-
Biochimica Et Biophysica Acta. General... Sep 2020Proline specific peptidases (PSPs) are a unique group of enzymes that specifically cleave bonds formed by a proline residue. The study of PSPs is important due to their... (Review)
Review
BACKGROUND
Proline specific peptidases (PSPs) are a unique group of enzymes that specifically cleave bonds formed by a proline residue. The study of PSPs is important due to their role in the maturation and degradation of peptide hormones and neuropeptides. In addition, changes in the activity of PSPs can result in pathological conditions, including various types of cancer.
SCOPE OF REVIEW
PSPs annotated from the Homo sapiens genome were compared and classified by their physicochemical and biochemical features and roles in vital processes. In addition to catalytic activity, we discuss non-enzymatic functions that may regulate cellular activity.
MAJOR CONCLUSIONS
PSPs apparently have multiple functions in animals. Two functions rely on the catalytic activity of the enzyme: one involved in a regulatory pathway associated with the ability of many PSPs to hydrolyze peptide hormones and neuropeptides, and the other involved in the trophic pathway associated with the proteolysis of total cellular protein or Pro-containing dietary proteins in the digestive tract. PSPs also participate in signal transduction without proteolytic activity by forming protein-protein interactions that trigger or facilitate the performance of certain functions.
GENERAL SIGNIFICANCE
PSPs are underestimated as a unique component of the normal human peptidase degradome, providing the body with free proline. A comparative analysis of PSPs can guide research to develop inhibitors that counteract the abnormalities associated with changes in PSP activity, and identify natural substrates of PSPs that will enable better understanding of the mechanisms of the action of PSPs in biological processes and disease.
Topics: Amino Acid Sequence; Animals; Humans; Hydrolysis; Peptide Hydrolases; Proline; Substrate Specificity
PubMed: 32433934
DOI: 10.1016/j.bbagen.2020.129636 -
Anaerobe Aug 2022Stickland amino acid fermentations occur primarily among species of Clostridia. An ancient form of metabolism, Stickland fermentations use amino acids as electron... (Review)
Review
Stickland amino acid fermentations occur primarily among species of Clostridia. An ancient form of metabolism, Stickland fermentations use amino acids as electron acceptors in the absence of stronger oxidizing agents and provide metabolic capabilities to support growth when other fermentable substrates, such as carbohydrates, are lacking. The reactions were originally described as paired fermentations of amino acid electron donors, such as the branched-chain amino acids, with recipients that include proline and glycine. We present a redox-focused view of Stickland metabolism following electron flow through metabolically diverse oxidative reactions and the defined-substrate reductase systems, including for proline and glycine, and the role of dual redox pathways for substrates such as leucine and ornithine. Genetic studies and Environment and Gene Regulatory Interaction Network (EGRIN) models for the pathogen Clostridioides difficile have improved our understanding of the regulation and metabolic recruitment of these systems, and their functions in modulating inter-species interactions within host-pathogen-commensal systems and uses in industrial and environmental applications.
Topics: Amino Acids; Clostridium; Fermentation; Glycine; Proline
PubMed: 35709938
DOI: 10.1016/j.anaerobe.2022.102600 -
Amino Acids May 2022Naturally occurring secondary amino acids, with proline as the main representative, contain an alpha-imino group in a cycle that is typically four-, five-, and... (Review)
Review
Naturally occurring secondary amino acids, with proline as the main representative, contain an alpha-imino group in a cycle that is typically four-, five-, and six-membered. The unique ring structure exhibits exceptional properties-conformational rigidity, chemical stability, and specific roles in protein structure and folding. Many proline analogues have been used as valuable compounds for the study of metabolism of both prokaryotic and eukaryotic cells and for the synthesis of compounds with desired biological, pharmaceutical, or industrial properties. The D-forms of secondary amino acids play different roles in living organisms than the L-forms. They have different metabolic pathways, biological, physiological, and pharmacological effects, they can be indicators of changes and also serve as biomarkers of diseases. In the scientific literature, the number of articles examining D-amino acids in biological samples is increasing. The review summarises information on the occurrence and importance of D- and L-secondary amino acids-azetidic acid, proline, hydroxyprolines, pipecolic, nipecotic, hydroxypipecolic acids and related peptides containing these D-AAs, as well as the main analytical methods (mostly chromatographic) used for their enantiomeric determination in different matrices (biological samples, plants, food, water, and soil).
Topics: Amino Acids; Imino Acids; Peptides; Proline; Stereoisomerism
PubMed: 35192062
DOI: 10.1007/s00726-022-03136-6 -
PLoS Pathogens Nov 2023Candida albicans, the primary etiology of human mycoses, is well-adapted to catabolize proline to obtain energy to initiate morphological switching (yeast to hyphal) and...
Candida albicans, the primary etiology of human mycoses, is well-adapted to catabolize proline to obtain energy to initiate morphological switching (yeast to hyphal) and for growth. We report that put1-/- and put2-/- strains, carrying defective Proline UTilization genes, display remarkable proline sensitivity with put2-/- mutants being hypersensitive due to the accumulation of the toxic intermediate pyrroline-5-carboxylate (P5C), which inhibits mitochondrial respiration. The put1-/- and put2-/- mutations attenuate virulence in Drosophila and murine candidemia models and decrease survival in human neutrophils and whole blood. Using intravital 2-photon microscopy and label-free non-linear imaging, we visualized the initial stages of C. albicans cells infecting a kidney in real-time, directly deep in the tissue of a living mouse, and observed morphological switching of wildtype but not of put2-/- cells. Multiple members of the Candida species complex, including C. auris, are capable of using proline as a sole energy source. Our results indicate that a tailored proline metabolic network tuned to the mammalian host environment is a key feature of opportunistic fungal pathogens.
Topics: Animals; Mice; Humans; Candida albicans; Virulence; Saccharomyces cerevisiae; Proline; Candida; Mammals
PubMed: 37917600
DOI: 10.1371/journal.ppat.1011677 -
American Journal of Medical Genetics.... Jul 2021Hyperprolinemia Type I and II are genetic metabolic disorders caused by disrupted proline degradation. It has been suggested that hyperprolinemia is associated with... (Review)
Review
Hyperprolinemia Type I and II are genetic metabolic disorders caused by disrupted proline degradation. It has been suggested that hyperprolinemia is associated with increased risk of developmental and mental disorders but detailed information on the psychiatric phenotype in hyperprolinemic patients is limited. Following PRISMA guidelines, we carried out a systematic review to clarify psychiatric phenotypes in patients with hyperprolinemia. We screened 1753 studies and included 35 for analysis, including 20 case reports and 15 case-control and cohort studies. From these studies, a common psychiatric phenotype is observed with a high prevalence of developmental delay, intellectual disability, autism spectrum disorders, and psychosis spectrum disorders. In most cases, a genetic cause of hyperprolinemia was known, these included mutations in the PRODH and ALDH4A1 genes and deletions of chromosome 22q11.2. No evidence for a biochemical phenotype-clinical phenotype correlation was found; that is, no association between higher proline levels and specific psychiatric phenotypes was observed. This suggests that genomic and environmental factors are likely to contribute to clinical outcomes. More studies are needed to clarify whether hyperprolinemia is a primary causal factor underlying the increased risk of developing psychiatric disorders seen in patients with hyperprolinemia, or whether hyperprolinemia and psychiatric disorders are both consequences of a shared underlying mechanism.
Topics: Case-Control Studies; Humans; Intellectual Disability; Phenotype; Proline; Proline Oxidase
PubMed: 34302426
DOI: 10.1002/ajmg.b.32869 -
Journal of Agricultural and Food... Oct 2022Febrifugine, a natural alkaloid, exhibits specific anti-phytophthora activity; however, its mode of action is unclear. In this study, halofuginone, a synthetic...
Febrifugine, a natural alkaloid, exhibits specific anti-phytophthora activity; however, its mode of action is unclear. In this study, halofuginone, a synthetic derivative of febrifugine, showed significantly higher anti-phytophthora activities than those of febrifugine and the commercial drug metalaxyl against , , and with effective concentration for 50% inhibition (EC) values of 0.665, 0.673, and 0.178 μg/mL, respectively. Proline could alleviate the growth inhibition of halofuginone on , implying that halofuginone might target prolyl-tRNA synthetase (PRS). The anti-phytophthora mechanism of halofuginone was then investigated by molecular docking, fluorescence titration, and enzymatic inhibition assays. The results revealed that halofuginone could bind to PRS and shared a similar binding site with the substrate proline. Point mutations at Glu316 and Arg345 led to 24.5 and 16.1% decreases in the enzymatic activity of PRS but 816.742- and 459.557-fold increases in the resistance to halofuginone, respectively. The results further confirmed that halofuginone was a competitive inhibitor of proline against PRS, and Glu316 and Arg345 played important roles in the binding of halofuginone and proline. Taken together, the results indicated that halofuginone is an alternative anti-phytophthora drug candidate and that PRS represents a potential target for the development of new pesticides.
Topics: Amino Acyl-tRNA Synthetases; Molecular Docking Simulation; Pesticides; Phytophthora; Piperidines; Proline; Quinazolinones
PubMed: 36126316
DOI: 10.1021/acs.jafc.2c04266 -
Plant Biology (Stuttgart, Germany) Mar 2022Abiotic stresses have a detrimental impact on plant growth and productivity and are a major threat to sustainable crop production in rapidly changing environments.... (Review)
Review
Abiotic stresses have a detrimental impact on plant growth and productivity and are a major threat to sustainable crop production in rapidly changing environments. Proline, an important amino acid, plays an important role in maintaining the metabolism and growth of plants under abiotic stress conditions. Many insights indicate a positive relationship between proline accumulation and tolerance of plants to various abiotic stresses. Because of its metal chelator properties, it acts as a molecular chaperone, an antioxidative defence molecule that scavenges reactive oxygen species (ROS), as well as having signalling behaviour to activate specific gene functions that are crucial for plant recovery from stresses. It also acts as an osmoprotectant, a potential source to acquire nitrogen as well as carbon, and plays a significant role in the flowering and development of plants. Overproduction of proline in plant cells contributes to maintaining cellular homeostasis, water uptake, osmotic adjustment and redox balance to restore the cell structures and mitigate oxidative damage. Many reports reveal that transgenic plants, particularly those overexpressing genes tailored for proline accumulation, exhibit better adaptation to abiotic stresses. Therefore, this review aims to provide a comprehensive update on proline biosynthesis and accumulation in plants and its putative regulatory roles in mediating plant defence against abiotic stresses. Additionally, the current and future directions in research concerning manipulation of proline to induce gene functions that appear promising in genetics and genomics approaches to improve plant adaptive responses under changing climate conditions are also highlighted.
Topics: Gene Expression Regulation, Plant; Plant Development; Plants, Genetically Modified; Proline; Reactive Oxygen Species; Stress, Physiological
PubMed: 34796604
DOI: 10.1111/plb.13363 -
Amino Acids Dec 2021Pyrroline-5-carboxylate reductase (PYCR), the last enzyme in proline synthesis that converts P5C into proline, was found promoting cancer growth and inhibiting apoptosis... (Review)
Review
Pyrroline-5-carboxylate reductase (PYCR), the last enzyme in proline synthesis that converts P5C into proline, was found promoting cancer growth and inhibiting apoptosis through multiple approaches, including regulating cell cycle and redox homeostasis, and promoting growth signaling pathways. Proline is abnormally up-regulated in multiple cancers and becomes one of the critical players in the reprogramming of cancer metabolism. As the last key enzymes in proline generation, PYCRs have been the subject of many investigations, and have been demonstrated to play an indispensable role in promoting tumorigenesis and cancer progression. In this article, we will thoroughly review the recent investigations on PYCRs in cancer development.
Topics: Animals; Carcinogenesis; Cell Cycle; Humans; Neoplasms; Oxidation-Reduction; Proline; Pyrroline Carboxylate Reductases
PubMed: 34273023
DOI: 10.1007/s00726-021-03047-y -
Theriogenology Apr 2023Successful in-vitro production of bovine embryos relies on meiotic maturation of oocytes in vitro (IVM) before they can be fertilised. High levels of IVM are currently...
Successful in-vitro production of bovine embryos relies on meiotic maturation of oocytes in vitro (IVM) before they can be fertilised. High levels of IVM are currently achieved using a complex medium that contains all 20 common amino acids, namely TCM199, but can also be achieved using a simple inorganic salt solution containing non-essential amino acids, proline, and glutamine. Further simplification of the amino acid content of medium used for IVM could lead to a more defined medium that provides reproducible IVM. The aim of this study was, therefore, to determine the minimal amino acid requirements for bovine oocyte nuclear maturation, as measured by progression to metaphase II (MII) of meiosis. Supplementation of a simple medium composed of inorganic salts (M1 medium) with multiple amino-acid combinations showed that M1 containing glutamine, proline, and isoleucine resulted in nuclear maturation comparable to that of TCM199 (57.4 ± 3.4% vs 67% ± 1.7%, respectively) but was reduced when cystine (Cys2) to that seen with M1 alone (38.0 ± 2.2%). Viability of oocytes matured in this simplified medium was equal to those matured in TCM199 since the same proportion of zygotes with 2 pronuclei were observed following fertilisation in medium containing no amino acids (33.9 ± 6.5% vs 33.3 ± 3.6%, respectively). Addition of glutamine, proline and isoleucine to fertilisation medium also increased the proportion of zygotes but did not increase blastocyst development rates. Thus, a defined medium containing only glutamine, proline and isoleucine is sufficient for oocyte maturation and successful fertilisation.
Topics: Animals; Cattle; Glutamine; Isoleucine; Proline; Oocytes; Amino Acids; Fertilization
PubMed: 36842262
DOI: 10.1016/j.theriogenology.2023.02.019 -
Amino Acids Dec 2021In the 35 years since the introduction of the "proline cycle", its relevance to human tumors has been widely established. These connections are based on a variety of...
In the 35 years since the introduction of the "proline cycle", its relevance to human tumors has been widely established. These connections are based on a variety of mechanisms discovered by many laboratories and have stimulated the search for small molecule inhibitors to treat cancer or metastases. In addition, the multi-layered connections of the proline cycle and the role of proline and hydroxyproline in collagen provide an important regulatory link between the extracellular matrix and metabolism.
Topics: Collagen; Extracellular Matrix; Humans; Hydroxyproline; Neoplasms; Proline; Small Molecule Libraries
PubMed: 34825974
DOI: 10.1007/s00726-021-03103-7