Abstract
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.
Highlights
Increasing evidence suggests that proline and collagen metabolism may determine cancer development and progression
Since collagen prolyl hydroxylase compete with DNA and histone demethylases for ascorbate and α-KG, collagen biosynthesis may influence metabolic epigenetics
The knowledge on functional significance of proline and collagen metabolism in complex metabolic regulatory mechanisms may contribute to understanding differential PRODH/proline oxidase (POX)-dependent functions in cancer cells (Fig. 1)
Summary
Increasing evidence suggests that proline and collagen metabolism may determine cancer development and progression. The family of dioxygenases that includes collagen prolyl hydroxylase, DNA and histone demethylases and HIF-1α prolyl hydroxylase (D’Aniello et al 2019). Since collagen prolyl hydroxylase compete with DNA and histone demethylases for ascorbate and α-KG, collagen biosynthesis may influence metabolic epigenetics. Another member of prolyl hydroxylases (α-KG and succinate dependent) was recently implicated in regulation of HIF-1α transcriptional activity by its targeting for proteasomal degradation (Xiong et al 2018). The processes may affect proline availability for PRODH/ POX-dependent functions. The knowledge on functional significance of proline and collagen metabolism in complex metabolic regulatory mechanisms may contribute to understanding differential PRODH/POX-dependent functions (apoptosis/autophagy/survival) in cancer cells (Fig. 1)
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