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1. The proton-coupled di- and tri-peptide transporters (PepTs)
PepT1 is now well accepted as the major route by which protein digestion products enter the body via the intestine, and are retained by the kidney (along with PepT2). PepT1 is also considered to be an excellent route for drug delivery, as it accepts a wide range of structurally diverse natural substrates, in addition to a number of classes of pharmaceutical compounds such as the β-lactam antibiotics, angiotensin-converting enzyme (ACE) inhibitors, antivirals (eg valacyclovir) and anticancer agents such as bestatin. Using expression of mammalian PepT1 in Xenopus laevis oocytes as a model system, we have been able to identify essential residues in the functioning of the protein, that the protein is a multimer, and to characterise the binding site in terms of a substrate template model.
2. The proton-coupled amino acid transporters (PATs)
Human PAT1 and PAT2 are well characterized as proton-coupled amino acid transporters, with glycine, alanine and proline as their main substrates. We have recently characterized human PAT4 as a non-proton coupled amino acid transporter with an unusually high affinity. I am also interested in PATs as nutrient receptors (“transceptors”), and in collaboration with Drs Boyd, Wilson and Goberdhan (Oxford University) we identified a Drosophila PAT homologue protein, PATH, which is also an extremely high affinity, low capacity amino acid transporter, and that is involved in cell growth and development via the target of rapamycin (TOR) intracellular signalling pathway. Thus PATs may play an important role in diseases such as diabetes and cancer. Further studies are ongoing into whether the human PAT4 behaves similarly, and into the function of the ‘orphan’ human transporter PAT3.
3. The monocarboxylate transporter (MCT) family
There are 14 members of the human MCT family, of which the first characterized were MCTs 1 to 4, which are proton-coupled lactate / pyruvate transporters. Other members to be later characterized were MCT8 (thyroid hormone transporter) and TAT1 (‘MCT10’, aromatic amino acid transporter). We have been investigating the role of ‘orphan’ MCTs, one of which we believe is involved in the mechanism by which cancer cells avoid eliciting an immune response, and another (MCT9) which we have demonstrated as an efflux system for carnitine following its linking through a metabolomic / genome screening approach.