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Schematic representation of systemic proline metabolism in health and disease. In normal conditions, proline and hydroxyproline are assimilated from the diet in the small intestine and about 60% will be released by enterocytes into the circulation. During disease, enhanced hydroxyproline levels are associated with bone tumours and hepatic fibrosis, whereas increased systemic proline levels mirror carcinogenesis, diabetes and cachexia
Source publication
Proline is a non-essential amino acid with key roles in protein structure/function and maintenance of cellular redox homeostasis. It is available from dietary sources, generated de novo within cells, and released from protein structures; a noteworthy source being collagen. Its catabolism within cells can generate ATP and reactive oxygen species (RO...
Citations
... Milk, being a source of microorganisms, plays a significant role in influencing gut colonization during lactation and the early development of the infant intestinal microbiota . Proline, for instance, has been implicated in maintaining a delicate balance between health and disease (Vettore, Westbrook, & Tennant, 2021). Moreover, proline's role in regulating metabolism suggests its potential to enhance the efficient utilization of dietary energy, thereby potentially contributing to increased fat content in the milk of various farm animal species (Alumot, Ascarelli, Bruckental, & Yosif, 2010;Alumot, Bruckental, Tadmor, Kennit, & Holstein, 1983). ...
Understanding the intricate relationship between genetics, metabolites, and microbiota is paramount for unraveling the complexities that define buffalo milk composition. In this study, we employed a multi-omics approach to dissect the genetic and metabolic determinants of buffalo milk traits. Metabolomics analysis of 100 buffalo milk samples revealed a rich profile of 446 metabolites, with a particular emphasis on those associated with amino acid biosynthesis. Metabolite-based Genome-Wide Association Studies (mGWAS) uncovered 13 significant genetic variants, with a pronounced focus on L-Proline. Notably, single nucleotide polymorphisms (SNPs) within the ATG16L1 gene implicated its role in proline production. Concurrently, an in-depth exploration of milk microbiota dynamics highlighted marked differences between buffaloes with high and low proline groups. High proline abundance correlated with increased microbial diversity, dominated by Firmicutes and Proteobacteria. Distinct genera, such as Acinetobacter and Corynebacterium, characterized low and high proline groups, respectively. Functional changes in milk microbiota, especially in amino acid biosynthesis pathways, underscored proline's pivotal role in shaping microbial functions. Correlations between milk microbiota abundance and proline levels emphasized the intricate relationship between host physiology and microbial composition. These findings not only advance our understanding of the genetic basis of metabolic traits in buffalo milk but also present potential biomarkers for targeted breeding strategies. This integrated approach provides a nuanced perspective on milk composition, offering implications for dairy quality and nutritional enhancement.
... Numerous studies have linked proline metabolism with ROS [40]. Proline synthesis and degradation are both highly redox-active processes [41]. Proline and proline metabolism can act as both ROS scavengers and producers [39]. ...
The consumption of low-mineral water has been increasing worldwide. Drinking low-mineral water is associated with cardiovascular disease, osteopenia, and certain neurodegenerative diseases. However, the specific mechanism remains unclear. The liver metabolic alterations in rats induced by drinking purified water for 3 months were investigated with a metabolomics-based strategy. Compared with the tap water group, 74 metabolites were significantly changed in the purified water group (6 increased and 68 decreased), including 29 amino acids, 11 carbohydrates, 10 fatty acids, 7 short chain fatty acids (SCFAs), and 17 other biomolecules. Eight metabolic pathways were significantly changed, namely aminoacyl–tRNA biosynthesis; nitrogen metabolism; alanine, aspartate and glutamate metabolism; arginine and proline metabolism; histidine metabolism; biosynthesis of unsaturated fatty acids; butanoate metabolism; and glycine, serine and threonine metabolism. These changes suggested that consumption of purified water induced negative nitrogen balance, reduced expression of some polyunsaturated fatty acids and SCFAs, and disturbed energy metabolism in rats. These metabolic disturbances may contribute to low-mineral-water-associated health risks. The health risk of consuming low-mineral water requires attention.
... In the failing heart, elevated levels of reactive oxygen species (ROS) lead to mitochondrial DNA damage, antioxidant depletion, and reduced mitochondrial ATP production, aggravating the cardiac remodeling eventually (29,30). PRODH has been previously reported to modulate mitochondrial function by regulating ROS and maintaining mitochondrial integrity (31). It has been found that PRODH expression is up-regulated in response to oxidative stress to maintain cellular redox balance (32). ...
Metabolic reprogramming is critical in the onset of pressure overload–induced cardiac remodeling. Our study reveals that proline dehydrogenase (PRODH), the key enzyme in proline metabolism, reprograms cardiomyocyte metabolism to protect against cardiac remodeling. We induced cardiac remodeling using transverse aortic constriction (TAC) in both cardiac-specific PRODH knockout and overexpression mice. Our results indicate that PRODH expression is suppressed after TAC. Cardiac-specific PRODH knockout mice exhibited worsened cardiac dysfunction, while mice with PRODH overexpression demonstrated a protective effect. In addition, we simulated cardiomyocyte hypertrophy in vitro using neonatal rat ventricular myocytes treated with phenylephrine. Through RNA sequencing, metabolomics, and metabolic flux analysis, we elucidated that PRODH overexpression in cardiomyocytes redirects proline catabolism to replenish tricarboxylic acid cycle intermediates, enhance energy production, and restore glutathione redox balance. Our findings suggest PRODH as a modulator of cardiac bioenergetics and redox homeostasis during cardiac remodeling induced by pressure overload. This highlights the potential of PRODH as a therapeutic target for cardiac remodeling.
... The pattern of elevated metabolite abundance in S. latissima was observed in the amino acid profile analysis ( Figure 1E). Notably, elevated abundance of proline, a non-essential amino acid with key roles in protein structure/function and maintenance of cellular redox homeostasis [41], and essential amino acids such as phenylalanine, alanine, leucine valine, and isoleucine were observed in unfermented S. latissima. ...
... Several of the compounds, especially the benzoic acids, exerted antimicrobial activity. Of the benzoic acids, we know from literature that gallic acid exhibits antimicrobial effect against S. aureus [40]; that 3-phenyllactic acid inhibits growth of species such as Staphylococcus aureus, Klebsiella oxytoca, and S. Typhimurium [41]; and that anthranillic acid exhibits the same effect against S. aureus, E.coli, and S. enterica Typhimurium [42]. The same result for benzoic acid is what we have observed to increase in the fermented products relative to the controls. ...
Higher plants produce secondary metabolites expressing antimicrobial effects as a defense mechanism against opportunistic microorganisms living in close proximity with the plant. Fermentation leads to bioconversion of plant substrates to these bioactive compounds and their subsequent release via breakdown of plant cell walls. Fermented feed products have recently started to become implemented in the pig industry to reduce overall disease pressure and have been found to reduce events such as post-weaning diarrhea. In this study, we investigate the antimicrobial potential of fermented soybean- and rapeseed-based pig feed supplements with and without added seaweed. The antimicrobial effect was tested in a plate well diffusion assay against a range of known human and livestock pathogenic bacteria. Further, we investigate the metabolite profiles based on liquid-chromatography mass-spectrometry (LC-MS) analysis of the fermented products in comparison to their unfermented constituents. We observed a pronounced release of potential antimicrobial secondary metabolites such as benzoic acids when the plant material was fermented, and a significantly increased antimicrobial effect compared to the unfermented controls against several pathogenic bacteria, especially Salmonella enterica Typhimurium, Listeria monocytogenes, Yersinia enterocolitica, and a strain of atopic dermatitis causing Staphylococcus aureus CC1. In conclusion, fermentation significantly enhances the antimicrobial properties of rapeseed, soybean, and seaweed, offering a promising alternative to zinc oxide for controlling pathogens in piglet feed. This effect is attributed to the release of bioactive metabolites effective against pig production-relevant bacteria.
... Proline is a non-essential amino acid with key roles in protein structure and function and in the maintenance of cellular redox homeostasis. It is either obtained through food or can be produced de novo within cells from protein structures, with collagen being a notable source [26]. ...
Respiratory distress syndrome (RDS) is a major morbidity of prematurity. In this case–control study, we prospectively evaluated whether untargeted metabolomic analysis (gas chromatography–mass spectrometry) of the gastric fluid could predict the need for surfactant in very preterm neonates. 43 infants with RDS necessitating surfactant (cases) were compared with 30 infants who were not treated with surfactant (controls). Perinatal–neonatal characteristics were recorded. Significant differences in gastric fluid metabolites (L-proline, L-glycine, L-threonine, acetyl-L-serine) were observed between groups, but none could solely predict surfactant administration with high accuracy. Univariate analysis revealed significant predictors of surfactant administration involving gastric fluid metabolites (L-glycine, acetyl-L-serine) and clinical parameters (gestational age, Apgar scores, intubation in the delivery room). Multivariable models were constructed for significant clinical variables as well as for the combination of clinical variables and gastric fluid metabolites. The AUC value of the first model was 0.69 (95% CI 0.57–0.81) and of the second, 0.76 (95% CI 0.64–0.86), in which acetyl-L-serine and intubation in the delivery room were found to be significant predictors of surfactant therapy. This investigation adds to the current knowledge of biomarkers in preterm neonates with RDS, but further research is required to assess the predictive value of gastric fluid metabolomics in this field.
... However, some hypotheses could be the following: a) the increase in proline might be related to pancreatic cell dysfunction. Prolonged proline exposure increased basal insulin secretion and decreased glucose-stimulated insulin secretion in both clonal INS1-E insulinoma cells and isolated rat islets [36,37]. b) Proline may function as a redox modulator. ...
... Both proline synthesis and catabolism are intricately involved in redox-active mechanisms. For instance, the catabolic activity of PRODH generates ATP and, when excessively active, leads to an elevation in reactive oxygen species (ROS) production [37]. Several studies have linked the production of ROS to IR [38][39][40]. ...
Circulating concentration of arginine, alanine, aspartate, isoleucine, leucine, phenylalanine, proline, tyrosine, taurine and valine are increased in subjects with insulin resistance, which could in part be attributed to the presence of single nucleotide polymorphisms (SNPs) within genes associated with amino acid metabolism. Thus, the aim of this work was to develop a Genetic Risk Score (GRS) for insulin resistance in young adults based on SNPs present in genes related to amino acid metabolism. We performed a cross-sectional study that included 452 subjects over 18 years of age. Anthropometric, clinical, and biochemical parameters were assessed including measurement of serum amino acids by high performance liquid chromatography. Eighteen SNPs were genotyped by allelic discrimination. Of these, ten were found to be in Hardy-Weinberg equilibrium, and only four were used to construct the GRS through multiple linear regression modeling. The GRS was calculated using the number of risk alleles of the SNPs in HGD , PRODH , DLD and SLC7A9 genes. Subjects with high GRS (≥ 0.836) had higher levels of glucose, insulin, homeostatic model assessment- insulin resistance (HOMA-IR), total cholesterol and triglycerides, and lower levels of arginine than subjects with low GRS ( p < 0.05). The application of a GRS based on variants within genes associated to amino acid metabolism may be useful for the early identification of subjects at increased risk of insulin resistance.
... Ornithine helps convert toxic ammonia to urea by the urea cycle and is a key substrate for excess polyamine production in many cancers (51,52). Proline is involved in collagen and polyamine synthesis, tissue repair, and redox reactions (53,54). Tyrosine is a precursor of neurotransmitters and a receiver of phosphate groups by way of protein kinases in signal transduction and regulation of enzymatic activity (55). ...
Background
Cachexia is a body wasting syndrome that significantly affects well-being and prognosis of cancer patients, without effective treatment. Serum metabolites take part in pathophysiological processes of cancer cachexia, but apart from altered levels of select serum metabolites, little is known on the global changes of the overall serum metabolome, which represents a functional readout of the whole-body metabolic state. Here, we aimed to comprehensively characterize serum metabolite alterations and analyze associated pathways in cachectic cancer patients to gain new insights that could help instruct strategies for novel interventions of greater clinical benefit.
Methods
Serum was sampled from 120 metastatic cancer patients (stage UICC IV). Patients were grouped as cachectic or non-cachectic according to the criteria for cancer cachexia agreed upon international consensus (main criterium: weight loss adjusted to body mass index). Samples were pooled by cachexia phenotype and assayed using non-targeted gas chromatography-mass spectrometry (GC-MS). Normalized metabolite levels were compared using t-test (p < 0.05, adjusted for false discovery rate) and partial least squares discriminant analysis (PLS-DA). Machine-learning models were applied to identify metabolite signatures for separating cachexia states. Significant metabolites underwent MetaboAnalyst 5.0 pathway analysis.
Results
Comparative analyses included 78 cachectic and 42 non-cachectic patients. Cachectic patients exhibited 19 annotable, significantly elevated (including glucose and fructose) or decreased (mostly amino acids) metabolites associating with aminoacyl-tRNA, glutathione and amino acid metabolism pathways. PLS-DA showed distinct clusters (accuracy: 85.6%), and machine-learning models identified metabolic signatures for separating cachectic states (accuracy: 83.2%; area under ROC: 88.0%). We newly identified altered blood levels of erythronic acid and glucuronic acid in human cancer cachexia, potentially linked to pentose-phosphate and detoxification pathways.
Conclusion
We found both known and yet unknown serum metabolite and metabolic pathway alterations in cachectic cancer patients that collectively support a whole-body metabolic state with impaired detoxification capability, altered glucose and fructose metabolism, and substrate supply for increased and/or distinct metabolic needs of cachexia-associated tumors. These findings together imply vulnerabilities, dependencies and targets for novel interventions that have potential to make a significant impact on future research in an important field of cancer patient care.
... The catabolism of proline is mediated by PRODH, in the reverse reaction to that catalysed by PYCR isozymes from P5C. The proline-P5C cycle mediated by PRODH and PYCR isozymes link mitochondria and the cytosol to maintain redox homeostasis [67,68]. Furthermore, proline biosynthesis functions as a vent for TGF-b induced mitochondrial redox stress in cancer associated fibroblasts [69]. ...
The pyruvate transporter MPC1 (mitochondrial pyruvate carrier 1) acts as a tumour-suppressor, loss of which correlates with a pro-tumorigenic phenotype and poor survival in several tumour types. In high-grade serous ovarian cancers (HGSOC), patients display copy number loss of MPC1 in around 78% of cases and reduced MPC1 mRNA expression. To explore the metabolic effect of reduced expression, we demonstrate that depleting MPC1 in HGSOC cell lines drives expression of key proline biosynthetic genes; PYCR1, PYCR2 and PYCR3, and biosynthesis of proline. We show that altered proline metabolism underpins cancer cell proliferation, reactive oxygen species (ROS) production, and type I and type VI collagen formation in ovarian cancer cells. Furthermore, exploring The Cancer Genome Atlas, we discovered the PYCR3 isozyme to be highly expressed in a third of HGSOC patients, which was associated with more aggressive disease and diagnosis at a younger age. Taken together, our study highlights that targeting proline metabolism is a potential therapeutic avenue for the treatment of HGSOC.
... All eight principal biomarkers of fecal metabolites in this study were inversely related to PM 2. Table S6). L-proline is crucial for maintaining redox and nucleotide homeostasis [58]. Elevated levels of circulating proline have been observed in patients with T2D, obesity, and insulin resistance [58]. ...
... L-proline is crucial for maintaining redox and nucleotide homeostasis [58]. Elevated levels of circulating proline have been observed in patients with T2D, obesity, and insulin resistance [58]. The reduction of L-proline in stools in the H-PM 2.5 group implies a potential disruption in PM 2.5 -related excretion of proline. ...
... By means of P5C and its tautomer, glutamic-γ-semialdehyde, the proline cycle is placed at the strategic crossing of several metabolic pathways, e.g., the TCA cycle, urea cycle, pentose phosphate pathway, and is closely linked with glutamate and ornithine metabolism [10]. A distinctive feature of the proline cycle is the so-called redox shuttle, which, thanks to the subcellular location of proline cycle enzymes, uses reduction of P5C to proline through PYCRs (PYCR 1/2/3) for replenishing NADH or NADPH, and as a result, maintains redox homeostasis in conditions of oxidative stress [11]. ...
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.
