Carnitine/choline acyltransferases play diverse roles in energy metabolism and neuronal signalling. Our knowledge of their evolutionary relationships, important for functional understanding, is incomplete. Therefore, we aimed to determine the evolutionary relationships of these eukaryotic transferases. We performed extensivephylogenetic and intron position analyses. We found that mammalian intramitochondrial CPT2 is most closely related to cytosolic yeast carnitine transferases (Sc-YAT1 and 2), whereas the other members of the family are related to intraorganellar yeast Sc-CAT2. Therefore, the cytosolically active CPT1 more closely resembles intramitochondrial ancestors than CPT2. The choline acetyltransferase is closely related to carnitine acetyltransferase and shows lower evolutionary rates than long chain acyltransferases. In the CPT1 family several duplications occurred during animal radiation, leading to the isoforms CPT1A, CPT1B and CPT1C. In addition, we found five CPT1-like genes in Caenorhabditis elegans that strongly group to the CPT1 family. The long branch leading to mammalian brain isoform CPT1C suggests that either strong positive or relaxed evolution has taken place on this node. The presented evolutionary delineation of carnitine/choline acyltransferases adds to current knowledge on their functions and provides tangible leads for further experimental research.
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From PLoS website: In general, dietary antigens are tolerated by the gut associated immune system. Impairment of this so-called oral tolerance is a serious health risk. We have previously shown that activation of the ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) by the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects both oral tolerance and food allergy. In this study, we determine whether a common plant-derived, dietary AhR-ligand modulates oral tolerance as well. We therefore fed mice with indole-3-carbinole (I3C), an AhR ligand that is abundant in cruciferous plants. We show that several I3C metabolites were detectable in the serum after feeding, including the high-affinity ligand 3,3´-diindolylmethane (DIM). I3C feeding robustly induced the AhR-target gene CYP4501A1 in the intestine; I3C feeding also induced the aldh1 gene, whose product catalyzes the formation of retinoic acid (RA), an inducer of regulatory T cells. We then measured parameters indicating oral tolerance and severity of peanut-induced food allergy. In contrast to the tolerance-breaking effect of TCDD, feeding mice with chow containing 2 g/kg I3C lowered the serum anti-ovalbumin IgG1 response in an experimental oral tolerance protocol. Moreover, I3C feeding attenuated symptoms of peanut allergy. In conclusion, the dietary compound I3C can positively influence a vital immune function of the gut.
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Background: G-protein coupled receptors (GPCRs) are involved in many different physiological processes and their function can be modulated by small molecules which bind in the transmembrane (TM) domain. Because of their structural and sequence conservation, the TM domains are often used in bioinformatics approaches to first create a multiple sequence alignment (MSA) and subsequently identify ligand binding positions. So far methods have been developed to predict the common ligand binding residue positions for class A GPCRs.Results: Here we present 1) ss-TEA, a method to identify specific ligand binding residue positions for any receptor, predicated on high quality sequence information. 2) The largest MSA of class A non olfactory GPCRs in the public domain consisting of 13324 sequences covering most of the species homologues of the human set of GPCRs. A set of ligand binding residue positions extracted from literature of 10 different receptors shows that our method has the best ligand binding residue prediction for 9 of these 10 receptors compared to another state-of-the-art method.Conclusions: The combination of the large multi species alignment and the newly introduced residue selection method ss-TEA can be used to rapidly identify subfamily specific ligand binding residues. This approach can aid the design of site directed mutagenesis experiments, explain receptor function and improve modelling. The method is also available online via GPCRDB at http://www.gpcr.org/7tm/. © 2011 Sanders et al; licensee BioMed Central Ltd.
