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Amino Acids Dec 2021Proline metabolism features prominently in the unique metabolism of cancer cells. Proline biosynthetic genes are consistently upregulated in multiple cancers, while the... (Review)
Review
Proline metabolism features prominently in the unique metabolism of cancer cells. Proline biosynthetic genes are consistently upregulated in multiple cancers, while the proline catabolic enzyme proline dehydrogenase has dual, context-dependent pro-cancer and pro-apoptotic functions. Furthermore, the cycling of proline and Δ-pyrroline-5-carboxylate through the proline cycle impacts cellular growth and death pathways by maintaining redox homeostasis between the cytosol and mitochondria. Here we focus on the last enzyme of proline biosynthesis, Δ-pyrroline-5-carboxylate reductase, known as PYCR in humans. PYCR catalyzes the NAD(P)H-dependent reduction of Δ-pyrroline-5-carboxylate to proline and forms the reductive half of the proline metabolic cycle. We review the research on the three-dimensional structure, biochemistry, inhibition, and cancer biology of PYCR. To provide a global view of PYCR gene upregulation in cancer, we mined RNA transcript databases to analyze differential gene expression in 28 cancer types. This analysis revealed strong, widespread upregulation of PYCR genes, especially PYCR1. Altogether, the research over the past 20 years makes a compelling case for PYCR as a cancer therapy target. We conclude with a discussion of some of the major challenges for the field, including developing isoform-specific inhibitors, elucidating the function of the long C-terminus of PYCR1/2, and characterizing the interactome of PYCR.
Topics: Animals; Gene Expression; Humans; Neoplasms; Proline; Pyrroline Carboxylate Reductases; Up-Regulation
PubMed: 34003320
DOI: 10.1007/s00726-021-02999-5 -
Analytical Biochemistry Jun 2024Prolidase (EC.3.4.13.9) is a dipeptidase known nowadays to play a pivotal role in several physiological and pathological processes. More in particular, this enzyme is... (Review)
Review
Prolidase (EC.3.4.13.9) is a dipeptidase known nowadays to play a pivotal role in several physiological and pathological processes. More in particular, this enzyme is involved in the cleavage of proline- and hydroxyproline-containing dipeptides (imidodipeptides), thus finely regulating the homeostasis of free proline and hydroxyproline. Abnormally high or low levels of prolidase have been found in numerous acute and chronic syndromes affecting humans (chronic liver fibrosis, viral and acute hepatitis, cancer, neurological disorders, inflammation, skin diseases, intellectual disability, respiratory infection, and others) for which the content of proline is well recognized as a clinical marker. As a consequence, the accurate analytical determination of prolidase activity is of greatly significant importance in clinical diagnosis and therapy. Apart from the Chinard's assay, some other more sensitive and well validated methodologies have been published. These include colorimetric and spectrophotometric determinations of free proline produced by enzymatic reactions, capillary electrophoresis, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, electrochemoluminescence, thin layer chromatography, and HPLC. The aim of this comprehensive review is to make a detailed survey of the in so far reported analytical techniques, highlighting their general features, as well as their advantages and possible drawbacks, providing in the meantime suggestions to stimulate further research in this intriguing field.
Topics: Humans; Colorimetry; Dipeptidases; Fibrosis; Hydroxyproline; Proline; Enzyme Assays
PubMed: 38460899
DOI: 10.1016/j.ab.2024.115506 -
Experimental Biology and Medicine... Jul 2022Amino acids (AAs) are required for syntheses of proteins and low-molecular-weight substances with enormous physiological importance. Since 1912, AAs have been classified...
Amino acids (AAs) are required for syntheses of proteins and low-molecular-weight substances with enormous physiological importance. Since 1912, AAs have been classified as nutritionally essential amino acids (EAAs) or nonessential amino acids (NEAAs) for animals. EAAs are those AAs that are either not synthesized or insufficiently synthesized de novo in the organisms. It was assumed that all NEAAs (now known as AAs that are synthesizable in animal cells de novo [AASAs]) were formed sufficiently in animals and were not needed in diets. However, studies over the past three decades have shown that sufficient dietary AASAs (e.g. glutamine, glutamate, glycine, and proline) are necessary for the maximum growth and optimum health of pigs, chickens, and fish. Thus, the concept of "ideal protein" (protein with an optimal EAA pattern that precisely meets the physiological needs of animals), which was originally proposed in the 1950s but ignored AASAs, is not ideal in animal nutrition. Ideal diets must provide all physiologically and nutritionally essential AAs. Improved patterns of AAs in diets for swine and chickens as well as zoo and companion animals have been proposed in recent years. Animal-sourced feedstuffs supply abundant EAAs and AASAs (including glutamate, glutamine, glycine, proline, 4-hydroxyproline, and taurine) for diets of swine, poultry, fish, and crustaceans to improve their growth, development, reproduction, and health, while sustaining global animal production. Nutritionists should move beyond the "ideal protein" concept to consider optimum ratios and amounts of all proteinogenic AAs in diets for mammals, birds, and aquatic animals, and, in the case of carnivores, also taurine.
Topics: Amino Acids; Animal Feed; Animals; Chickens; Diet; Glutamic Acid; Glutamine; Glycine; Mammals; Proline; Swine; Taurine
PubMed: 35410533
DOI: 10.1177/15353702221082658 -
Bioinformatics (Oxford, England) May 2020The proteomics field requires the production and publication of reliable mass spectrometry-based identification and quantification results. Although many tools or...
MOTIVATION
The proteomics field requires the production and publication of reliable mass spectrometry-based identification and quantification results. Although many tools or algorithms exist, very few consider the importance of combining, in a unique software environment, efficient processing algorithms and a data management system to process and curate hundreds of datasets associated with a single proteomics study.
RESULTS
Here, we present Proline, a robust software suite for analysis of MS-based proteomics data, which collects, processes and allows visualization and publication of proteomics datasets. We illustrate its ease of use for various steps in the validation and quantification workflow, its data curation capabilities and its computational efficiency. The DDA label-free quantification workflow efficiency was assessed by comparing results obtained with Proline to those obtained with a widely used software using a spiked-in sample. This assessment demonstrated Proline's ability to provide high quantification accuracy in a user-friendly interface for datasets of any size.
AVAILABILITY AND IMPLEMENTATION
Proline is available for Windows and Linux under CECILL open-source license. It can be deployed in client-server mode or in standalone mode at http://proline.profiproteomics.fr/#downloads.
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Algorithms; Mass Spectrometry; Proline; Proteomics; Software
PubMed: 32096818
DOI: 10.1093/bioinformatics/btaa118 -
International Journal of Molecular... Oct 2021Studies of cancer metabolism have focused on the production of energy and the interconversion of carbons between cell cycles. More recently, amino acid metabolism,... (Review)
Review
Studies of cancer metabolism have focused on the production of energy and the interconversion of carbons between cell cycles. More recently, amino acid metabolism, especially non-essential amino acids (NEAAs), has been investigated, underlining their regulatory role. One of the important mediators in energy production and interconversion of carbons in the cell is Δ-pyrroline-5-carboxylate (P5C)-the physiological intracellular intermediate of the interconversion of proline, ornithine, and glutamate. As a central component of these conversions, it links the tricarboxylic acid cycle (TCA), urea cycle (UC), and proline cycle (PC). P5C has a cyclic structure containing a tertiary nitrogen atom (N) and is in tautomeric equilibrium with the open-chain form of L-glutamate--semialdehyde (GSAL). P5C is produced by P5C synthase (P5CS) from glutamate, and ornithine via ornithine -amino acid transferase (OAT). It can also be converted to glutamate by P5C dehydrogenase (P5CDH). P5C is both a direct precursor of proline and a product of its degradation. The conversion of P5C to proline is catalyzed by P5C reductase (PYCR), while proline to P5C by proline dehydrogenase/oxidase (PRODH/POX). P5C-proline-P5C interconversion forms a functional redox couple. Their transformations are accompanied by the transfer of a reducing-oxidizing potential, that affect the NADP+/NADPH ratio and a wide variety of processes, e.g., the synthesis of phosphoribosyl pyrophosphate (PRPP), and purine ribonucleotides, which are crucial for DNA synthesis. This review focuses on the metabolism of P5C in the cell as an interconversion mediator of proline, glutamate, and ornithine and its role in the regulation of survival and death with particular emphasis on the metabolic context.
Topics: Amino Acids; Animals; Apoptosis; Cell Survival; Humans; Ornithine-Oxo-Acid Transaminase; Proline; Pyrroles
PubMed: 34769188
DOI: 10.3390/ijms222111763 -
Psychiatry and Clinical Neurosciences Apr 2023Depression is a psychiatric disease which is accompanied by metabolic disorder. Though depression has been widely studied, its metabolism is yet to be illustrated. We...
Identification of proline, 1-pyrroline-5-carboxylate and glutamic acid as biomarkers of depression reflecting brain metabolism using carboxylomics, a new metabolomics method.
AIM
Depression is a psychiatric disease which is accompanied by metabolic disorder. Though depression has been widely studied, its metabolism is yet to be illustrated. We aimed to manifest the underlying mechanisms to diagnose depression.
METHODS
One hundred thirty serum samples, including 65 patients and 65 healthy controls from different hospitals (training and validation cohorts), were recruited into the research. Sensitive Profiling for ChemoSelective Derivatization Carboxylomics (SPCSDCarboxyl) was applied to deeply hunt for the differential metabolites. Then, the serum, CSF, and hippocampus from depression rat models (CUMS group) were used to further confirm the results. Additionally, the co-occurrence between enzymes and biomarkers, as well as the combinatorial marker panel and the correlation of biomarkers among serum, CSF, or hippocampus were elucidated.
RESULTS
Two hundred eight metabolites were identified from the sera of patients. Proline, 1-pyrroline-5-carboxylate (P5C), and glutamic acid could discriminate patients from healthy humans and were confirmed to be the potential biomarkers. After further validation through CUMS rats, proline, and P5C were enriched, while glutamic acid was depleted in the CUMS group. The co-occurrence analysis of enzymes and biomarkers indicated that they could be used for the diagnosis of depression. Moreover, the combinatorial marker panel and the correlation analysis of biomarkers between serum and CSF or between serum and hippocampus revealed that serum could be an alternative approach to directly reflect the potential physiological mechanisms and diagnose depression instead of brain samples.
CONCLUSION
These integrated methods may facilitate the identification of biomarkers and help manifest the underlying mechanisms of depression.
Topics: Humans; Rats; Animals; Glutamic Acid; Depression; Proline; Metabolomics; Brain; Biomarkers
PubMed: 36468242
DOI: 10.1111/pcn.13517 -
Scientific Reports Aug 2022The epidermal differentiation complex (EDC) is a cluster of genes encoding components of the skin barrier in terrestrial vertebrates. EDC genes can be categorized as...
The epidermal differentiation complex (EDC) is a cluster of genes encoding components of the skin barrier in terrestrial vertebrates. EDC genes can be categorized as S100 fused-type protein (SFTP) genes such as filaggrin, which contain two coding exons, and single-coding-exon EDC (SEDC) genes such as loricrin. SFTPs are known to be present in amniotes (mammals, reptiles and birds) and amphibians, whereas SEDCs have not yet been reported in amphibians. Here, we show that caecilians (Amphibia: Gymnophiona) have both SFTP and SEDC genes. Two to four SEDC genes were identified in the genomes of Rhinatrema bivittatum, Microcaecilia unicolor and Geotrypetes seraphini. Comparative analysis of tissue transcriptomes indicated predominant expression of SEDC genes in the skin of caecilians. The proteins encoded by caecilian SEDC genes resemble human SEDC proteins, such as involucrin and small proline-rich proteins, with regard to low sequence complexity and high contents of proline, glutamine and lysine. Our data reveal diversification of EDC genes in amphibians and suggest that SEDC-type skin barrier genes have originated either in a common ancestor of tetrapods followed by loss in Batrachia (frogs and salamanders) or, by convergent evolution, in caecilians and amniotes.
Topics: Amphibians; Animals; Epidermis; Humans; Mammals; Phylogeny; Proline; Reptiles; S100 Proteins
PubMed: 35948609
DOI: 10.1038/s41598-022-18053-7 -
Nutrition Reviews May 2022Collagen is the central structural component of extracellular connective tissue, which provides elastic qualities to tissues. For skeletal muscle, extracellular... (Review)
Review
Collagen is the central structural component of extracellular connective tissue, which provides elastic qualities to tissues. For skeletal muscle, extracellular connective tissue transmits contractile force to the tendons and bones. Connective tissue proteins are in a constant state of remodeling and have been shown to express a high level of plasticity. Dietary-protein ingestion increases muscle protein synthesis rates. High-quality, rapidly digestible proteins are generally considered the preferred protein source to maximally stimulate myofibrillar (contractile) protein synthesis rates. In contrast, recent evidence demonstrates that protein ingestion does not increase muscle connective tissue protein synthesis. The absence of an increase in muscle connective tissue protein synthesis after protein ingestion may be explained by insufficient provision of glycine and/or proline. Dietary collagen contains large amounts of glycine and proline and, therefore, has been proposed to provide the precursors required to facilitate connective tissue protein synthesis. This literature review provides a comprehensive evaluation of the current knowledge on the proposed benefits of dietary collagen consumption to stimulate connective tissue remodeling to improve health and functional performance.
Topics: Collagen; Connective Tissue; Eating; Glycine; Humans; Muscle, Skeletal; Proline
PubMed: 34605901
DOI: 10.1093/nutrit/nuab083 -
Scientific Reports Sep 20225-Oxoproline (5OP) is a poorly researched ubiquitous natural amino acid found in all life forms. We have previously shown that Salmonella enterica serovar Typhimurium...
5-Oxoproline (5OP) is a poorly researched ubiquitous natural amino acid found in all life forms. We have previously shown that Salmonella enterica serovar Typhimurium (Salmonella) responds to 5OP exposure by reducing cyclic-di-GMP levels, and resultant cellulose dependent cellular aggregation in a YfeA and BcsA dependent manner. To understand if 5OP was specifically sensed by Salmonella we compared the interaction of Salmonella with 5OP to that of the chemically similar and biologically relevant molecule, L-proline. We show that L-proline but not 5OP can be utilized by Salmonella as a nutrient source. We also show that 5OP but not L-proline regulates cellulose dependent cellular aggregation. These results imply that 5OP is utilized by Salmonella as a specific signal. However, L-proline is a 5OP aggregation inhibitor implying that while it cannot activate the aggregation pathway by itself, it can inhibit 5OP dependent activation. We then show that in a L-proline transporter knockout mutant L-proline competition remain unaffected, implying sensing of 5OP is extracellular. Last, we identify a transcriptional effect of 5OP exposure, upregulation of the mgtCBR operon, known to be activated during host invasion. While mgtCBR is known to be regulated by both low pH and L-proline starvation, we show that 5OP regulation of mgtCBR is indirect through changes in pH and is not dependent on the 5OP chemical structure similarity to L-proline. We also show this response to be PhoPQ dependent. We further show that the aggregation response is independent of pH modulation, PhoPQ and MgtC and that the mgtCBR transcriptional response is independent of YfeA and BcsA. Thus, the two responses are mediated through two independent signaling pathways. To conclude, we show Salmonella responds to 5OP specifically to regulate aggregation and not specifically to regulate gene expression. When and where in the Salmonella life cycle does 5OP sensing takes place remains an open question. Furthermore, because 5OP inhibits c-di-GMP through the activation of an external sensor, and does not require an internalization step like many studied biofilm inhibitors, 5OP or derivatives might be developed into useful biofilm inhibitors.
Topics: Bacterial Proteins; Cellulose; Gene Expression Regulation, Bacterial; Proline; Pyrrolidonecarboxylic Acid; Salmonella typhimurium; Serogroup
PubMed: 36153368
DOI: 10.1038/s41598-022-20407-0 -
Journal of the American Chemical Society Sep 2021Peptides constrained by intramolecular cross-links, especially stapled α-helices, have emerged as versatile scaffolds for drug development. However, there are fewer...
Peptides constrained by intramolecular cross-links, especially stapled α-helices, have emerged as versatile scaffolds for drug development. However, there are fewer examples of similarly constrained scaffolds for other secondary structures. Here, we used a novel computational strategy to identify an optimal staple for antiparallel β-strands, and then we incorporated that staple within a β-hairpin peptide. The hairpin uses 4-mercaptoproline as a novel staple component, which contributes to a unique, kinked structure. The stapled hairpins show a high degree of structure in aqueous solution, excellent resistance to degradation in cell lysates, and cytosolic penetration at micromolar concentrations. They also overlay with a unique subset of kinked hairpin motifs at protein-protein interaction interfaces. Thus, these scaffolds represent promising starting points for developing inhibitors of cellular protein-protein interactions.
Topics: Amino Acid Sequence; Models, Molecular; Peptides; Proline; Protein Structure, Secondary
PubMed: 34516087
DOI: 10.1021/jacs.1c04378