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  • Carnitine acetyltransferase CrAT transesterifies short


    Carnitine acetyltransferase (CrAT) transesterifies short-chain acyl-CoAs, and is located both in mitochondria and peroxisomes. In yeasts and mammals this protein is the product of a single gene [20,21] and the sorting to different organelles is evolutionary conserved, although the mechanism of differential sorting is quite different [[21], [22], [23]] (reviewed by van der Leij et al. [6]). The yeast Sc-CrAT is expressed by Sc-CAT2 (Fig. 1) [24]. However, two more genes responsible for acetyltransferase activity have been described [25,26]. These transferases, Sc-YAT1 and Sc-YAT2, are located in the cytosol (Fig. 1). Apart from these three acetyltransferases, of which orthologues exist in other fungi, no other fungal carnitine or choline acyltransferases have been described. Finally, choline acetyltransferase (ChAT) is located in the nucleus and cytoplasm of cholinergic neurons of the central and peripheral nervous systems [27,28]. This is the only transferase within this family that transfers acetyl-CoAs to choline instead of carnitine, which results in the formation of the neurotransmitter PD 0332991 (the function of acetylcholine in the central nervous system is reviewed by Oda et al. [29]). Cholinergic neurons are involved in the regulation of memory, learning, motor function and in the control of several visceral functions [[30], [31], [32]]. Low ChAT activity has been associated with a number of neurodegenerative diseases [29]. Two isoforms of ChAT exist. Next to the common form of ChAT (cChAT), a second isoform has been discovered (pChAT), which is mainly expressed in the peripheral nerve tissue [33]. In the cell, cChAT is mainly present in the cytosol, but can also bind to the plasma membrane and localize to the nucleus, whereas pChAT is only present in the cytosol [34]. Both isoforms are encoded by the same sequence, but the isoform cChAT (640 amino acids) results from conventional splicing, whereas pChAT (430 amino acids) results from alternative splicing by exon skipping (exon 6–9). In mammals, the nine amino acid residues necessary for binding choline and acetyl-CoA are present in both isoforms, but in pChAT the amino acid residue histidine involved in the catalytic centre is lost during exon skipping [33,34]. However, both isoforms have ChAT activity, that of pChAT being lower than cChAT [35]. Since acetylcholine is also involved in non-neuronal functions [34], it needs to be clarified whether and to what extend pChAT is involved in cholinergic neurotransmission. The expression of pChAT is conserved during evolution, since it is widely spread among invertebrate and vertebrate phyla [33,34,36]. This stresses the importance of the cholinergic system in peripheral tissues. The substrates carnitine (L-3-hydroxy-4-N,N,N-trimethylaminobutyrate, C7H15NO3) and choline (2-hydroxy-N,N,N-trimethylethaneaminium, C5H14NO) are quite similar (Fig. 2). The major difference being the presence of a carboxyl unit in carnitine, and hence a quaternary carbon in position 3. Of the stereoisomers that are possible, the L-enantiomer of carnitine is the biologically active one. Although carnitine- and choline acyltransferases are not known for prokaryotes, both the substrates carnitine and choline are present in bacteria where they serve as osmo-, thermo- and cryoprotectants, and also can be metabolized as nutrient sources (reviewed by Meadows and Wargo [37]). Choline can be synthesized by bacteria, but this has never been demonstrated for carnitine [37,38]. The aim of this paper is to get a deeper insight in the origin and evolution of the carnitine/choline acyltransferase family in order to better understand form and function of these physiologically important enzymes. The focus will be on the analysis of (a) the Sc-YAT1-related origin and evolution of CPT2 compared to the other members of the family, which are Sc-CAT2-related; (b) the phylogenetic position of ChAT within this family; (c) the finding of several CPT1-like genes in Caenorhabditis elegans; and (d) the peculiar evolution of mammalian CPT1C. Evidence will be provided that (a) during evolution the animal proteins CPT2 and CPT1 switched their location from the mitochondrial matrix to the mitochondrial outer membrane and vice versa; (b) ChAT is most closely related to CrAT and shows higher protein conservation throughout evolution than the long chain acyltransferases; (c) five extra genes in C. elegans exist with characteristic features resembling CPT1; and (d) a particular long branch leading to mammalian CPT1C suggests either strong positive or relaxed evolution on this node and indicates elevated evolution of CPT1C.