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  • Introduction The carnitine choline acyltransferase family is


    Introduction The carnitine/choline acyltransferase family is a family of enzymes that play diverse roles, ranging from (the regulation of) CP-809101 hydrochloride and fuel metabolism in mitochondria and peroxisomes to the generation of the neurotransmitter acetylcholine. In mammals, this family consists of seven transferases that catalyse the reversible transfer of acyl moieties from acyl-CoA (short-chain acyl-CoAs like acetyl-CoA; medium-chain acyl-CoAs like octanoyl-CoA, and long-chain acyl-CoAs like palmitoyl-CoA) to carnitine or choline [[1], [2], [3], [4], [5]]. A common effect of this catalytic capacity is the buffering of cellular levels of free coenzyme A (HSCoA). The transferases are different from each other regarding their physiological function, location, kinetics and substrate specificity, but have a presumed common ancestral gene from which all genes encoding these proteins have evolved [3,6] (for the carnitine transferases this has been reviewed, choline-carnitine transferase relations were also known by then [3]). These genes are only present in eukaryotes and have no prokaryotic equivalent with carnitine- or choline transferase activity, however, distant relations are known to exist between this eukaryotic family and bacterial enzymes like chloramphenicol acetyltransferase [7]. The carnitine palmitoyltransferases (CPT) 1 and 2 are traditionally known to be located at the outer and inner mitochondrial membrane, respectively, where they transesterify medium- and long chain acyl-CoAs (Fig. 1). Together with a carnitine/acylcarnitine transporter, CPT1 and 2 facilitate the net transport of fatty acyl-CoA across the mitochondrial inner membrane [2]. This carnitine shuttle enables the oxidation of fatty acids within the mitochondrial matrix. The mammalian expression of CPT2 is ubiquitous [2] and tissue specificity of the carnitine shuttle is hence provided by tissue specific expression of CPT1. Although CPT1 and CPT2 must have co-evolved to establish carnitine shuttling, the genes encoding these enzymes are the most distantly related of the carnitine and choline acyl transferases [6]. In fact, a number of databases, including Ensembl, consider CPT2 and its orthologues as a separate gene set compared to the rest of the carnitine and choline acyltransferases. In mammals, three different CPT1 protein isoforms exist, namely CPT1A (liver-type), CPT1B (muscle-type) and CPT1C (brain-type) [8]. The CPT1 isoforms are encoded by three different genes on different chromosomal locations. Based on compiled physical [7], biochemical [9] and cytological [10] evidence, it is thought that CPT1 has a N-terminal domain consisting of two transmembrane regions and a short connecting loop, and a large catalytic C-terminal domain containing both the catalytic site and the malonyl-CoA binding site, as malonyl-CoA inhibits the CPT1 enzymes [11]. Both the N-terminus and the C-terminal domain of CPT1 enzymes are projected into the cytosol [12,13]. Because of the homology, it is thought that the proposed tertiary structure applies to all three isoforms of CPT1. However, unlike CPT1A and CPT1B, which are localized in mitochondria, CPT1C is mainly localized in the ER [8,14]. Whereas CPT1A and CPT1B control the rate of mitochondrial fatty acid oxidation, it is likely that CPT1C has another physiological function. It is hypothesized that ghrelin induces CPT1C to synthesize hypothalamic ceramides, enhancing the expression of orexigenic neuropeptides leading to food intake [15]. In addition, CPT1C is involved in spatial learning and motor function, and the regulation of the peripheral metabolism (reviewed in Casals et al. [16]). Recently, Lopes-Marques et al. [17] reassessed the evolutionary relationships of the CPT1 genes and found that CPT1C is not only present in mammals, but also in other phyla like teleosts, amphibians and coelacanth. Not only CPT1 and CPT2, but also carnitine octanoyltransferase (CrOT) transesterifies medium- and long-chain acyl-CoAs, although this enzyme is located in peroxisomes rather than mitochondria. Its function is to enable the transport of octanoyl-CoA derived from the ω-oxidation of very-long-chain and branched-chain fatty acids [1,18,19]. Octanoylcarnitine is able to be shuttled into mitochondria for further oxidation.