The Proline Cycle As a Potential Cancer Therapy Target,Biochemistry

当前位置： X-MOL 学术 › Biochemistry › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

The Proline Cycle As a Potential Cancer Therapy Target
Biochemistry ( IF 2.9 ) Pub Date : 2018-04-12 00:00:00 , DOI: 10.1021/acs.biochem.8b00215
John J Tanner , Sarah-Maria Fendt _{1,

2} , Donald F Becker ₃

Affiliation

Interest in how proline contributes to cancer biology is expanding because of the emerging role of a novel proline metabolic cycle in cancer cell survival, proliferation, and metastasis. Proline biosynthesis and degradation involve the shared intermediate Δ¹-pyrroline-5-carboxylate (P5C), which forms l-glutamate-γ-semialdehyde (GSAL) in a reversible non-enzymatic reaction. Proline is synthesized from glutamate or ornithine through GSAL/P5C, which is reduced to proline by P5C reductase (PYCR) in a NAD(P)H-dependent reaction. The degradation of proline occurs in the mitochondrion and involves two oxidative steps catalyzed by proline dehydrogenase (PRODH) and GSAL dehydrogenase (GSALDH). PRODH is a flavin-dependent enzyme that couples proline oxidation with reduction of membrane-bound quinone, while GSALDH catalyzes the NAD⁺-dependent oxidation of GSAL to glutamate. PRODH and PYCR form a metabolic relationship known as the proline–P5C cycle, a novel pathway that impacts cellular growth and death pathways. The proline–P5C cycle has been implicated in supporting ATP production, protein and nucleotide synthesis, anaplerosis, and redox homeostasis in cancer cells. This Perspective details the structures and reaction mechanisms of PRODH and PYCR and the role of the proline–P5C cycle in cancer metabolism. A major challenge in the field is to discover inhibitors that specifically target PRODH and PYCR isoforms for use as tools for studying proline metabolism and the functions of the proline–P5C cycle in cancer. These molecular probes could also serve as lead compounds in cancer drug discovery targeting the proline–P5C cycle.

中文翻译：

脯氨酸循环作为潜在的癌症治疗靶点

由于新型脯氨酸代谢循环在癌细胞存活、增殖和转移中的作用日益显现，人们对脯氨酸如何促进癌症生物学的兴趣日益浓厚。脯氨酸生物合成和降解涉及共享中间体 Δ ^{1 -}吡咯啉-5-羧酸酯 (P5C)，它在可逆的非酶促反应中形成l -谷氨酸-γ-半醛 (GSAL)。脯氨酸由谷氨酸或鸟氨酸通过 GSAL/P5C 合成，并在 NAD(P)H 依赖性反应中被 P5C 还原酶 (PYCR) 还原为脯氨酸。脯氨酸的降解发生在线粒体中，涉及由脯氨酸脱氢酶 (PRODH) 和 GSAL 脱氢酶 (GSALDH) 催化的两个氧化步骤。 PRODH 是一种黄素依赖性酶，可将脯氨酸氧化与膜结合醌的还原结合起来，而 GSALDH 则催化 GSAL 向谷氨酸的 NAD ⁺依赖性氧化。 PRODH 和 PYCR 形成一种称为脯氨酸-P5C 循环的代谢关系，这是一种影响细胞生长和死亡途径的新途径。脯氨酸-P5C 循环与支持癌细胞中的 ATP 产生、蛋白质和核苷酸合成、回补和氧化还原稳态有关。该观点详细介绍了 PRODH 和 PYCR 的结构和反应机制以及脯氨酸-P5C 循环在癌症代谢中的作用。该领域的一个主要挑战是发现专门针对 PRODH 和 PYCR 同工型的抑制剂，作为研究脯氨酸代谢和癌症中脯氨酸-P5C 循环功能的工具。这些分子探针还可以作为针对脯氨酸-P5C 循环的癌症药物发现的先导化合物。

更新日期：2018-04-12

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南