00570.2006
- ↑ Zhao H, Martin BM, Bisoffi M, Dunaway-Mariano D. The Akt C-terminal modulator protein is an acyl-CoA thioesterase of the Hotdog-Fold family. Biochemistry. 2009 Jun 23;48(24):5507-9. doi: 10.1021/bi900710w. PMID:19453107 doi:http://dx.doi.org/10.1021/bi900710w
- ↑ Parcellier A, Tintignac LA, Zhuravleva E, Cron P, Schenk S, Bozulic L, Hemmings BA. Carboxy-Terminal Modulator Protein (CTMP) is a mitochondrial protein that sensitizes cells to apoptosis. Cell Signal. 2009 Apr;21(4):639-50. doi: 10.1016/j.cellsig.2009.01.016. Epub 2009, Jan 8. PMID:19168129 doi:http://dx.doi.org/10.1016/j.cellsig.2009.01.016
- ↑ Parcellier A, Tintignac LA, Zhuravleva E, Dummler B, Brazil DP, Hynx D, Cron P, Schenk S, Olivieri V, Hemmings BA. The Carboxy-Terminal Modulator Protein (CTMP) regulates mitochondrial dynamics. PLoS One. 2009;4(5):e5471. doi: 10.1371/journal.pone.0005471. Epub 2009 May 7. PMID:19421406 doi:http://dx.doi.org/10.1371/journal.pone.0005471
- ↑ Zhao H, Lim K, Choudry A, Latham JA, Pathak MC, Dominguez D, Luo L, Herzberg O, Dunaway-Mariano D. Correlation of Structure and Function in the Human Hotdog-fold Enzyme hTHEM4. Biochemistry. 2012 Aug 21;51(33):6490-2. Epub 2012 Aug 9. PMID:22871024 doi:10.1021/bi300968n
- ↑ Zhuravleva E, Gut H, Hynx D, Marcellin D, Bleck CK, Genoud C, Cron P, Keusch JJ, Dummler B, Esposti MD, Hemmings BA. Acyl coenzyme a thioesterase them5/acot15 is involved in cardiolipin remodeling and Fatty liver development. Mol Cell Biol. 2012 Jul;32(14):2685-97. Epub 2012 May 14. PMID:22586271 doi:10.1128/MCB.00312-12
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