Investigating the Proline Cycle as a Potential Cancer Therapy Target

修改后的项目摘要/摘要 脯氨酸生物合成和催化剂共有共同的中间体Δ1-吡咯啉-5-羧酸（P5 C），并且脯氨酸和P5 C的酶促相互转化被称为“脯氨酸循环”。催化剂的第一种酶脯氨酸脱氢酶（PRODH）催化脯氨酸向P5 C的FAD依赖性氧化，而生物合成的最后一种酶P5 C还原酶（PYCR 1）催化P5 C向脯氨酸的NAD（P）H依赖性还原。PRODH和PYCR 1共同形成脯氨酸循环，这是一种新的途径，可以影响电子从细胞质中的NAD（P）H净转移到线粒体中ATP的合成。最近的研究表明，转移性乳腺癌细胞改变其代谢，利用脯氨酸循环产生能量，这表明PRODH和PYCR 1是潜在的癌症治疗靶点的假设。这一想法得到了体内数据的支持，体内数据显示脯氨酸类似物对PRODH的抑制损害了乳腺癌原位小鼠模型中肺转移的形成。这些结果促使这个短期项目使用集中和高通量筛选方法开发针对PRODH和PYCR 1的化学探针。待开发的探针组将使未来的研究能够机械地剖析脯氨酸代谢在癌症进展中的作用，并评估脯氨酸循环作为癌症治疗靶点的易处理性。我们希望这些知识将导致长期的新的癌症治疗策略。

Modified Project Summary/Abstract Proline biosynthesis and catabolism share a common intermediate, Δ1-pyrroline-5-carboxylate (P5C), and the enzymatic interconversion of proline and P5C is known as the “proline cycle”. The first enzyme of catabolism, proline dehydrogenase (PRODH), catalyzes the FAD-dependent oxidation of proline to P5C, while the last enzyme of biosynthesis, P5C reductase (PYCR1), catalyzes the NAD(P)H-dependent reduction of P5C to proline. Together, PRODH and PYCR1 form the proline cycle, a novel pathway that effects the net transfer of electrons from NAD(P)H in the cytoplasm to the synthesis of ATP in mitochondria. Recent studies have shown that metastatic breast cancer cells alter their metabolism to harness the proline cycle for energy production, suggesting the hypothesis that PRODH and PYCR1 are potential cancer therapy targets. This idea is supported by in vivo data showing that the inhibition of PRODH by a proline analog impairs the formation of lung metastases in orthotopic mouse models of breast cancer. These results motivate this short-term project to develop chemical probes against PRODH and PYCR1 using focused and high-throughput screening approaches. The set of probes to be developed will enable future studies to mechanistically dissect the role of proline metabolism in cancer progression and assess the tractability of the proline cycle as a cancer therapy target. We expect that this knowledge will result in the long-term in new therapeutic strategies against cancer.