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Proline cycle and its basic metabolic links in the human cell. Proline released during collagen catabolism can feed back to collagen resynthesis, or, through the proline cycle, it may be used for energetic purposes, redox balance, parametabolic regulation, or anaplerosis. PRO—proline, P5C—pyrroline-5-carboxylate, ORN—ornithine, GLN—glutamine, GLU—glutamate, αKG—alpha-ketoglutarate, PEPD—prolidase, POX/PRODH—proline oxidase/proline dehydrogenase, PYCR 1/2/3—pyrroline-5-carboxylate reductase 1/2/3, MMPs—metalloproteinases, PPP—pentose phosphate pathway, TCA cycle—tricarboxylic acid cycle. Created with BioRender.com, accessed on 2 February 2022.
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Background:
Proline has attracted growing interest because of its diverse influence on tumor metabolism and the discovery of the regulatory mechanisms that appear to be involved. In contrast to general oncology, data on proline metabolism in central nervous system malignancies are limited.
Materials and methods:
We performed a systematic literat...
Citations
... even though extracellular collagenases start the collagen breakdown, prolidase completes the ultimate stage of collagen degradation (Eni-Aganga et al., 2021) Prolidase catalyzes the hydrolysis of iminodipeptides that have Hydroxyproline or Proline at the C-terminal (X-Pro), resulting in release of the proline component (Kabashima et al., 2023) Recent attention has been drawn to proline metabolism due to its role in the metabolic reprogramming that takes place in cancer cells (Elia et al., 2018). Furthermore, in the last few years, there has been an increase of evidence establishing a link between proline metabolism & critical regulatory routes, including: mTOR, ERK, JAK/STAT, & ROS-driven signaling (Sawicka et al., 2022) One distinctive feature of metabolism ofProline is the process of cycling proline and P5C to ensure a balanced redox state throughout the cytosol & mitochondria. The complete understanding of proline production in cancer is still limited. ...
Iraqi women have had more cancers of the breast in recent years. To achieve successful treatment, delay dissemination, and reduce fatalities in breast cancer, the best way is to monitor protein levels in body fluids for early diagnosis and prognosis.The objective of the present research was to determine the diagnostic and prognostic significance of proline as a marker in individuals diagnosed with breast cancerTo examine the correlations between proline and the established biomarker CA 15-3, as well as clinicopathological characteristics. This research involved 30 newly diagnosed female with breast cancer before surgical operation and compare with their levels after one month of the surgical operation, and 28femalehad noncancerous breast tumors as control subjects. CA15˗3was measuredby ELISA technique and proline level by HPLC technique.A notable variations in the average proline levels was observed between the categories of study participants; the benign group exhibited the highest level, then post-operative category, and finally the newly diagnosed category.Additionally, notable variations were observed in the average CA-15-3 levels with the newly diagnosed category having the highest level, then the post-operative category and then benign category.Proline concentration showed a significant positive correlation with CA15-3 in malignant and benign groups. Both of Proline & CA-15-3 were strong predictors by ROC, 100% & 90%for Proline, 93% &93%, for CA-15-3 respectively.
... Although promising, the available body of evidence lacks robust experimental proof for alterations in proline metabolism in GG4; most of the studies were performed as in-vitro models and have not been verified in a clinical setting [19]. The most likely reason for this gap in knowledge is inherent to all studies on the CNS; for ethical reasons, it is very difficult to obtain samples of healthy brain tissue. ...
Simple Summary
Proline metabolism has been found to play an important role in neoplasms, but little is known about proline in gliomas or in the normal brain. This work investigates how the metabolism of proline in the brain and in gliomas of WHO grade 4 (GG4) may differ. A total of 20 pairs of samples were studied, consisting of both tumor and unaffected brain tissue, partially removed to make a surgical corridor. The levels of proline oxidase/proline dehydrogenase (POX/PRODH), Δ¹-pyrroline-5-carboxylate reductases (PYCR1/2/3), prolidase (PEPD), and metalloproteinase-2 and -9 (MMP-2 and MMP-9) were measured. Proline concentration was evaluated. GG4 levels of POX/PRODH were found to be lower, while PYCR1, PEPD, and MMPs were significantly higher than in brain tissue. In GG4, proline concentration was 358% higher. The results confirm changes in proline metabolism in GG4, with a low-POX/PRODH/high-PYCR pattern like that in other neoplasms. High levels of PEPD and MMPs are in keeping with GG4 aggressiveness.
Abstract
Proline metabolism has been identified as a significant player in several neoplasms, but knowledge of its role in gliomas is limited despite it providing a promising line of pursuit. Data on proline metabolism in the brain are somewhat historical. This study aims to investigate alterations of proline metabolism in gliomas of WHO grade 4 (GG4) in the context of the brain. A total of 20 pairs of samples were studied, consisting of excised tumor and unaffected brain tissue, obtained when partial brain resection was required to reach deep-seated lesions. Levels of proline oxidase/proline dehydrogenase (POX/PRODH), Δ¹-pyrroline-5-carboxylate reductases (PYCR1/2/3), prolidase (PEPD), and metalloproteinases (MMP-2, MMP-9) were assessed, along with the concentration of proline and proline-related metabolites. In comparison to normal brain tissue, POX/PRODH expression in GG4 was found to be suppressed, while PYCR1 expression and activity of PEPD, MMP-2, and -9 were upregulated. The GG4 proline concentration was 358% higher. Hence, rewiring of the proline metabolism in GG4 was confirmed for the first time, with a low-POX/PRODH/high-PYCR profile. High PEPD and MMPs activity is in keeping with GG4-increased collagen turnover and local aggressiveness. Further studies on the mechanisms of the interplay between altered proline metabolism and the GG4 microenvironment are warranted.
... Proline participates in several critical metabolic cycles, including glycolysis, the tricarboxylic acid cycle, the urea cycle, and the pentose phosphate pathway [12]. Proline synthesis requires P5CS (pyrroline-5 carboxylate synthase) and PYCRs (pyrroline carboxylate reductases), and its degradation is catalyzed by PRODH (proline dehydrogenase) [13]. ...
... The altered metabolism of Arg and proline in cancer cells may lead to several therapeutic approaches targeting these metabolic pathways. These include using Arg-depleting substances like pegylated Arg deiminase (ADI-PEG20) (Synakiewicz et al. 2014) and proline metabolism inhibitors, including the azetidine-2-carboxylic acid (AZC) (Ashino et al. 2003), proline analogs, and 2-pyrrolidine-carboxylic acid (PCA) (Sawicka et al. 2022). In conclusion, the dysregulation of Arg and proline metabolism in cancer cells may play a significant role in cancer etiology and may provide a possible route for creating new therapeutic approaches. ...
Amino acids not only play a vital role in the synthesis of biological molecules such as proteins in cancer malignant cells, they are also essential metabolites for immune cell activation and antitumor effects in the tumor microenvironment. The abnormal changes in amino acid metabolism are closely related to the occurrence and development of tumors and immunity. Intestinal microorganisms play an essential role in amino acid metabolism, and tryptophan and its intestinal microbial metabolites are typical representatives. However, it is known that the cyclic amino acid profile is affected by specific cancer types, so relevant studies mainly focus on one type of cancer and rarely study different cancer forms at the same time. The objective of this study was to examine the PFAA profile of five cancer patients and the characteristics of tryptophan intestinal microbial metabolites to determine whether there are general amino acid changes across tumors. Plasma samples were collected from esophageal (n = 53), lung (n = 73), colorectal (n = 94), gastric (n = 55), breast cancer (n = 25), and healthy control (HC) (n = 139) subjects. PFAA profile and tryptophan metabolites were measured, and their perioperative changes were examined using high-performance liquid chromatography. Univariate analysis revealed significant differences between cancer patients and HC. Furthermore, multivariate analysis discriminated cancer patients from HC. Regression diagnosis models were established for each cancer group using differential amino acids from univariate analysis. Receiver-operating characteristic analysis was applied to evaluate these diagnosis models. Finally, GABA, arginine, tryptophan, taurine, glutamic acid, and melatonin showed common alterations across all types of cancer patients. Metabolic pathway analysis shows that the most significant enrichment pathways were tryptophan, arginine, and proline metabolism. This study provides evidence that common alterations of the metabolites mentioned above suggest their role in the pathogenesis of each cancer patient. It was suggested that multivariate models based on PFAA profiles and tryptophan metabolites might be applicable in the screening of cancer patients.
... Current literatures found that the concentration of proline in GBM was higher than in normal brain 32 . Similarly, IDH-mutant high-grade oligodendrogliomas was found to utilize the proline cycle as a redox shuttle to maintain redox balance 33 . Our findings support the hypothesis that regulating the disorder of arginine and proline metabolism pathway in cancer cells can affect the proliferation of tumor cells, which provides a new idea for the targeted therapy of glioma. ...
Anlotinib, as a promising oral small-molecule antitumor drug, its role in glioma has been only reported in a small number of case reports. Therefore, anlotinib has been considered as a promising candidate in glioma. The aim of this study was to investigate the metabolic network of C6 cells after exposure to anlotinib and to identify anti-glioma mechanism from the perspective of metabolic reprogramming. Firstly, CCK8 method was used to evaluate the effects of anlotinib on cell proliferation and apoptosis. Secondly, ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS)-based metabolomic and lipidomic were developed to characterize the metabolite and lipid changes in cell and cell culture medium (CCM) caused by anlotinib in the treatment of glioma. As a result, anlotinib had concentration-dependent inhibitory effect with the concentration range. In total, twenty-four and twenty-three disturbed metabolites in cell and CCM responsible for the intervention effect of anlotinib were screened and annotated using UHPLC-HRMS. Altogether, seventeen differential lipids in cell were identified between anlotinib exposure and untreated groups. Metabolic pathways, including amino acid metabolism, energy metabolism, ceramide metabolism, and glycerophospholipid metabolism, were modulated by anlotinib in glioma cell. Overall, anlotinib has an effective treatment against the development and progression of glioma, and these remarkable pathways can generate the key molecular events in cells treated with anlotinib. Future research into the mechanisms underlying the metabolic changes is expected to provide new strategies for treating glioma.
... Next, we assessed the mRNA levels of enzymes of the urea cycle and proline metabolism, since the polyamine precursor putrescine is synthesized from a non-proteinogenic amino acid ornithine of this cycle, which is also linked to Pro/Glu metabolic system [12,52]. The results, presented in Figure 5a-c, show that in hepatocyte-like HepaRG cells, the level of the transcript encoding argininosuccinate synthase (ASS1) is fifteen-fold higher than in Huh7.5 cells, and the mRNA of the argininosuccinate lyase gene (ASL), which synthesizes arginine, is two times higher. ...
... In Huh7.5 hepatoma cells, the expression of proteins synthesizing proline from P5C (PYCR1, PYCR2, PYCR3) prevails over proline-utilizing proteins (PRODH and PRODH2) and the coordinated action of PYCR3, PRODH, and PRODH2 proteins. P5C, being exported into the cytoplasm, is converted into proline, resulting in proline being transferred back to the mitochondria, where it was again oxidized into P5C by PRODH and PRODH2 [52]. Hence, a closed cycle leads to an increase in the concentration of NADP + in the cytoplasm and the generation of ROS in mitochondria [73]. ...
Reactive oxygen species (ROS) play a major role in the regulation of various processes in the cell. The increase in their production is a factor contributing to the development of numerous pathologies, including inflammation, fibrosis, and cancer. Accordingly, the study of ROS production and neutralization, as well as redox-dependent processes and the post-translational modifications of proteins, is warranted. Here, we present a transcriptomic analysis of the gene expression of various redox systems and related metabolic processes, such as polyamine and proline metabolism and the urea cycle in Huh7.5 hepatoma cells and the HepaRG liver progenitor cell line, that are widely used in hepatitis research. In addition, changes in response to the activation of polyamine catabolism that contribute to oxidative stress were studied. In particular, differences in the gene expression of various ROS-producing and ROS-neutralizing proteins, the enzymes of polyamine metabolisms and proline and urea cycles, as well as calcium ion transporters between cell lines, are shown. The data obtained are important for understanding the redox biology of viral hepatitis and elucidating the influence of the laboratory models used.
... Proline is one of the most important amino acids for protein synthesis in the human body. Proline metabolism plays a main role in tumor development [27]. Arginine underwent hydrolysis, the formed ornithine can be changed into polyamines and proline, and the urea from its metabolism is drained by kidneys [28]. ...
Mepiquat (Mep) is a contaminant produced by Maillard reaction with reducing sugar, free lysine and an alkylating agent under typical roasting conditions, particularly in the range of 200–240 °C. It has been reported that exposure to Mep is harmful to rats. However, its metabolic mechanism is still not clear. In this study, untargeted metabolomics was used to reveal the effect of Mep on the metabolic profile of adipose tissue in Sprague-Dawley rats. Twenty-six differential metabolites were screened out. Eight major perturbed metabolic pathways were found, which were linoleic acid metabolism, Phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism, arachidonic acid metabolism, Glycine, serine, and threonine metabolism, glycerolipid metabolism, Alanine, aspartate, and glutamate metabolism, and glyoxylate and dicarboxylic acid metabolism. This study lays a solid foundation for clarifying the toxic mechanism of Mep.
... The Arg [23], Try [22] and Ala [20] into seed [26]. This is in the literature [26]. ...
Upon considering the anticancer effects of larger oligomeric proanthocyanidins and observing various papers reporting the high resolution mass spectroscopy of the oligomeric proanthocyanidins, it is determined that the unusual 13C enrichment in some plant oligomeric proanthocyanidins may be responsible for the anticancer activities of these food products. Such correlation of the 13C in the oligomeric proanthocyanidins also correlate with their scavenging of free-radicals, anti-virial and anti-bacterial properties. Proanthocyanidins in grape seeds are observed to have high enrichment in heavy isotopes of 2H, 13C, 15N and/or 17O. Mass analysis of DNA from human cancer cells are compared to normal human cells and cancer cells show bond specific enrichment of heavy isotopes in nucleotides G, A, T and C. On such basis, this study suggests possible stronger interactions of proanthocyanidins with DNA in cancer verses DNA in normal cells due to heavy isotope bond specific enrichments in both proanthocyanidins and the cancer DNA. Such 13C interactions from oligomeric proanthocyanidins with nucleic acids and proteins involved in replications, transcriptions and translations in cancer cells for interacting and chemically altering anabolism and cell division of the cancer cells are consistent with the author’s mechanism for normal cell to cancer cell transformations via possible replacements of primordial 1H, 12C, 14N, 16O, and 24Mg isotopes by nonprimordial 2H, 13C, 15N, and 17O and 25Mg isotopes in the proteins and nucleic acids. Such is also consistent with the proposed treatment for cancer by the author by use of foods containing proteins, nucleic acids, carbohydrates and/or drug molecules enriched with the nonprimordial isotopes of 2H, 13C, 15N, and 17O and 25Mg.
... Proline is oxidized to glutamate in the mitochondria and has been linked to glutamate metabolism in GBM and cell proliferation (Cappelletti et al., 2018). In a recent systematic review, Sawicka et al. found proline to be a prognostic factor and a signal of malignancy (Sawicka et al., 2022). ...
Gliomas are central nervous system (CNS) cancers that are challenging to treat due to their high proliferation and mutation rates. High grade gliomas include grade 3 and grade 4 tumors, which characteristically have a poor prognosis despite advancements in diagnostic methods and therapeutic options. Advances in metabolomics are resulting in more insight as to how cancer modifies the metabolism of the cell and surrounding tissue. Hence, this avenue of research may also emerge as a way to precisely target metabolites unique to gliomas. These biomarkers may provide opportunities for glioma diagnosis, prognosis and future therapeutic intervention.
In this review, we harvest the literature that highlights notable biomolecules in high grade gliomas and promising therapeutic targets and interventions.
Objective
The aim of this study was to optimize the currently used direct spectrophotometric serum prolidase enzyme activity (SPEA) assay method and compare its diagnostic accuracy with current precipitation and direct spectrophotometric assay methods, AST-to-ALT ratio, age platelet index, AST-to-platelet ratio index, cirrhosis discriminate score, Doha score, FIB-4, FibroQ, fibrosis index, Goteborg University Cirrhosis Index , King’s score, and Pohl score for distinguishing Ishak F0 from F1–F3 in patients with chronic hepatitis B (CHB) infection.
Methods
Liver biopsy results from 112 patients were included in this study.
Results
The SPEA values were 529 (292–794) U/L, 671 (486–927) U/L, and 1077 (867–1399) U/L with the precipitation, current, and optimized direct spectrophotometric assay methods, respectively. According to multivariate logistic regression analysis optimized direct spectrophotometric SPEA was the only statistically significant parameter to predict the early stages of liver fibrosis.
Conclusions
Optimized direct spectrophotometric SPEA assay method could be used to distinguish early stages of liver fibrosis in patients with CHB infection instead of the currently used spectrophotometric SPEA assay methods and other evaluated liver fibrosis indexes.
