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Amino Acids Dec 2021L-proline catabolism is emerging as a key pathway that is critical to cellular metabolism, growth, survival, and death. Proline dehydrogenase (PRODH) enzyme, which... (Review)
Review
L-proline catabolism is emerging as a key pathway that is critical to cellular metabolism, growth, survival, and death. Proline dehydrogenase (PRODH) enzyme, which catalyzes the first step of proline catabolism, has diverse functional roles in regulating many pathophysiological processes, including apoptosis, autophagy, cell senescence, and cancer metastasis. Notably, accumulated evidence demonstrated that PRODH plays complex role in many types of cancers. In this review, we briefly introduce the function of PRODH, then its expression in different types of cancer. We next discuss the regulation of PRODH in cancer, the downstream pathways of PRODH and the therapies that are under investigation. Finally, we propose novel insights for future perspectives on the modulation of PRODH.
Topics: Animals; Apoptosis; Autophagy; Cellular Senescence; Humans; Neoplasms; Proline; Proline Oxidase; Signal Transduction
PubMed: 34283310
DOI: 10.1007/s00726-021-03032-5 -
Future Medicinal Chemistry Sep 2020
Topics: Adenocarcinoma; Amides; Antineoplastic Agents; Colorectal Neoplasms; Enzyme Inhibitors; Humans; N-Acetylgalactosaminyltransferases; Proline; Sarcosine
PubMed: 32752887
DOI: 10.4155/fmc-2020-0137 -
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 -
International Journal of Food Sciences... May 2020The aim of this study was to investigate the association of total proline intake, proline of various food sources, and substitution analysis for proline of food sources...
The aim of this study was to investigate the association of total proline intake, proline of various food sources, and substitution analysis for proline of food sources with blood pressure (BP) and 3.1-year incidence of hypertension in the framework of the Tehran Lipid and Glucose Study. The cohort consisted of 4287 participants (41.9% male), aged ≥ 20-70 years. In fully-adjusted model, individuals in the highest tertile for proline intake had an increased risk of incident hypertension than those in the lowest one (OR: 1.45; 95%CI: 1.06-1.97; for trend: .017). Replacing proline of cheese and legumes source with that of yogurt, poultry, milk, and red meat source was associated with significant negative β coefficient for BP. The present study indicated that high dietary intakes of proline may increase the risk of incident hypertension. Also, substituting proline intake of cheese and legumes by those of proline intake of meats and milk is associated with a lower risk of high BP.
Topics: Adult; Aged; Blood Pressure; Cohort Studies; Diet; Female; Food Analysis; Humans; Hypertension; Iran; Male; Middle Aged; Proline; Risk Factors; Young Adult
PubMed: 31460809
DOI: 10.1080/09637486.2019.1650004 -
Chembiochem : a European Journal of... Dec 2022Proline residues within proteins lack a traditional hydrogen bond donor. However, the hydrogens of the proline ring are all sterically accessible, with polarized C-H...
Proline residues within proteins lack a traditional hydrogen bond donor. However, the hydrogens of the proline ring are all sterically accessible, with polarized C-H bonds at Hα and Hδ that exhibit greater partial positive character and can be utilized as alternative sites for molecular recognition. C-H/O interactions, between proline C-H bonds and oxygen lone pairs, have been previously identified as modes of recognition within protein structures and for higher-order assembly of protein structures. In order to better understand intermolecular recognition of proline residues, a series of proline derivatives was synthesized, including 4R-hydroxyproline nitrobenzoate methyl ester, acylated on the proline nitrogen with bromoacetyl and glycolyl groups, and Boc-4S-(4-iodophenyl)hydroxyproline methyl amide. All three derivatives exhibited multiple close intermolecular C-H/O interactions in the crystallographic state, with H⋅⋅⋅O distances as close as 2.3 Å. These observed distances are well below the 2.72 Å sum of the van der Waals radii of H and O, and suggest that these interactions are particularly favorable. In order to generalize these results, we further analyzed the role of C-H/O interactions in all previously crystallized derivatives of these amino acids, and found that all 26 structures exhibited close intermolecular C-H/O interactions. Finally, we analyzed all proline residues in the Cambridge Structural Database of small-molecule crystal structures. We found that the majority of these structures exhibited intermolecular C-H/O interactions at proline C-H bonds, suggesting that C-H/O interactions are an inherent and important mode for recognition of and higher-order assembly at proline residues. Due to steric accessibility and multiple polarized C-H bonds, proline residues are uniquely positioned as sites for binding and recognition via C-H/O interactions.
Topics: Proline; Models, Molecular; Hydroxyproline; Hydrogen Bonding; Proteins
PubMed: 36129371
DOI: 10.1002/cbic.202200409 -
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 -
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 -
Biochemistry Nov 2021Thiazolidine carboxylates such as thiazolidine-4-carboxylate (T4C) and thiazolidine-2-carboxylate (T2C) are naturally occurring sulfur analogues of proline. These...
Thiazolidine carboxylates such as thiazolidine-4-carboxylate (T4C) and thiazolidine-2-carboxylate (T2C) are naturally occurring sulfur analogues of proline. These compounds have been observed to have both beneficial and toxic effects in cells. Given that proline dehydrogenase has been proposed to be a key enzyme in the oxidative metabolism of thioprolines, we characterized T4C and T2C as substrates of proline catabolic enzymes using proline utilization A (PutA), which is a bifunctional enzyme with proline dehydrogenase (PRODH) and l-glutamate-γ-semialdehyde dehydrogenase (GSALDH) activities. PutA is shown here to catalyze the FAD-dependent PRODH oxidation of both T4C and T2C with catalytic efficiencies significantly higher than with proline. Stopped-flow experiments also demonstrate that l-T4C and l-T2C reduce PutA-bound FAD at rates faster than proline. Unlike proline, however, oxidation of T4C and T2C does not generate a substrate for NAD-dependent GSALDH. Instead, PutA/PRODH oxidation of T4C leads to cysteine formation, whereas oxidation of T2C generates an apparently stable Δ-thiazoline-2-carboxylate species. Our results provide new insights into the metabolism of T2C and T4C.
Topics: Bacterial Proteins; Cysteine; Enzyme Assays; Kinetics; Membrane Proteins; Proline; Recombinant Proteins; Sinorhizobium meliloti; Thiazolidines
PubMed: 34752700
DOI: 10.1021/acs.biochem.1c00625 -
Molecules (Basel, Switzerland) Dec 2021The 3D structure and surface characteristics of proteins and peptides are crucial for interactions with receptors or ligands and can be modified to some extent to... (Review)
Review
The 3D structure and surface characteristics of proteins and peptides are crucial for interactions with receptors or ligands and can be modified to some extent to modulate their biological roles and pharmacological activities. The introduction of halogen atoms on the side-chains of amino acids is a powerful tool for effecting this type of tuning, influencing both the physico-chemical and structural properties of the modified polypeptides, helping to first dissect and then rationally modify features that affect their mode of action. This review provides examples of the influence of different types of halogenation in amino acids that replace native residues in proteins and peptides. Examples of synthetic strategies for obtaining halogenated amino acids are also provided, focusing on some representative compounds and their biological effects. The role of halogenation in native and designed antimicrobial peptides (AMPs) and their mimetics is then discussed. These are in the spotlight for the development of new antimicrobial drugs to counter the rise of antibiotic-resistant pathogens. AMPs represent an interesting model to study the role that natural halogenation has on their mode of action and also to understand how artificially halogenated residues can be used to rationally modify and optimize AMPs for pharmaceutical purposes.
Topics: Anti-Bacterial Agents; Antimicrobial Peptides; Gram-Negative Bacteria; Gram-Positive Bacteria; Halogenation; Halogens; Humans; Microbial Sensitivity Tests; Peptidomimetics; Peptoids; Proline; Structure-Activity Relationship
PubMed: 34885985
DOI: 10.3390/molecules26237401 -
Biopreservation and Biobanking Dec 2022This study investigated the effect of ascorbic acid (vitamin C) and proline amino acid alone or together on the quality and fertility of frozen/thawed honey bee...
This study investigated the effect of ascorbic acid (vitamin C) and proline amino acid alone or together on the quality and fertility of frozen/thawed honey bee spermatozoa. The experiments were designed to compare a single ascorbic acid, a single proline amino acid, and different combinations of ascorbic acid with proline amino acid on the cryopreservation of honey bee semen based on sperm motility, viability, intact membrane (hypo-osmotic swelling test), and fertility rates. Eight cryopreserved study groups comprised Control II with no supplement, along with groups with ascorbic acid (2 mg), proline 25 mM, proline 50 mM, proline 100 mM, and combination groups of both ascorbic acid (2 mg) and proline 25 mM, proline 50 mM, and lastly proline 100 mM groups, respectively. Using 50 mM proline in the tested groups had the greatest impact on sperm motility, viability, the percentage of spermatozoa with intact membrane, and fertility. The cryopreservation process caused a gradual decrease in motility, viability, intact membrane ( < 0.05), and fertility rates ( < 0.01) in all the tested research groups as against the fresh semen control group. Successful honey bee sperm cryopreservation and fertility are achievable when using an appropriate sperm freezing protocol and antioxidant. Proline amino acid as an antioxidant in semen extender had a more beneficial influence on sperm quality parameters and fertility. The success of cryopreservation with antioxidants is related to the chosen antioxidant in a dose-dependent manner.
Topics: Animals; Bees; Male; Semen; Ascorbic Acid; Antioxidants; Birth Rate; Proline; Cryoprotective Agents; Semen Preservation; Sperm Motility; Spermatozoa; Cryopreservation; Amino Acids; Dietary Supplements
PubMed: 35020446
DOI: 10.1089/bio.2021.0077