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Antioxidants & Redox Signaling Feb 2019Proline metabolism has complex roles in a variety of biological processes, including cell signaling, stress protection, and energy production. Proline also contributes... (Review)
Review
SIGNIFICANCE
Proline metabolism has complex roles in a variety of biological processes, including cell signaling, stress protection, and energy production. Proline also contributes to the pathogenesis of various disease-causing organisms. Understanding the mechanisms of how pathogens utilize proline is important for developing new strategies against infectious diseases. Recent Advances: The ability of pathogens to acquire amino acids is critical during infection. Besides protein biosynthesis, some amino acids, such as proline, serve as a carbon, nitrogen, or energy source in bacterial and protozoa pathogens. The role of proline during infection depends on the physiology of the host/pathogen interactions. Some pathogens rely on proline as a critical respiratory substrate, whereas others exploit proline for stress protection.
CRITICAL ISSUES
Disruption of proline metabolism and uptake has been shown to significantly attenuate virulence of certain pathogens, whereas in other pathogens the importance of proline during infection is not known. Inhibiting proline metabolism and transport may be a useful therapeutic strategy against some pathogens. Developing specific inhibitors to avoid off-target effects in the host, however, will be challenging. Also, potential treatments that target proline metabolism should consider the impact on intracellular levels of Δ-pyrroline-5-carboxylate, a metabolite intermediate that can have opposing effects on pathogenesis.
FUTURE DIRECTIONS
Further characterization of how proline metabolism is regulated during infection would provide new insights into the role of proline in pathogenesis. Biochemical and structural characterization of proline metabolic enzymes from different pathogens could lead to new tools for exploring proline metabolism during infection and possibly new therapeutic compounds.
Topics: Animals; Host-Pathogen Interactions; Humans; Oxidation-Reduction; Proline
PubMed: 29241353
DOI: 10.1089/ars.2017.7335 -
Applied Microbiology and Biotechnology Nov 2008Proline is an important amino acid in terms of its biological functions and biotechnological applications. In response to osmotic stress, proline is accumulated in many... (Review)
Review
Proline is an important amino acid in terms of its biological functions and biotechnological applications. In response to osmotic stress, proline is accumulated in many bacterial and plant cells as an osmoprotectant. However, it has been shown that proline levels are not increased under various stress conditions in the yeast Saccharomyces cerevisiae cells. Proline is believed to serve multiple functions in vitro such as protein and membrane stabilization, lowering the T (m) of DNA, and scavenging of reactive oxygen species, but the mechanisms of these functions in vivo are poorly understood. Yeast cells biosynthesize proline from glutamate in the cytoplasm via the same pathway found in bacteria and plants and also convert excess proline to glutamate in the mitochondria. Based on the fact that proline has stress-protective activity, S. cerevisiae cells that accumulate proline were constructed by disrupting the PUT1 gene involved in the degradation pathway and by expressing the mutant PRO1 gene encoding the feedback inhibition-less sensitive gamma-glutamate kinase to enhance the biosynthetic activity. The engineered yeast strains successfully showed enhanced tolerance to many stresses, including freezing, desiccation, oxidation, and ethanol. However, the appropriate cellular level and localization of proline play pivotal roles in the stress-protective effect. These results indicate that the increased stress protection is observed in yeast cells under the artificial condition of proline accumulation. Proline is expected to contribute to yeast-based industries by improving the production of frozen dough and alcoholic beverages or breakthroughs in bioethanol production.
Topics: Proline; Saccharomyces cerevisiae
PubMed: 18802692
DOI: 10.1007/s00253-008-1698-5 -
Plant Signaling & Behavior Nov 2012When exposed to stressful conditions, plants accumulate an array of metabolites, particularly amino acids. Amino acids have traditionally been considered as precursors... (Review)
Review
When exposed to stressful conditions, plants accumulate an array of metabolites, particularly amino acids. Amino acids have traditionally been considered as precursors to and constituents of proteins, and play an important role in plant metabolism and development. A large body of data suggests a positive correlation between proline accumulation and plant stress. Proline, an amino acid, plays a highly beneficial role in plants exposed to various stress conditions. Besides acting as an excellent osmolyte, proline plays three major roles during stress, i.e., as a metal chelator, an antioxidative defense molecule and a signaling molecule. Review of the literature indicates that a stressful environment results in an overproduction of proline in plants which in turn imparts stress tolerance by maintaining cell turgor or osmotic balance; stabilizing membranes thereby preventing electrolyte leakage; and bringing concentrations of reactive oxygen species (ROS) within normal ranges, thus preventing oxidative burst in plants. Reports indicate enhanced stress tolerance when proline is supplied exogenously at low concentrations. However, some reports indicate toxic effects of proline when supplied exogenously at higher concentrations. In this article, we review and discuss the effects of exogenous proline on plants exposed to various abiotic stresses. Numerous examples of successful application of exogenous proline to improve stress tolerance are presented. The roles played by exogenous proline under varying environments have been critically examined and reviewed.
Topics: Plants; Proline; Reactive Oxygen Species
PubMed: 22951402
DOI: 10.4161/psb.21949 -
Journal of Natural Products Dec 1996
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Biologie Aujourd'hui 2012In addition to its role in primary metabolism as a component of proteins, proline is one of the most widely distributed compatible solutes that accumulates in plants... (Review)
Review
In addition to its role in primary metabolism as a component of proteins, proline is one of the most widely distributed compatible solutes that accumulates in plants during adverse environmental constraints and plays an important role in plant stress tolerance. Proline was proposed to act as stabilizer for proteins and macromolecular complexes, scavenger of free radicals and regulator of cellular redox potential. Intracellular proline concentration depends on a tight regulation between its biosynthesis and catabolism. However the exact role of proline and the signaling pathways involved in the regulation of its metabolism are not completely known yet. Investigation of proline metabolism in model plants would allow to acquire information about the diversity of the mechanisms developed by plants to overcome environmental constraints and to establish some reliable tools for the improvement of crop tolerance.
Topics: Adaptation, Physiological; Environment; Plant Physiological Phenomena; Plants; Proline; Signal Transduction; Stress, Physiological
PubMed: 23419256
DOI: 10.1051/jbio/2012030 -
Advanced Drug Delivery Reviews Mar 2008Proline-rich peptides are a chemically and structurally diverse family of cell-penetrating vectors characterised by the presence of pyrrolidine rings from prolines.... (Review)
Review
Proline-rich peptides are a chemically and structurally diverse family of cell-penetrating vectors characterised by the presence of pyrrolidine rings from prolines. Amphipathic Pro-rich peptides are particularly effective, demonstrating efficient cellular uptake and non-cytotoxicity. Derivatives with hydrophobic moieties, such as fatty acids or silaproline, have shown highly improved internalisation efficiency; an all D-amino acid version of the CPP SAP was shown to be completely protease resistant and was evaluated in a preliminary in vivo study. CD and TEM studies regarding the self-assembly properties of this family of peptides highlight the possible role of aggregated species in the internalisation process. Finally, these CPPs were shown to be internalised via caveolae or lipid-rafts mediated endocytosis, which circumvents the lysosomal route of degradation.
Topics: Animals; Cell Membrane; Cell Membrane Permeability; Circular Dichroism; Drug Delivery Systems; Humans; Microscopy, Electron, Transmission; Peptides; Proline; Protein Conformation; Protein Transport
PubMed: 18187229
DOI: 10.1016/j.addr.2007.09.012 -
Frontiers in Bioscience (Landmark... Jun 2023Intrinsically disordered proteins and protein regions (IDPs/IDRs) are important in diverse biological processes. Lacking a stable secondary structure, they display an...
BACKGROUND
Intrinsically disordered proteins and protein regions (IDPs/IDRs) are important in diverse biological processes. Lacking a stable secondary structure, they display an ensemble of conformations. One factor contributing to this conformational heterogeneity is the proline isomerization. The knowledge and value of a given proline ratio are paramount, as the different conformational states can be responsible for different biological functions. Nuclear Magnetic Resonance (NMR) spectroscopy is the only method to characterize the two co-existing isomers on an atomic level, and only a few works report on these data.
METHODS
After collecting the available experimental literature findings, we conducted a statistical analysis regarding the influence of the neighboring amino acid types ( ± 4 regions) on forming a -Pro isomer. Based on this, several regularities were formulated. NMR spectroscopy was then used to define the Pro content on model peptides and desired point mutations.
RESULTS
Analysis of NMR spectra prove the dependence of the Pro content on the type of the neighboring amino acid-with special attention on aromatic and positively charged sidechains.
CONCLUSIONS
Our results may benefit the design of protein regions with a given -Pro content, and contribute to a better understanding of the roles and functions of IDPs.
Topics: Isomerism; Intrinsically Disordered Proteins; Proline; Peptides; Magnetic Resonance Spectroscopy; Protein Conformation
PubMed: 37395034
DOI: 10.31083/j.fbl2806127 -
Applied Microbiology and Biotechnology Aug 2013Due to the unique role of L-proline in the folding and structure of protein, a variety of synthetic proline analogues have been developed. L-Proline analogues have been... (Review)
Review
Due to the unique role of L-proline in the folding and structure of protein, a variety of synthetic proline analogues have been developed. L-Proline analogues have been proven to be valuable reagents for studying cellular metabolism and the regulation of macromolecule synthesis in both prokaryotic and eukaryotic cells. In addition to these fundamental researches, they are useful compounds for industrial use. For instance, microorganisms that overproduce L-proline have been obtained by isolating mutants resistant to L-proline analogues. They are also promising candidates for tuning the biological, pharmaceutical, or physicochemical properties of naturally occurring or de novo designed peptides. Among L-proline analogues, L-azetidine-2-carboxylic acid (L-AZC) is a toxic non-proteinogenic amino acid originally found in lily of the valley plants and trans-4-hydroxy-L-proline (4-L-THOP) is the most abundant component of mammalian collagen. Many hydroxyprolines (HOPs), such as 4-L-THOP and cis-4-hydroxy-L-proline (4-L-CHOP), are useful chiral building blocks for the organic synthesis of pharmaceuticals. In addition, L-AZC and 4-L-CHOP, which are potent inhibitors of cell growth, have been tested for their antitumor activity in tissue culture and in vivo. In this review, we describe the recent discoveries regarding the physiological properties and microbial production and metabolism of L-proline analogues, particularly L-AZC and HOPs. Their applications in fundamental research and industrial use are also discussed.
Topics: Azetidinecarboxylic Acid; Biotransformation; Proline
PubMed: 23780584
DOI: 10.1007/s00253-013-5022-7 -
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 -
Molecules (Basel, Switzerland) Oct 2022An efficient way to access highly functionalized proline derivatives was developed based on a Cu(I)-catalyzed reaction between CF-substituted allenynes and tosylazide,...
An efficient way to access highly functionalized proline derivatives was developed based on a Cu(I)-catalyzed reaction between CF-substituted allenynes and tosylazide, which involved a cascade of [3 + 2]-cycloaddition/ketenimine and a rearrangement/Alder-ene cyclization to afford the new proline framework with a high diastereoselectivity.
Topics: Proline; Stereoisomerism; Catalysis; Cyclization; Cycloaddition Reaction; Molecular Structure
PubMed: 36296490
DOI: 10.3390/molecules27206898