10/16/2023 0 Comments Collagen catabolismIncreasing evidence suggests that proline and collagen metabolism may determine cancer development and progression. These aspects of proline metabolism are discussed in the review as an approach to understand complex regulatory mechanisms driving PRODH/POX-dependent apoptosis/survival. 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. 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. 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. Proline availability is dependent on the rate of glycolysis, TCA and urea cycles, proline metabolism, collagen biosynthesis and its degradation. 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. 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. However, the mechanism for switching survival/apoptosis mode is unknown. 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. The process is catalysed by proline dehydrogenase/proline oxidase (PRODH/POX), a mitochondrial flavin-dependent enzyme converting proline into ∆1-pyrroline-5-carboxylate (P5C). Taken all together, this study showed that peptides which are larger than tripeptide could reach to the circulation system after administration of CH, revealing previously unknown dynamics of absorption of CH.Recent studies on the regulatory role of amino acids in cell metabolism have focused on the functional significance of proline degradation. Finally, analysis of portal vein blood revealed that the larger peptides, such as pentadecapeptide identified in this study, could be absorbed in vivo. Peptide quantitation by liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed that di- and tri-peptides, which are previously identified as major peptides in circulating blood, comprise only a part of HCPs in intestinal and liver perfusate. Mass spectrometric analysis of intestinal perfusate finally identified three CH-derived peptides, which are surprisingly large as food-derived circulating peptides. Size exclusion chromatography showed that perfusates include significant amount of HCPs larger than tripeptides, leading us to analyze these peptides in detail. Thus, the results demonstrated that CH is absorbed predominantly as peptides, which subsequently enter systemic circulation. In addition, HCPs were also reliably detected in hepatic perfusate at the level higher than free Hyp. The total amount of absorbed HCPs during 1 h of perfusion was 16.6 μmol, which was significantly higher than that of free Hyp (6.6 μmol). In order to understand the dynamics of CH absorption and metabolism, molecular profiles of hydroxyproline (Hyp) and Hyp-containing peptides (HCPs) were analyzed by in situ perfusion of rat intestine and liver. A number of studies have shown that oral administration of collagen hydrolysate (CH) results in the absorption of di- and tri-peptides.
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