Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2D, 15-222, Bialystok, Poland.
Amino Acids. 2021 Dec;53(12):1917-1925. doi: 10.1007/s00726-021-02968-y. Epub 2021 Apr 5.
Recent studies on the regulatory role of amino acids in cell metabolism have focused on the functional significance of proline degradation. The process is catalysed by proline dehydrogenase/proline oxidase (PRODH/POX), a mitochondrial flavin-dependent enzyme converting proline into ∆1-pyrroline-5-carboxylate (P5C). During this process, electrons are transferred to electron transport chain producing ATP for survival or they directly reduce oxygen, producing reactive oxygen species (ROS) inducing apoptosis/autophagy. However, the mechanism for switching survival/apoptosis mode is unknown. Although PRODH/POX activity and energetic metabolism were suggested as an underlying mechanism for the survival/apoptosis switch, proline availability for this enzyme is also important. Proline availability is regulated by prolidase (proline supporting enzyme), collagen biosynthesis (proline utilizing process) and proline synthesis from glutamine, glutamate, α-ketoglutarate (α-KG) and ornithine. Proline availability is dependent on the rate of glycolysis, TCA and urea cycles, proline metabolism, collagen biosynthesis and its degradation. It is well established that proline synthesis enzymes, P5C synthetase and P5C reductase as well as collagen prolyl hydroxylases are up-regulated in most of cancer types and control rates of collagen biosynthesis. Up-regulation of collagen prolyl hydroxylase and its exhaustion of ascorbate and α-KG may compete with DNA and histone demethylases (that require the same cofactors) to influence metabolic epigenetics. This knowledge led us to hypothesize that up-regulation of prolidase and PRODH/POX with inhibition of collagen biosynthesis may represent potential pharmacotherapeutic approach to induce apoptosis or autophagic death in cancer cells. These aspects of proline metabolism are discussed in the review as an approach to understand complex regulatory mechanisms driving PRODH/POX-dependent apoptosis/survival.
最近关于氨基酸在细胞代谢中调节作用的研究集中在脯氨酸降解的功能意义上。这个过程由脯氨酸脱氢酶/脯氨酸氧化酶（PRODH/POX）催化，它是一种依赖黄素的线粒体酶，将脯氨酸转化为 ∆1-吡咯啉-5-羧酸（P5C）。在此过程中，电子被转移到电子传递链，产生生存所需的 ATP，或者它们直接还原氧气，产生诱导细胞凋亡/自噬的活性氧（ROS）。然而，切换生存/凋亡模式的机制尚不清楚。虽然 PRODH/POX 活性和能量代谢被认为是生存/凋亡开关的潜在机制，但这种酶的脯氨酸可用性也很重要。脯氨酸可用性受脯氨酸酶（脯氨酸支持酶）、胶原生物合成（脯氨酸利用过程）和脯氨酸从谷氨酰胺、谷氨酸、α-酮戊二酸（α-KG）和鸟氨酸合成的调节。脯氨酸可用性取决于糖酵解、三羧酸循环和尿素循环、脯氨酸代谢、胶原生物合成及其降解的速度。众所周知，脯氨酸合成酶、P5C 合成酶和 P5C 还原酶以及胶原脯氨酰羟化酶在大多数癌症类型中上调，并控制胶原生物合成的速度。胶原脯氨酰羟化酶的上调及其对抗坏血酸和 α-KG 的消耗可能与 DNA 和组蛋白去甲基酶（需要相同的辅因子）竞争，从而影响代谢表观遗传学。这一知识使我们假设，脯氨酸酶和 PRODH/POX 的上调以及胶原生物合成的抑制可能代表诱导癌细胞凋亡或自噬死亡的潜在药物治疗方法。该综述讨论了脯氨酸代谢的这些方面，作为理解驱动 PRODH/POX 依赖性凋亡/生存的复杂调节机制的一种方法。
