Structure, biochemistry, and gene expression patterns of the proline biosynthetic enzyme pyrroline-5-carboxylate reductase (PYCR), an emerging cancer therapy target.
Structure, biochemistry, and gene expression patterns of the proline biosynthetic enzyme pyrroline-5-carboxylate reductase (PYCR), an emerging cancer therapy target.
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DOI：
10.1007/s00726-021-02999-5
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发表时间：
2021-12
期刊：
影响因子：
3.5
通讯作者：
Tanner JJ
中科院分区：
文献类型：
--
作者：
Bogner AN;Stiers KM;Tanner JJ
脯氨酸代谢在癌细胞独特的代谢中占有重要地位。脯氨酸生物合成基因在多种癌症中一致上调，而脯氨酸分解代谢酶脯氨酸脱氢酶具有双重的、环境依赖性的促癌和促凋亡功能。此外，脯氨酸和Δ1-吡咯啉-5-羧酸通过脯氨酸循环的循环通过维持细胞溶质和线粒体之间的氧化还原稳态来影响细胞生长和死亡途径。在这里，我们专注于脯氨酸生物合成的最后一种酶，Δ1-吡咯啉-5-羧酸还原酶，在人类中称为PYCR。PYCR催化Δ1-吡咯啉-5-羧酸盐的NAD（P）H依赖性还原为脯氨酸，并形成脯氨酸代谢循环的还原性一半。本文就PYCR的三维结构、生物化学、抑制作用及肿瘤生物学等方面的研究进展作一综述。为了提供癌症中PYCR基因上调的全局视图，我们挖掘RNA转录数据库以分析28种癌症类型中的差异基因表达。该分析揭示了PYCR基因，特别是PYCR 1的强烈、广泛的上调。总之，过去20年的研究为PYCR作为癌症治疗靶点提供了令人信服的理由。最后，我们讨论了该领域的一些主要挑战，包括开发亚型特异性抑制剂，阐明PYCR 1/2的长C-末端的功能，并表征PYCR的相互作用组。
Proline metabolism features prominently in the unique metabolism of cancer cells. Proline biosynthetic genes are consistently upregulated in multiple cancers, while the proline catabolic enzyme proline dehydrogenase has dual, context-dependent pro-cancer and pro-apoptotic functions. Furthermore, the cycling of proline and Δ1-pyrroline-5-carboxylate through the proline cycle impacts cellular growth and death pathways by maintaining redox homeostasis between the cytosol and mitochondria. Here we focus on the last enzyme of proline biosynthesis, Δ1-pyrroline-5-carboxylate reductase, known as PYCR in humans. PYCR catalyzes the NAD(P)H-dependent reduction of Δ1-pyrroline-5-carboxylate to proline and forms the reductive half of the proline metabolic cycle. We review the research on the three-dimensional structure, biochemistry, inhibition, and cancer biology of PYCR. To provide a global view of PYCR gene upregulation in cancer, we mined RNA transcript databases to analyze differential gene expression in 28 cancer types. This analysis revealed strong, widespread upregulation of PYCR genes, especially PYCR1. Altogether, the research over the past 20 years makes a compelling case for PYCR as a cancer therapy target. We conclude with a discussion of some of the major challenges for the field, including developing isoform-specific inhibitors, elucidating the function of the long C-terminus of PYCR1/2, and characterizing the interactome of PYCR.
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影响因子：
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作者：
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影响因子：
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