Lipid Transport Proteins as Pharmacological Target Molecules

细胞内稳态是多种调节代谢途径相互作用的结果，在病理背景下，这些代谢途径可能上调或下调。为了从药物上影响单个代谢物的浓度，相关代谢途径的起搏酶(限速步骤)通常被抑制。在过去，许多代谢途径的限速酶是用放射性标记的代谢物从细胞裂解物中确定的。然而，拓扑问题往往被忽视。鞘脂的生物合成跨越不同的隔间，需要在它们之间进行特定的运输过程。由于脂类在定义上是不溶于水的，不同膜之间的转运需要复杂的囊泡运输系统或蛋白质或酶形式的脂类转运体。鞘脂代谢产物的转运过程是鞘脂生物合成的重要组成部分。最近的研究表明，这些运输过程而不是生物合成酶决定了鞘脂生物合成的速度。因此，鞘磷脂代谢物的转运体可能是更合适的药理靶点。拟议的项目侧重于不同的转运体过程及其催化剂。

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.