Lipid Transport Proteins as Pharmacological Target Molecules

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Cellular homeostasis results from the interplay of numerous regulated metabolic pathways, which may be up- or down-regulated in a pathological context. To pharmacologically influence the concentration of individual metabolites, the pacemaker enzyme (rate-limiting step) of a relevant metabolic pathway is usually inhibited. In the past, the rate-limiting enzymes of many metabolic pathways were determined from cell lysates using radiolabeled metabolites. However, topological issues were often overlooked. Biosynthesis of sphingolipids spans different compartments, requiring specific transport processes between them. Since lipids are by definition not water soluble, translocation between different membranes requires either a complex vesicular transport system or a lipid transporter in the form of a protein or enzyme. The transport processes of sphingolipid metabolites are essential components of sphingolipid biosynthesis. Recent studies show that these transport processes rather than biosynthetic enzymes determine the rate of sphingolipid biosynthesis. Therefore, transporters of sphingolipid metabolites are likely to be the more appropriate pharmacological targets.The proposed project focuses on different transport processes and their catalysts.