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Cells Nov 2023The culture of embryos in the non-essential amino acid L-proline (Pro) or its analogues pipecolic acid (PA) and L-4-thiazolidine carboxylic acid (L4T) improves embryo...
The culture of embryos in the non-essential amino acid L-proline (Pro) or its analogues pipecolic acid (PA) and L-4-thiazolidine carboxylic acid (L4T) improves embryo development, increasing the percentage that develop to the blastocyst stage and hatch. Staining of 2-cell and 4-cell embryos with tetramethylrhodamine methyl ester and 2',7'-dichlorofluorescein diacetate showed that the culture of embryos in the presence of Pro, or either of these analogues, reduced mitochondrial activity and reactive oxygen species (ROS), respectively, indicating potential mechanisms by which embryo development is improved. Inhibition of the Pro metabolism enzyme, proline oxidase, by tetrahydro-2-furoic-acid prevented these reductions and concomitantly prevented the improved development. The ways in which Pro, PA and L4T reduce mitochondrial activity and ROS appear to differ, despite their structural similarity. Specifically, the results are consistent with Pro reducing ROS by reducing mitochondrial activity while PA and L4T may be acting as ROS scavengers. All three may work to reduce ROS by contributing to the GSH pool. Overall, our results indicate that reduction in mitochondrial activity and oxidative stress are potential mechanisms by which Pro and its analogues act to improve pre-implantation embryo development.
Topics: Animals; Mice; Reactive Oxygen Species; Proline; Oxidative Stress; Blastocyst; Embryonic Development
PubMed: 37998375
DOI: 10.3390/cells12222640 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Dec 2022L-proline (L-Pro) is the only imino acid among the 20 amino acids that constitute biological proteins, and its main hydroxylated product is -4-hydroxy-L-proline... (Review)
Review
L-proline (L-Pro) is the only imino acid among the 20 amino acids that constitute biological proteins, and its main hydroxylated product is -4-hydroxy-L-proline (T-4-Hyp). Both of them have unique biological activities and play important roles in biomedicine, food and beauty industry. With the in-depth exploration of the functions of L-Pro and T-4-Hyp, the demand for them is gradually increasing. Traditional methods of biological extraction and chemical synthesis are unable to meet the demand of "green, environmental protection and high efficiency". In recent years, synthetic biology has developed rapidly. Through the intensive analysis of the synthetic pathways of L-Pro and T-4-Hyp, microbial cell factories were constructed for large-scale production, which opened a new chapter for the green and efficient production of L-Pro and T-4-Hyp. This paper reviews the application and production methods of L-Pro and T-4-Hyp, the metabolic pathways for microbial synthesis of L-Pro and T-4-Hyp, and the engineering strategies and advances on microbial production of L-Pro and T-4-Hyp, aiming to provide a theoretical basis for the "green bio-manufacturing" of L-Pro and T-4-Hyp and promote their industrial production.
Topics: Proline; Hydroxyproline
PubMed: 36593190
DOI: 10.13345/j.cjb.220739 -
Current Medicinal Chemistry 2023COVID-19 is a contagious disease. Paxlovid, a combination of Nirmatrelvir and Ritonavir, was granted emergency use authorization by the United States Food and Drug...
COVID-19 is a contagious disease. Paxlovid, a combination of Nirmatrelvir and Ritonavir, was granted emergency use authorization by the United States Food and Drug Administration (FDA) for the treatment of COVID-19 on December 22, 2021. These are peptidomimetic coronavirus main protease inhibitors. Nirmatrelvir is a proline derivative. The present patent describes similar proline- like compounds, their preparation, use, pharmaceutical composition, and treatment.
Topics: United States; Humans; COVID-19; Lactams; Proline; Antiviral Agents
PubMed: 36154584
DOI: 10.2174/0929867329666220922095343 -
Biomedicine & Pharmacotherapy =... Feb 2017Ornithine is a non-essential amino acid produced as an intermediate molecule in urea cycle. It is a key substrate for the synthesis of proline, polyamines and... (Review)
Review
Ornithine is a non-essential amino acid produced as an intermediate molecule in urea cycle. It is a key substrate for the synthesis of proline, polyamines and citrulline. Ornithine also plays an important role in the regulation of several metabolic processes leading to diseases like hyperorithinemia, hyperammonemia, gyrate atrophy and cancer in humans. However, the mechanism of action behind the multi-faceted roles of ornithine is yet to be unraveled completely. Several types of cancers are also characterized by excessive polyamine synthesis from ornithine by different rate limiting enzymes. Hence, in this review we aim to provide extensive insights on potential roles of ornithine in many of the disease related cellular processes and also on the structural features of ornithine interacting proteins, enabling development of therapeutic modalities.
Topics: Animals; Humans; Metabolic Diseases; Ornithine; Polyamines; Proline; Protein Binding; Protein Structure, Secondary
PubMed: 27978498
DOI: 10.1016/j.biopha.2016.12.024 -
Marine Drugs Oct 2016Peptides have gained increased interest as therapeutics during recent years. More than 60 peptide drugs have reached the market for the benefit of patients and several... (Review)
Review
Peptides have gained increased interest as therapeutics during recent years. More than 60 peptide drugs have reached the market for the benefit of patients and several hundreds of novel therapeutic peptides are in preclinical and clinical development. The key contributor to this success is the potent and specific, yet safe, mode of action of peptides. Among the wide range of biologically-active peptides, naturally-occurring marine-derived cyclopolypeptides exhibit a broad range of unusual and potent pharmacological activities. Because of their size and complexity, proline-rich cyclic peptides (PRCPs) occupy a crucial chemical space in drug discovery that may provide useful scaffolds for modulating more challenging biological targets, such as protein-protein interactions and allosteric binding sites. Diverse pharmacological activities of natural cyclic peptides from marine sponges, tunicates and cyanobacteria have encouraged efforts to develop cyclic peptides with well-known synthetic methods, including solid-phase and solution-phase techniques of peptide synthesis. The present review highlights the natural resources, unique structural features and the most relevant biological properties of proline-rich peptides of marine-origin, focusing on the potential therapeutic role that the PRCPs may play as a promising source of new peptide-based novel drugs.
Topics: Animals; Aquatic Organisms; Biological Products; Cyanobacteria; Drug Discovery; Humans; Peptides, Cyclic; Porifera; Proline; Urochordata
PubMed: 27792168
DOI: 10.3390/md14110194 -
Genetics May 2021The final step in proline biosynthesis is catalyzed by three pyrroline-5-carboxylate reductases, PYCR1, PYCR2, and PYCR3, which convert pyrroline-5-carboxylate (P5C) to...
The final step in proline biosynthesis is catalyzed by three pyrroline-5-carboxylate reductases, PYCR1, PYCR2, and PYCR3, which convert pyrroline-5-carboxylate (P5C) to proline. Mutations in human PYCR1 and ALDH18A1 (P5C Synthetase) cause Cutis Laxa (CL), whereas mutations in PYCR2 cause hypomyelinating leukodystrophy 10 (HLD10). Here, we investigated the genetics of Pycr1 and Pycr2 in mice. A null allele of Pycr1 did not show integument or CL-related phenotypes. We also studied a novel chemically-induced mutation in Pycr2. Mice with recessive loss-of-function mutations in Pycr2 showed phenotypes consistent with neurological and neuromuscular disorders, including weight loss, kyphosis, and hind-limb clasping. The peripheral nervous system was largely unaffected, with only mild axonal atrophy in peripheral nerves. A severe loss of subcutaneous fat in Pycr2 mutant mice is reminiscent of a CL-like phenotype, but primary features such as elastin abnormalities were not observed. Aged Pycr2 mutant mice had reduced white blood cell counts and altered lipid metabolism, suggesting a generalized metabolic disorder. PYCR1 and -2 have similar enzymatic and cellular activities, and consistent with previous studies, both were localized in the mitochondria in fibroblasts. Both PYCR1 and -2 were able to complement the loss of Pro3, the yeast enzyme that converts P5C to proline, confirming their activity as P5C reductases. In mice, Pycr1; Pycr2 double mutants were sub-viable and unhealthy compared to either single mutant, indicating the genes are largely functionally redundant. Proline levels were not reduced, and precursors were not increased in serum from Pycr2 mutant mice or in lysates from skin fibroblast cultures, but placing Pycr2 mutant mice on a proline-free diet worsened the phenotype. Thus, Pycr1 and -2 have redundant functions in proline biosynthesis, and their loss makes proline a semi-essential amino acid. These findings have implications for understanding the genetics of CL and HLD10, and for modeling these disorders in mice.
Topics: Animals; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mutation; Phenotype; Proline; Pyrroline Carboxylate Reductases
PubMed: 33734376
DOI: 10.1093/genetics/iyab048 -
International Journal of Molecular... Oct 2022Abiotic stresses, such as drought, salinity, heat, cold, and heavy metals, are associated with global climate change and hamper plant growth and development, affecting... (Review)
Review
Abiotic stresses, such as drought, salinity, heat, cold, and heavy metals, are associated with global climate change and hamper plant growth and development, affecting crop yields and quality. However, the negative effects of abiotic stresses can be mitigated through exogenous treatments using small biomolecules. For example, the foliar application of melatonin provides the following: it protects the photosynthetic apparatus; it increases the antioxidant defenses, osmoprotectant, and soluble sugar levels; it prevents tissue damage and reduces electrolyte leakage; it improves reactive oxygen species (ROS) scavenging; and it increases biomass, maintains the redox and ion homeostasis, and improves gaseous exchange. Glutathione spray upregulates the glyoxalase system, reduces methylglyoxal (MG) toxicity and oxidative stress, decreases hydrogen peroxide and malondialdehyde accumulation, improves the defense mechanisms, tissue repairs, and nitrogen fixation, and upregulates the phytochelatins. The exogenous application of proline enhances growth and other physiological characteristics, upregulates osmoprotection, protects the integrity of the plasma lemma, reduces lipid peroxidation, increases photosynthetic pigments, phenolic acids, flavonoids, and amino acids, and enhances stress tolerance, carbon fixation, and leaf nitrogen content. The foliar application of glycine betaine improves growth, upregulates osmoprotection and osmoregulation, increases relative water content, net photosynthetic rate, and catalase activity, decreases photorespiration, ion leakage, and lipid peroxidation, protects the oxygen-evolving complex, and prevents chlorosis. Chemical priming has various important advantages over transgenic technology as it is typically more affordable for farmers and safe for plants, people, and animals, while being considered environmentally acceptable. Chemical priming helps to improve the quality and quantity of the yield. This review summarizes and discusses how exogenous melatonin, glutathione, proline, and glycine betaine can help crops combat abiotic stresses.
Topics: Melatonin; Betaine; Proline; Glutathione; Antioxidants; Stress, Physiological
PubMed: 36361700
DOI: 10.3390/ijms232112913 -
Experimental Biology and Medicine... Mar 2016The amino acids in the placenta have multiple functions; however, the therapeutic effects of proline remain poorly for relief postmenopausal symptoms. The aim of present...
The amino acids in the placenta have multiple functions; however, the therapeutic effects of proline remain poorly for relief postmenopausal symptoms. The aim of present study was to evaluate the effects of proline in the treatment of menopause using in vitro and in vivo models. We assessed the therapeutic effects and regulatory mechanisms of proline by using MCF-7 estrogen-dependent cells, MG63 osteoblast cells, and ovariectomized mice model. An in vivo study was carried out in eight-week-old sham and ovariectomized group. The ovariectomized mouse was further subdivided into two groups administered orally with 17β-estradiol or proline (10 mg/kg/day) for eight weeks. Proline significantly increased cell proliferation and Ki-67 levels in MCF-7 cells and enhanced cell proliferation, alkaline phosphatase activity, extracellular signal-regulated kinase phosphorylation, and glutamyl-prolyl-tRNA synthetase activation in MG63 cells. The estrogen receptor-β and estrogen-response elements luciferase activity were significantly increased by proline in MCF-7 and MG63 cells. In ovariectomized mice, oral administration of proline (10 mg/kg/day) for eight weeks significantly reduced body and vaginal weights. Proline also significantly increased serum estradiol and alkaline phosphatase levels, whereas serum luteinizing hormone was decreased by proline. In addition, detailed microcomputed tomography analysis showed that the proline notably enhanced bone mineral density, trabecular bone volume, and trabecular number in ovariectomized mice. Those findings implied that proline can be a promising candidate for the treatment of menopause.
Topics: Administration, Oral; Animals; Disease Models, Animal; Female; Humans; Menopause; Mice, Inbred BALB C; Models, Biological; Osteoporosis, Postmenopausal; Proline; Treatment Outcome
PubMed: 26830682
DOI: 10.1177/1535370216629011 -
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