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Aging Cell Feb 2021Infertility is an increasingly common health issue, with rising prevalence in advanced parental age. Environmental stress has established negative effects on...
Infertility is an increasingly common health issue, with rising prevalence in advanced parental age. Environmental stress has established negative effects on reproductive health, however, the impact of altering cellular metabolism and its endogenous reactive oxygen species (ROS) on fertility remains unclear. Here, we demonstrate the loss of proline dehydrogenase, the first committed step in proline catabolism, is relatively benign. In contrast, disruption of alh-6, which facilitates the second step of proline catabolism by converting 1-pyrroline-5-carboxylate (P5C) to glutamate, results in premature reproductive senescence, specifically in males. The premature reproductive senescence in alh-6 mutant males is caused by aberrant ROS homeostasis, which can be countered by genetically limiting the first committed step of proline catabolism that functions upstream of ALH-6 or by pharmacological treatment with antioxidants. Taken together, our work uncovers proline metabolism as a critical component of normal sperm function that can alter the rate of aging in the male reproductive system.
Topics: Animals; Caenorhabditis elegans; Cellular Senescence; Germ Cells; Male; Proline; Spermatozoa
PubMed: 33480139
DOI: 10.1111/acel.13308 -
Genes & Development May 2023DROSHA serves as a gatekeeper of the microRNA (miRNA) pathway by processing primary transcripts (pri-miRNAs). While the functions of structured domains of DROSHA have...
DROSHA serves as a gatekeeper of the microRNA (miRNA) pathway by processing primary transcripts (pri-miRNAs). While the functions of structured domains of DROSHA have been well documented, the contribution of N-terminal proline-rich disordered domain (PRD) remains elusive. Here we show that the PRD promotes the processing of miRNA hairpins located within introns. We identified a DROSHA isoform (p140) lacking the PRD, which is produced by proteolytic cleavage. Small RNA sequencing revealed that p140 is significantly impaired in the maturation of intronic miRNAs. Consistently, our minigene constructs demonstrated that PRD enhances the processing of intronic hairpins, but not those in exons. Splice site mutations did not affect the PRD's enhancing effect on intronic constructs, suggesting that the PRD acts independently of splicing reaction by interacting with sequences residing within introns. The N-terminal regions from zebrafish and DROSHA can replace the human counterpart, indicating functional conservation despite poor sequence alignment. Moreover, we found that rapidly evolving intronic miRNAs are generally more dependent on PRD than conserved ones, suggesting a role of PRD in miRNA evolution. Our study reveals a new layer of miRNA regulation mediated by a low-complexity disordered domain that senses the genomic contexts of miRNA loci.
Topics: Animals; Humans; Introns; MicroRNAs; Proline; Ribonuclease III; RNA Processing, Post-Transcriptional; Zebrafish
PubMed: 37236670
DOI: 10.1101/gad.350275.122 -
American Journal of Physiology. Lung... Jun 2015The lack of a well-characterized biomarker for the diagnosis of chronic obstructive pulmonary disease (COPD) has increased interest toward finding one, because this... (Review)
Review
The lack of a well-characterized biomarker for the diagnosis of chronic obstructive pulmonary disease (COPD) has increased interest toward finding one, because this would provide potential insight into disease pathogenesis and progression. Since persistent neutrophilia is an important hallmark in COPD Pro-Gly-Pro (PGP), an extracellular matrix-derived neutrophil chemoattractant, has been suggested to be a potential biomarker in COPD. The purpose of this review is to critically examine both biological and clinical data related to the role of PGP in COPD, with particular focus on its role as a clinical biomarker and potential therapeutic target in disease. The data provided in this review will offer insight into the potential use of PGP as end point for future clinical studies in COPD lung disease. Following PGP levels during disease might serve as a guide for the progression of lung disorders.
Topics: Animals; Biomarkers; Chemokines; Extracellular Matrix; Humans; Leukotriene A4; Neutrophils; Oligopeptides; Proline; Pulmonary Disease, Chronic Obstructive
PubMed: 26033353
DOI: 10.1152/ajplung.00040.2015 -
Journal of Microbiology, Immunology,... Apr 2021K. pneumoniae, a common pathogen that frequently causes bacteremia in clinic, is unresponsive to most of known antibiotics, thus cumulatively exacerbating empirical...
OBJECTIVE
K. pneumoniae, a common pathogen that frequently causes bacteremia in clinic, is unresponsive to most of known antibiotics, thus cumulatively exacerbating empirical therapy failures. Effective strategies to control Klebsiella pneumoniae bacteremia are in high demand. One possibility is to mobilize host defense mechanisms against bacterial pathogens.
METHODS
We employed GC/MS-based metabolomics to identify the changes of metabolism in mice challenged by K. pneumoniae (ATCC 43816) bacteremia.
RESULTS
Compared with the mice that compromised from K. pneumoniae bacteremia, mice that survived from infection displayed the varied metabolomic profile. The differential analysis of metabolome showed that Ethanedioic acid, d-Glucose, l-Glutamine, Myo-inositol, and l-Proline were more likely associated with the host surviving a K. pneumoniae bacteremia. Further pathway enrichment analysis proposed that arginine and proline metabolism involved in outcome of K. pneumoniae bacteremia. The follow-up data showed that exogenous l-Proline but not d-Proline could decline the loads of Klebsiella pneumonia in infected blood and tissues (lung, liver and spleen) and increase the mouse survival.
CONCLUSION
Our study provides an exercisable strategy of identifying metabolic biomarkers from surviving host and highlights the possibility of utilizing the metabolic biomarker as a therapy for K. pneumoniae bacteremia.
Topics: Animals; Anti-Bacterial Agents; Arginine; Bacteremia; Biomarkers; Disease Models, Animal; Female; Klebsiella Infections; Klebsiella pneumoniae; Metabolomics; Mice; Mice, Inbred C57BL; Proline
PubMed: 31324551
DOI: 10.1016/j.jmii.2019.05.013 -
EMBO Molecular Medicine Jul 2023Prolyl-tRNA synthetase 1 (PARS1) has attracted much interest in controlling pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases....
Prolyl-tRNA synthetase 1 (PARS1) has attracted much interest in controlling pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases. However, there are concerns about its catalytic inhibition for potential adverse effects on global protein synthesis. We developed a novel compound, DWN12088, whose safety was validated by clinical phase 1 studies, and therapeutic efficacy was shown in idiopathic pulmonary fibrosis model. Structural and kinetic analyses revealed that DWN12088 binds to catalytic site of each protomer of PARS1 dimer in an asymmetric mode with different affinity, resulting in decreased responsiveness at higher doses, thereby expanding safety window. The mutations disrupting PARS1 homodimerization restored the sensitivity to DWN12088, validating negative communication between PARS1 promoters for the DWN12088 binding. Thus, this work suggests that DWN12088, an asymmetric catalytic inhibitor of PARS1 as a novel therapeutic agent against fibrosis with enhanced safety.
Topics: Humans; Amino Acyl-tRNA Synthetases; Fibrosis; Proline; Protein Biosynthesis
PubMed: 37212275
DOI: 10.15252/emmm.202216940 -
Journal of the American Chemical Society Feb 2022Analyzing the δH values in individual amino acids of proteins extracted from vertebrates, we unexpectedly found in some samples, notably bone collagen from seals, more...
Analyzing the δH values in individual amino acids of proteins extracted from vertebrates, we unexpectedly found in some samples, notably bone collagen from seals, more than twice as much deuterium in proline and hydroxyproline residues than in seawater. This corresponds to at least 4 times higher δH than in any previously reported biogenic sample. We ruled out diet as a plausible mechanism for such anomalous enrichment. This finding puts into question the old adage that "you are what you eat".
Topics: Animals; Anseriformes; Bone and Bones; Collagen; Deuterium; Fibroblasts; Humans; Hydroxyproline; Mice; Proline; Seals, Earless; Ursidae
PubMed: 35107291
DOI: 10.1021/jacs.1c12512 -
The Journal of Biological Chemistry Jun 2019The retinal pigment epithelium (RPE) is a monolayer of pigmented cells between the choroid and the retina. RPE dysfunction underlies many retinal degenerative diseases,...
The retinal pigment epithelium (RPE) is a monolayer of pigmented cells between the choroid and the retina. RPE dysfunction underlies many retinal degenerative diseases, including age-related macular degeneration, the leading cause of age-related blindness. To perform its various functions in nutrient transport, phagocytosis of the outer segment, and cytokine secretion, the RPE relies on an active energy metabolism. We previously reported that human RPE cells prefer proline as a nutrient and transport proline-derived metabolites to the apical, or retinal, side. In this study, we investigated how RPE utilizes proline and why proline is a preferred substrate. By using [C]proline labeling both and , we found that the retina rarely uses proline directly, whereas the RPE utilizes it at a high rate, exporting proline-derived mitochondrial intermediates for use by the retina. We observed that in primary human RPE cell culture, proline is the only amino acid whose uptake increases with cellular maturity. In human RPE, proline was sufficient to stimulate serine synthesis, increase reductive carboxylation, and protect against oxidative damage. Blocking proline catabolism in RPE impaired glucose metabolism and GSH production. Notably, in an acute model of RPE-induced retinal degeneration, dietary proline improved visual function. In conclusion, proline is an important nutrient that supports RPE metabolism and the metabolic demand of the retina.
Topics: Animals; Carbon Radioisotopes; Cell Differentiation; Energy Metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Mitochondria; Oxidation-Reduction; Proline; Retina; Retinal Degeneration; Retinal Pigment Epithelium
PubMed: 31110046
DOI: 10.1074/jbc.RA119.007983 -
Biomolecules Jun 2023This review provides a fresh overview of non-canonical amino acids and their applications in the design of peptidomimetics. Non-canonical amino acids appear widely... (Review)
Review
This review provides a fresh overview of non-canonical amino acids and their applications in the design of peptidomimetics. Non-canonical amino acids appear widely distributed in nature and are known to enhance the stability of specific secondary structures and/or biological function. Contrary to the ubiquitous DNA-encoded amino acids, the structure and function of these residues are not fully understood. Here, results from experimental and molecular modelling approaches are gathered to classify several classes of non-canonical amino acids according to their ability to induce specific secondary structures yielding different biological functions and improved stability. Regarding side-chain modifications, symmetrical and asymmetrical α,α-dialkyl glycines, Cα to Cα cyclized amino acids, proline analogues, β-substituted amino acids, and α,β-dehydro amino acids are some of the non-canonical representatives addressed. Backbone modifications were also examined, especially those that result in retro-inverso peptidomimetics and depsipeptides. All this knowledge has an important application in the field of peptidomimetics, which is in continuous progress and promises to deliver new biologically active molecules and new materials in the near future.
Topics: Amino Acids; Peptidomimetics; Proline; Amines; Glycine
PubMed: 37371561
DOI: 10.3390/biom13060981 -
The Journal of Experimental Medicine Mar 2020Cancer cells often proliferate under hypoxia and reprogram their metabolism. However, how to find targets to effectively block the hypoxia-associated metabolic pathways...
Cancer cells often proliferate under hypoxia and reprogram their metabolism. However, how to find targets to effectively block the hypoxia-associated metabolic pathways remains unclear. Here, we developed a tool to conveniently calculate electrons dissipated in metabolic transformations. Based on the law of conservation of electrons in chemical reactions, we further built up an electron balance model for central carbon metabolism, and it can accurately outline metabolic plasticity under hypoxia. Our model specifies that glutamine metabolism reprogrammed for biosynthesis of lipid and/or proline actually acts as the alternative electron bin to enable electron transfer in proliferating cells under hypoxia. Inhibition of both proline biosynthesis and lipogenesis can synergistically suppress cancer cell growth under hypoxia and in vivo tumor onset. Therefore, our model helps to reveal combinations of potential targets to inhibit tumor growth by blocking hypoxia-rewired metabolism and provides a useful tool for future studies on cancer metabolism.
Topics: A549 Cells; Animals; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Female; Glutamine; HeLa Cells; Hep G2 Cells; Humans; Lipogenesis; MCF-7 Cells; Metabolic Networks and Pathways; Mice; Mice, Nude; Neoplasms; Proline
PubMed: 31961917
DOI: 10.1084/jem.20191226 -
Scientific Reports Oct 2023Silicon (Si) and/or proline (Pro) are natural supplements that are considered to induce plants' stress tolerance against various abiotic stresses. Sweet corn (Zea mays...
Silicon (Si) and/or proline (Pro) are natural supplements that are considered to induce plants' stress tolerance against various abiotic stresses. Sweet corn (Zea mays L. saccharata) production is severely afflicted by salinity stress. Therefore, two field tests were conducted to evaluate the potential effects of Si and/or Pro (6mM) used as seed soaking (SS) and/or foliar spray (FS) on Sweet corn plant growth and yield, physio-biochemical attributes, and antioxidant defense systems grown in a saline (EC = 7.14dS m) soil. The Si and/or Pro significantly increased growth and yield, photosynthetic pigments, free proline, total soluble sugars (TSS), K/Naratios, relative water content (RWC), membrane stability index (MSI), α-Tocopherol (α-TOC), Ascorbate (AsA), glutathione (GSH), enzymatic antioxidants activities and other anatomical features as compared to controls. In contrast, electrolytes, such as SS and/or FS under salt stress compared to controls (SS and FS using tap water) were significantly decreased. The best results were obtained when SS was combined with FS via Si or Pro. These alterations are brought about by the exogenous application of Si and/or Pro rendering these elements potentially useful in aiding sweet corn plants to acclimate successfully to saline soil.
Topics: Antioxidants; Zea mays; Silicon; Proline; Salt Stress; Glutathione; Water; Soil
PubMed: 37880216
DOI: 10.1038/s41598-023-45003-8