Substrate Specificity Determinants in Cancer-related Solute Carrier Transporters

总结 细胞代谢的改变支持细胞的快速生长和增殖-癌症的关键标志。溶质 载体（SLC）转运蛋白是介导代谢物等溶质运动的膜蛋白 和跨膜药物，也可以在癌症代谢途径中协同发挥作用。为了考试- 例如，氨基酸转运蛋白LAT-1和ASCT 2在胶质瘤中高度上调，它们在胶质瘤中发挥关键作用。 为生长中的肿瘤细胞提供必需氨基酸，这些必需氨基酸被用作构建生物质的营养素， 信号分子来增强增殖。我们的主要目标是了解癌症机制，通过去- 在选定的癌症相关转运蛋白家族中， 综合实验和计算方法。 首先，我们将确定新的配体，包括内源性代谢物和处方药的三种癌症- 相关SLC转运蛋白（即，GLUT 1、ASCT 2和LAT-1），使用比较建模、虚拟筛选和 化学信息学方法，然后进行实验验证（由合作者进行）。结果 本研究将揭示转运蛋白的未知功能，并为研究转运蛋白的功能提供新的化学工具。 进一步发挥其功能。其次，我们将定义结构相关的底物特异性规则， 转运蛋白，使用预测的转运蛋白-配体复合物的结构比较方法和分析。 特异性决定因素将用于合理化和预测遗传变异对跨- 搬运工功能。第三，我们将开发合理设计用于转运的多药理学配体的方法- 在癌症代谢途径中的作用，并检查所发现的配体对癌症的抗增殖作用。 多形性胶质母细胞瘤（GBM）细胞系。我们将进一步确定转运蛋白及其配体的作用 在癌症中，通过化学相似性预测以前未知的蛋白质-小分子相互作用， 方法.最后，根据我们的研究结果，我们将合理化代谢之间的差异和共性， 正常和转化细胞的途径。 表征关键膜转运蛋白和它们的小分子配体之间的相互作用将有助于 这是对我们理解溶质如何穿过细胞膜和细胞器的贡献， 这对生命的许多过程都至关重要。此外，描述蛋白质中的底物特异性， 癌症代谢的重要性将提供化学工具，使我们能够了解如何扰乱 代谢网络与癌症有关，并发现新的线索，设计小分子与光学， 对新的癌症药物靶点的混合亲和力。最终，我们研究中获得的结果可能是一个信号- 这是设计抗癌药物的重要一步

SUMMARY Alterations in cell metabolism support rapid growth and proliferation of cells - key hallmarks of cancer. Solute Carrier (SLC) transporters are membrane proteins that mediate the movement of solutes such as metabolites and drugs across membranes, and can also function cooperatively in cancer metabolism pathways. For exam- ple, the amino acid transporters LAT-1 and ASCT2 are highly upregulated in glioma, where they play a key role in supplying growing tumor cells with essential amino acids that are used as nutrients to build biomass and signaling molecules to enhance proliferation. Our broad goal is to understand cancer mechanisms, by de- scribing the substrate specificity determinants in selected cancer-related transporter families via an integrated experimental and computational approach. First, we will identify novel ligands including endogenous metabolites and prescription drugs for three cancer- related SLC transporters (i.e., GLUT1, ASCT2, and LAT-1), using comparative modeling, virtual screening, and chemoinformatics methods, followed by experimental validation (performed by collaborators). The results obtained in this Aim will reveal unknown functions of the transporters and provide novel chemical tools to further characterize their functions. Second, we will define rules for substrate specificity of structurally related transporters, using structural comparison methods and analysis of the predicted transporter-ligand complexes. The specificity determinants will be used to rationalize and predict the impact of genetic variation on trans- porter function. Third, we will develop methods to rationally design polypharmacological ligands for transport- ers in cancer-metabolism pathways and examine the anti-proliferative effect of the discovered ligands on glioblastoma multiforme (GBM) cell lines. We will further establish the role of the transporters and their ligands in cancer, by predicting previously unknown protein-small molecule interactions via chemical similarity methods. Finally, based on our results, we will rationalize differences and commonalities between metabolic pathways of normal and transformed cells. Characterizing the interactions between key membrane transporters and their small molecule ligands will con- tribute to our understanding of how solutes get transported across the membranes of cells and organelles, which is essential for many of life's processes. Furthermore, describing substrate specificity in proteins im- portant for cancer metabolism will provide chemical tools that would allow us to understand how perturbed metabolic networks are related to cancer and to discover novel leads for designing small molecules with opti- mized affinities against novel cancer drug targets. Ultimately, the results obtained in our studies can be a sig- nificant step toward designing cancer drugs.