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Cell Host & Microbe Mar 2021Most viral vaccines are based on inducing neutralizing antibodies (NAbs) against the virus envelope or spike glycoproteins. Many viral surface proteins exist as trimers... (Review)
Review
Most viral vaccines are based on inducing neutralizing antibodies (NAbs) against the virus envelope or spike glycoproteins. Many viral surface proteins exist as trimers that transition from a pre-fusion state when key NAb epitopes are exposed to a post-fusion form in which the potential for virus-cell fusion no longer exists. For optimal vaccine performance, these viral proteins are often engineered to enhance stability and presentation of these NAb epitopes. The method involves the structure-guided introduction of proline residues at key positions that maintain the trimer in the pre-fusion configuration. We review how this technique emerged during HIV-1 Env vaccine development and its subsequent wider application to other viral vaccines including SARS-CoV-2.
Topics: Antibodies, Neutralizing; COVID-19 Vaccines; Humans; Models, Molecular; Proline; Protein Engineering; Viral Vaccines
PubMed: 33705704
DOI: 10.1016/j.chom.2021.02.002 -
F1000Research 2019Despite recent advances in understanding and treating trigeminal neuralgia, its management remains a considerable challenge. Better classification of different types of... (Review)
Review
Despite recent advances in understanding and treating trigeminal neuralgia, its management remains a considerable challenge. Better classification of different types of facial pain and the identification of prognostic factors for different treatment options lead the way toward better quality of life for the individual patient. Although the principles of treating trigeminal neuralgia remain basically the same, antiepileptic drugs, muscle relaxants, and neuroleptic agents are widely used medical treatment options. They were not originally developed for treating trigeminal neuralgia. Carbamazepine was studied in adequate placebo-controlled clinical trials in the 1960s and is still considered the most effective drug. Among emerging treatment options currently under clinical investigation are local botulinum neurotoxin type A injections and a novel sodium channel blocker (CNV1014802) that selectively blocks the Na 1.7 sodium channel. Non-pharmacological treatment options are non-invasive electrical stimulation with either transcranial direct-current stimulation or repetitive transcranial magnetic stimulation which both require further evaluation in regard to applicability. Surgical options remain a valid choice for patients not responding to medical treatment and include Gasserian ganglion percutaneous techniques, gamma knife surgery, and microvascular decompression. There is continual effort to improve these techniques and predict the outcome for better patient selection.
Topics: Carbamazepine; Humans; Phenyl Ethers; Proline; Quality of Life; Radiosurgery; Sodium Channel Blockers; Transcranial Direct Current Stimulation; Trigeminal Neuralgia
PubMed: 31069052
DOI: 10.12688/f1000research.16092.1 -
Journal of Bacteriology Aug 2022Clostridioides difficile is a nosocomial pathogen that colonizes the gut and causes diarrhea, colitis, and severe inflammation. Recently, C. difficile has been shown to...
Clostridioides difficile is a nosocomial pathogen that colonizes the gut and causes diarrhea, colitis, and severe inflammation. Recently, C. difficile has been shown to use toxin-mediated inflammation to promote host collagen degradation, which releases several amino acids into the environment. Amino acids act as electron donors and acceptors in Stickland metabolism, an anaerobic process involving redox reactions between pairs of amino acids. Proline, glycine, and hydroxyproline are the three main constituents of collagen and are assumed to act as electron acceptors, but their exact effects on the growth and physiology of C. difficile are still unclear. Using three standard culture media (supplemented brain heart infusion [BHIS], tryptone-yeast [TY], and minimal medium [CDMM]) supplemented with proline, glycine, or hydroxyproline, we grew C. difficile strains R20291, JIR8094, and a panel of mutants unable to express the Stickland selenoenzymes d-proline reductase and glycine reductase. In the wild-type strains, growth yields in rich media (BHIS and TY) were higher with proline and hydroxyproline but not glycine; moreover, proline-stimulated growth yields required the activity of d-proline reductase, whereas hydroxyproline-stimulated growth yields were independent of its activity. While assumed to be a proline auxotroph, C. difficile could surprisingly grow in a defined medium (CDMM) without proline but only if d-proline reductase was absent. We believe the mere presence of this enzyme ultimately determines the organism's strict dependence on proline and likely defines the bioenergetic priorities for thriving in the host. Finally, we demonstrated that addition of proline and hydroxyproline to the culture medium could reduce toxin production but not in cells lacking selenoproteins. Stickland metabolism is a core facet of C. difficile physiology that likely plays a major role in host colonization. Here, we carefully delineate the effects of each amino acid on the growth of C. difficile with respect to the selenoenzymes d-proline reductase and glycine reductase. Moreover, we report that d-proline reductase forces C. difficile to strictly depend on proline for growth. Finally, we provide evidence that proline and hydroxyproline suppress toxin production and that selenoproteins are involved in this mechanism. Our findings highlight the significance of selenium-dependent Stickland reactions and may provide insight on what occurs during host infection, especially as it relates to the decision to colonize based on proline as a nutrient.
Topics: Amino Acid Oxidoreductases; Amino Acids; Clostridioides; Clostridioides difficile; Glycine; Humans; Hydroxyproline; Inflammation; Proline; Selenoproteins
PubMed: 35862761
DOI: 10.1128/jb.00229-22 -
Cell Death and Differentiation May 2022The p53 protein is structurally and functionally divided into five domains. The proline-rich domain is localized at amino acids 55-100. 319 missense mutations were... (Review)
Review
The p53 protein is structurally and functionally divided into five domains. The proline-rich domain is localized at amino acids 55-100. 319 missense mutations were identified solely in the proline domain from human cancers. Six hotspot mutations were identified at amino acids 72, 73, 82, 84, 89, and 98. Codon 72 contains a polymorphism that changes from proline (and African descent) to arginine (with Caucasian descent) with increasing latitudes northward and is under natural selection for pigmentation and protection from UV light exposure. Cancers associated with mutations in the proline domain were considerably enriched for melanomas and skin cancers compared to mutations in other p53 domains. These hotspot mutations are enriched at UV mutational signatures disrupting amino acid signals for binding SH-3-containing proteins important for p53 function. Among the protein-protein interaction sites identified by hotspot mutations were MDM-2, a negative regulator of p53, XAF-1, promoting p53 mediated apoptosis, and PIN-1, a proline isomerase essential for structural folding of this domain.
Topics: Genotype; Humans; Mutation, Missense; Neoplasms; Phenotype; Proline; Tumor Suppressor Protein p53
PubMed: 35383292
DOI: 10.1038/s41418-022-00980-7 -
Molecules (Basel, Switzerland) Apr 2018Due to the increasing emergence of drug-resistant pathogenic microorganisms, there is a world-wide quest to develop new-generation antibiotics. Antimicrobial peptides... (Review)
Review
Due to the increasing emergence of drug-resistant pathogenic microorganisms, there is a world-wide quest to develop new-generation antibiotics. Antimicrobial peptides (AMPs) are small peptides with a broad spectrum of antibiotic activities against bacteria, fungi, protozoa, viruses and sometimes exhibit cytotoxic activity toward cancer cells. As a part of the native host defense system, most AMPs target the membrane integrity of the microorganism, leading to cell death by lysis. These membrane lytic effects are often toxic to mammalian cells and restrict their systemic application. However, AMPs containing predominantly either tryptophan or proline can kill microorganisms by targeting intracellular pathways and are therefore a promising source of next-generation antibiotics. A minimum length of six amino acids is required for high antimicrobial activity in tryptophan-rich AMPs and the position of these residues also affects their antimicrobial activity. The aromatic side chain of tryptophan is able to rapidly form hydrogen bonds with membrane bilayer components. Proline-rich AMPs interact with the 70S ribosome and disrupt protein synthesis. In addition, they can also target the heat shock protein in target pathogens, and consequently lead to protein misfolding. In this review, we will focus on describing the structures, sources, and mechanisms of action of the aforementioned AMPs.
Topics: Animals; Anti-Infective Agents; Bacteria; Fungi; Humans; Peptides; Proline; Tryptophan
PubMed: 29614844
DOI: 10.3390/molecules23040815 -
Nature Genetics Nov 2022Histone post-translational modifications (PTMs) are important for regulating various DNA-templated processes. Here, we report the existence of a histone PTM in mammalian...
Histone post-translational modifications (PTMs) are important for regulating various DNA-templated processes. Here, we report the existence of a histone PTM in mammalian cells, namely histone H3 with hydroxylation of proline at residue 16 (H3P16oh), which is catalyzed by the proline hydroxylase EGLN2. We show that H3P16oh enhances direct binding of KDM5A to its substrate, histone H3 with trimethylation at the fourth lysine residue (H3K4me3), resulting in enhanced chromatin recruitment of KDM5A and a corresponding decrease of H3K4me3 at target genes. Genome- and transcriptome-wide analyses show that the EGLN2-KDM5A axis regulates target gene expression in mammalian cells. Specifically, our data demonstrate repression of the WNT pathway negative regulator DKK1 through the EGLN2-H3P16oh-KDM5A pathway to promote WNT/β-catenin signaling in triple-negative breast cancer (TNBC). This study characterizes a regulatory mark in the histone code and reveals a role for H3P16oh in regulating mammalian gene expression.
Topics: Animals; Histones; Methylation; Proline; Hydroxylation; Gene Expression; Mammals
PubMed: 36347944
DOI: 10.1038/s41588-022-01212-x -
Journal of Computational Chemistry Jun 2021Computation of the thermodynamic consequences of protein mutations holds great promise in protein biophysics and design. Alchemical free energy methods can give improved...
Computation of the thermodynamic consequences of protein mutations holds great promise in protein biophysics and design. Alchemical free energy methods can give improved estimates of mutational free energies, and are already widely used in calculations of relative and absolute binding free energies in small molecule design problems. In principle, alchemical methods can address any amino acid mutation with an appropriate alchemical pathway, but identifying a strategy that produces such a path for proline and glycine mutations is an ongoing challenge. Most current strategies perturb only side chain atoms, while proline and glycine mutations also alter the backbone parameters and backbone ring topology. Some strategies also perturb backbone parameters and enable glycine mutations. This work presents a strategy that enables both proline and glycine mutations and comprises two key elements: a dual backbone with restraints and scaling of bonded terms, facilitating backbone parameter changes, and a soft bond in the proline ring, enabling ring topology changes in proline mutations. These elements also have utility for core hopping and macrocycle studies in computer-aided drug design. This new strategy shows slight improvements over an alternative side chain perturbation strategy for a set T4 lysozyme mutations lacking proline and glycine, and yields good agreement with experiment for a set of T4 lysozyme proline and glycine mutations not previously studied. To our knowledge this is the first report comparing alchemical predictions of proline mutations with experiment. With this strategy in hand, alchemical methods now have access to the full palette of amino acid mutations.
Topics: Glycine; Molecular Dynamics Simulation; Muramidase; Mutation; Proline; Thermodynamics
PubMed: 33844328
DOI: 10.1002/jcc.26525 -
Chemical Communications (Cambridge,... Dec 2022We present our design of a cross-catalytic system based on organocatalysis. The system features two organic reactions, namely a deprotection reaction of Fmoc protected...
We present our design of a cross-catalytic system based on organocatalysis. The system features two organic reactions, namely a deprotection reaction of Fmoc protected proline and a Mannich reaction between acetone and dihydroisoquinoline. The products of these two reactions, proline and a tetrahydroisoquinoline, respectively, are capable of reciprocal reaction rate enhancement. Detailed kinetic studies of the system and seeding experiments support the cross-catalytic relationship in the reaction network.
Topics: Kinetics; Catalysis; Proline; Acetone
PubMed: 36448644
DOI: 10.1039/d2cc05610k -
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 -
Molecules (Basel, Switzerland) Nov 2017Cyclodipeptides, called 2,5-diketopiperazines (2,5-DKPs), are obtained by the condensation of two amino acids. Fungi have been considered to be a rich source of novel... (Review)
Review
Cyclodipeptides, called 2,5-diketopiperazines (2,5-DKPs), are obtained by the condensation of two amino acids. Fungi have been considered to be a rich source of novel and bioactive cyclodipeptides. This review highlights the occurrence, structures and biological activities of the fungal cyclodipeptides with the literature covered up to July 2017. A total of 635 fungal cyclodipeptides belonging to the groups of tryptophan-proline, tryptophan-tryptophan, tryptophan-Xaa, proline-Xaa, non-tryptophan-non-proline, and thio-analogs have been discussed and reviewed. They were mainly isolated from the genera of Aspergillus and Penicillium. More and more cyclodipeptides have been isolated from marine-derived and plant endophytic fungi. Some of them were screened to have cytotoxic, phytotoxic, antimicrobial, insecticidal, vasodilator, radical scavenging, antioxidant, brine shrimp lethal, antiviral, nematicidal, antituberculosis, and enzyme-inhibitory activities to show their potential applications in agriculture, medicinal, and food industry.
Topics: Amino Acids; Diketopiperazines; Fungi; Molecular Structure; Proline; Structure-Activity Relationship; Tryptophan
PubMed: 29168781
DOI: 10.3390/molecules22122026