4ae7
Crystal structure of human THEM5
Structural highlights
FunctionTHEM5_HUMAN Has acyl-CoA thioesterase activity towards long-chain (C16 and C18) fatty acyl-CoA substrates, with a preference for linoleyl-CoA and other unsaturated long-chain fatty acid-CoA esters. Plays an important role in mitochondrial fatty acid metabolism, and in remodeling of the mitochondrial lipid cardiolipin. Required for normal mitochondrial function.[1] Publication Abstract from PubMedAcyl 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[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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