The Proline Cycle As a Potential Cancer Therapy Target.
The Proline Cycle As a Potential Cancer Therapy Target.
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DOI：
10.1021/acs.biochem.8b00215
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发表时间：
2018-06-26
期刊：
影响因子：
2.9
通讯作者：
Becker DF
中科院分区：
文献类型：
--
作者：
Tanner JJ;Fendt SM;Becker DF
由于一种新的脯氨酸代谢周期在癌细胞存活、增殖和转移中的新作用，人们对脯氨酸如何有助于癌症生物学的兴趣正在扩大。脯氨酸的生物合成和降解涉及共有的中间体Δ1-吡咯烷-5-羧酸(P5C)，它在可逆的非酶反应中形成L-谷氨酸-γ-半醛(GSAL)。由谷氨酸或鸟氨酸通过GSAL/P5C合成脯氨酸，在NAD(P)H依赖的反应中被P5C还原酶(PYCR)还原为Pro。脯氨酸的降解发生在线粒体中，包括两个氧化步骤，分别由Pro脱氢酶(PROH)和GSAL脱氢酶(GSALDH)催化。PROSH是一种依赖黄素的酶，它将膜上结合的苯二酚的氧化与脯氨酸的氧化结合在一起，而GSALDH催化依赖NAD+的GSAL氧化成谷氨酸。PROSH和PYCR形成一种称为Pro-P5C循环的代谢关系，这是一种影响细胞生长和死亡的新途径。Pro-P5C循环在支持癌细胞的ATP合成、蛋白质和核苷酸合成、修复和氧化还原动态平衡方面起着重要作用。这一视角详细介绍了PROSH和PYCR的结构和反应机制，以及Pro-P5C循环在癌症新陈代谢中的作用。该领域的一个主要挑战是发现专门针对PROSH和PYCR亚型的抑制剂，以用作研究Pro代谢和癌症中Pro-P5C循环功能的工具。这些分子探针还可以作为针对Pro-P5C循环的癌症药物发现的先导化合物。
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.
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影响因子：
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