Chalecka Magda, Hermanowicz Justyna Magdalena, Palka Jerzy, Surazynski Arkadiusz
Department of Medicinal Chemistry, Medical University of Bialystok, Bialystok, Poland.
Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland.
Front Cell Dev Biol. 2025 May 16;13:1556770. doi: 10.3389/fcell.2025.1556770. eCollection 2025.
Although the role of proline (Pro) in regulatory mechanisms of cell metabolism is well recognized, the interest in metabolic significance of hydroxyproline (Hyp) has received little attention. Hyp was considered as a waste metabolite of protein degradation, mainly degradation of collagen. This amino acid is not synthesized and is not incorporated into proteins. Hyp is a product of Pro hydroxylation in proteins by specific Pro hydroxylase. Therefore, Hyp is derived from degradation of proteins, and it is further metabolized by specific Hyp dehydrogenase 2 (PRODH2), known also as a Hyp oxidase (OH-POX). The enzyme catalyzes conversion of Hyp into Δ-pyrroline-3-OH-5-carboxylic acid (OH-P5C), yielding electrons that are used in electron transport chain for ATP production. However, in certain conditions the electrons are accepted by oxygen forming reactive oxygen species (ROS). The product, OH-P5C could be also converted by OH-P5C reductase to recycle NADP in pentose phosphate pathway (PPP), yielding nucleotides for DNA synthesis. Interestingly, Pro hydroxylase requires the same cofactors (α-KG, ascorbate and Fe) as a DNA and histone demethylases, suggesting the role of Pro hydroxylation in epigenetic regulation. Hyp could be also converted to highly energetic amino acid, glycine (Gly). Of great importance is the role of Hyp in upregulation of transcriptional activity of hypoxia-inducible factor 1α (HIF-1α), inducing angiogenesis and metastasis. Therefore, Hyp is involved in several critical metabolic processes regulating DNA synthesis, gene expression, apoptosis/survival, angiogenesis, metastasis and energy production, suggesting a key role of Hyp in reprogramming metabolism of cancer cells. It suggests that Hyp metabolism could be considered as a target in novel experimental strategy for cancer treatment.
尽管脯氨酸（Pro）在细胞代谢调节机制中的作用已得到充分认识，但羟脯氨酸（Hyp）的代谢意义却很少受到关注。Hyp曾被认为是蛋白质降解的废物代谢产物，主要是胶原蛋白的降解产物。这种氨基酸不能合成，也不掺入蛋白质中。Hyp是蛋白质中脯氨酸通过特定的脯氨酸羟化酶羟基化的产物。因此，Hyp来源于蛋白质的降解，并通过特定的羟脯氨酸脱氢酶2（PRODH2，也称为Hyp氧化酶（OH-POX））进一步代谢。该酶催化Hyp转化为Δ-吡咯啉-3-OH-5-羧酸（OH-P5C），产生的电子用于电子传递链以产生ATP。然而，在某些条件下，电子被氧接受形成活性氧（ROS）。产物OH-P5C也可以被OH-P5C还原酶转化，以在磷酸戊糖途径（PPP）中循环NADP，产生用于DNA合成的核苷酸。有趣的是，脯氨酸羟化酶与DNA和组蛋白去甲基化酶需要相同的辅因子（α-酮戊二酸、抗坏血酸和铁），这表明脯氨酸羟化在表观遗传调控中的作用。Hyp也可以转化为高能氨基酸甘氨酸（Gly）。Hyp在缺氧诱导因子1α（HIF-1α）转录活性上调、诱导血管生成和转移方面的作用非常重要。因此，Hyp参与了调节DNA合成、基因表达、细胞凋亡/存活、血管生成、转移和能量产生的几个关键代谢过程，表明Hyp在癌细胞代谢重编程中起关键作用。这表明Hyp代谢可被视为癌症治疗新实验策略的一个靶点。
