-
Journal of Peptide Science : An... Jan 2016Today, Fmoc SPPS is the method of choice for peptide synthesis. Very-high-quality Fmoc building blocks are available at low cost because of the economies of scale... (Review)
Review
Today, Fmoc SPPS is the method of choice for peptide synthesis. Very-high-quality Fmoc building blocks are available at low cost because of the economies of scale arising from current multiton production of therapeutic peptides by Fmoc SPPS. Many modified derivatives are commercially available as Fmoc building blocks, making synthetic access to a broad range of peptide derivatives straightforward. The number of synthetic peptides entering clinical trials has grown continuously over the last decade, and recent advances in the Fmoc SPPS technology are a response to the growing demand from medicinal chemistry and pharmacology. Improvements are being continually reported for peptide quality, synthesis time and novel synthetic targets. Topical peptide research has contributed to a continuous improvement and expansion of Fmoc SPPS applications.
Topics: Amino Acids; Aspartic Acid; Cell Line; Epithelial Cells; Fluorenes; Glycosylation; Humans; Methylation; Peptides; Phosphorylation; Protein Prenylation; Protein Processing, Post-Translational; Solid-Phase Synthesis Techniques
PubMed: 26785684
DOI: 10.1002/psc.2836 -
The EMBO Journal Jul 2019The guanylate binding protein (GBP) family of interferon-inducible GTPases promotes antimicrobial immunity and cell death. During bacterial infection, multiple mouse...
The guanylate binding protein (GBP) family of interferon-inducible GTPases promotes antimicrobial immunity and cell death. During bacterial infection, multiple mouse Gbps, human GBP2, and GBP5 support the activation of caspase-1-containing inflammasome complexes or caspase-4 which trigger pyroptosis. Whether GBPs regulate other forms of cell death is not known. The apicomplexan parasite Toxoplasma gondii causes macrophage death through unidentified mechanisms. Here we report that Toxoplasma-induced death of human macrophages requires GBP1 and its ability to target Toxoplasma parasitophorous vacuoles through its GTPase activity and prenylation. Mechanistically, GBP1 promoted Toxoplasma detection by AIM2, which induced GSDMD-independent, ASC-, and caspase-8-dependent apoptosis. Identical molecular determinants targeted GBP1 to Salmonella-containing vacuoles. GBP1 facilitated caspase-4 recruitment to Salmonella leading to its enhanced activation and pyroptosis. Notably, GBP1 could be bypassed by the delivery of Toxoplasma DNA or bacterial LPS into the cytosol, pointing to its role in liberating microbial molecules. GBP1 thus acts as a gatekeeper of cell death pathways, which respond specifically to infecting microbes. Our findings expand the immune roles of human GBPs in regulating not only pyroptosis, but also apoptosis.
Topics: Caspases, Initiator; DNA-Binding Proteins; GTP-Binding Proteins; Humans; Macrophages; Protein Prenylation; Pyroptosis; THP-1 Cells; Toxoplasma; Toxoplasmosis
PubMed: 31268602
DOI: 10.15252/embj.2018100926 -
Biomedicine & Pharmacotherapy =... Aug 2023Prenyltransferases (PTases) are known to play a role in embryonic development, normal tissue homeostasis and cancer by posttranslationally modifying proteins involved in... (Review)
Review
Prenyltransferases (PTases) are known to play a role in embryonic development, normal tissue homeostasis and cancer by posttranslationally modifying proteins involved in these processes. They are being discussed as potential drug targets in an increasing number of diseases, ranging from Alzheimer's disease to malaria. Protein prenylation and the development of specific PTase inhibitors (PTIs) have been subject to intense research in recent decades. Recently, the FDA approved lonafarnib, a specific farnesyltransferase inhibitor that acts directly on protein prenylation; and bempedoic acid, an ATP citrate lyase inhibitor that might alter intracellular isoprenoid composition, the relative concentrations of which can exert a decisive influence on protein prenylation. Both drugs represent the first approved agent in their respective substance class. Furthermore, an overwhelming number of processes and proteins that regulate protein prenylation have been identified over the years, many of which have been proposed as molecular targets for pharmacotherapy in their own right. However, certain aspects of protein prenylation, such as the regulation of PTase gene expression or the modulation of PTase activity by phosphorylation, have attracted less attention, despite their reported influence on tumor cell proliferation. Here, we want to summarize the advances regarding our understanding of the regulation of protein prenylation and the potential implications for drug development. Additionally, we want to suggest new lines of investigation that encompass the search for regulatory elements for PTases, especially at the genetic and epigenetic levels.
Topics: Protein Prenylation; Proteins; Dimethylallyltranstransferase; Enzyme Inhibitors; Terpenes; Prenylation
PubMed: 37236024
DOI: 10.1016/j.biopha.2023.114915 -
Characterisation of lepidopteran geranylgeranyl diphosphate synthase as a putative pesticide target.Insect Molecular Biology Apr 2024Geranylgeranyl pyrophosphate (diphosphate) synthase (GGPPS) plays an important role in various physiological processes in insects, such as isoprenoid biosynthesis and...
Geranylgeranyl pyrophosphate (diphosphate) synthase (GGPPS) plays an important role in various physiological processes in insects, such as isoprenoid biosynthesis and protein prenylation. Here, we functionally characterised the GGPPS from the major agricultural lepidopteran pests Spodoptera frugiperda and Helicoverpa armigera. Partial disruption of GGPPS by CRISPR in S. frugiperda decreased embryo hatching rate and larval survival, suggesting that this gene is essential. Functional expression in vitro of Helicoverpa armigera GGPPS in Escherichia coli revealed a catalytically active enzyme. Next, we developed and optimised an enzyme assay to screen for potential inhibitors, such as the zoledronate and the minodronate, which showed a dose-dependent inhibition. Phylogenetic analysis of GGPPS across insects showed that GGPPS is highly conserved but also revealed several residues likely to be involved in substrate binding, which were substantially different in bee pollinator and human GGPPS. Considering the essentiality of GGPPS and its putative binding residue variability qualifies a GGPPS as a novel pesticide target. The developed assay may contribute to the identification of novel insecticide leads.
Topics: Humans; Animals; Bees; Farnesyltranstransferase; Pesticides; Phylogeny; Zoledronic Acid
PubMed: 37962063
DOI: 10.1111/imb.12885 -
Cell Nov 2018Motivated by the clinical observation that interruption of the mevalonate pathway stimulates immune responses, we hypothesized that this pathway may function as a...
Motivated by the clinical observation that interruption of the mevalonate pathway stimulates immune responses, we hypothesized that this pathway may function as a druggable target for vaccine adjuvant discovery. We found that lipophilic statin drugs and rationally designed bisphosphonates that target three distinct enzymes in the mevalonate pathway have potent adjuvant activities in mice and cynomolgus monkeys. These inhibitors function independently of conventional "danger sensing." Instead, they inhibit the geranylgeranylation of small GTPases, including Rab5 in antigen-presenting cells, resulting in arrested endosomal maturation, prolonged antigen retention, enhanced antigen presentation, and T cell activation. Additionally, inhibiting the mevalonate pathway enhances antigen-specific anti-tumor immunity, inducing both Th1 and cytolytic T cell responses. As demonstrated in multiple mouse cancer models, the mevalonate pathway inhibitors are robust for cancer vaccinations and synergize with anti-PD-1 antibodies. Our research thus defines the mevalonate pathway as a druggable target for vaccine adjuvants and cancer immunotherapies.
Topics: Adjuvants, Immunologic; Animals; Antigen Presentation; Antigen-Presenting Cells; Cancer Vaccines; Cell Line, Tumor; Diphosphonates; Endosomes; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Macaca fascicularis; Male; Mevalonic Acid; Mice; Mice, Inbred C57BL; Protein Prenylation; rab5 GTP-Binding Proteins
PubMed: 30270039
DOI: 10.1016/j.cell.2018.08.070 -
Aging Jul 2019
Topics: Adipose Tissue, Brown; Animals; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 31303605
DOI: 10.18632/aging.102056 -
ACS Chemical Biology Jan 2015Protein prenylation is a ubiquitous covalent post-translational modification found in all eukaryotic cells, comprising attachment of either a farnesyl or a... (Review)
Review
Protein prenylation is a ubiquitous covalent post-translational modification found in all eukaryotic cells, comprising attachment of either a farnesyl or a geranylgeranyl isoprenoid. It is essential for the proper cellular activity of numerous proteins, including Ras family GTPases and heterotrimeric G-proteins. Inhibition of prenylation has been extensively investigated to suppress the activity of oncogenic Ras proteins to achieve antitumor activity. Here, we review the biochemistry of the prenyltransferase enzymes and numerous isoprenoid analogs synthesized to investigate various aspects of prenylation and prenyltransferases. We also give an account of the current status of prenyltransferase inhibitors as potential therapeutics against several diseases including cancers, progeria, aging, parasitic diseases, and bacterial and viral infections. Finally, we discuss recent progress in utilizing protein prenylation for site-specific protein labeling for various biotechnology applications.
Topics: Animals; Biotechnology; Dimethylallyltranstransferase; Enzyme Inhibitors; Humans; Protein Prenylation; Substrate Specificity; Terpenes; ras Proteins
PubMed: 25402849
DOI: 10.1021/cb500791f -
Molecular Reproduction and Development 2023Male fertility declines with age. The mevalonate pathway, through which cholesterol and nonsteroidal isoprenoids are synthesized, plays key role in metabolic processes... (Review)
Review
Male fertility declines with age. The mevalonate pathway, through which cholesterol and nonsteroidal isoprenoids are synthesized, plays key role in metabolic processes and is an essential pathway for cholesterol production and protein prenylation. Male reproductive aging is accompanied by dramatic changes in the metabolic microenvironment of the testis. Since the mevalonate pathway has an important role in spermatogenesis, we attempted to explore the association between male reproductive aging and the mevalonate pathway to explain the mechanism of male reproductive aging. Alterations in the mevalonate pathway may affect male reproductive aging by decreasing cholesterol synthesis and altering testis protein prenylation. Decreased cholesterol levels affect cholesterol modification, testosterone production, and remodeling of germ cell membranes. Aging-related metabolic disorders also affect the metabolic coupling between somatic cells and spermatogenic cells, leading to male fertility decline. Therefore, we hypothesized that alterations in the mevalonate pathway represent one of the metabolic causes of reproductive aging.
Topics: Male; Humans; Mevalonic Acid; Cholesterol; Reproduction; Testis
PubMed: 37733694
DOI: 10.1002/mrd.23705 -
Molecules (Basel, Switzerland) Oct 2019Protein prenylation is one of the most important posttranslational modifications of proteins. Prenylated proteins play important roles in different developmental... (Review)
Review
Protein prenylation is one of the most important posttranslational modifications of proteins. Prenylated proteins play important roles in different developmental processes as well as stress responses in plants as the addition of hydrophobic prenyl chains (mostly farnesyl or geranyl) allow otherwise hydrophilic proteins to operate as peripheral lipid membrane proteins. This review focuses on selected aspects connecting protein prenylation with plant responses to both abiotic and biotic stresses. It summarizes how changes in protein prenylation impact plant growth, deals with several families of proteins involved in stress response and highlights prominent regulatory importance of prenylated small GTPases and chaperons. Potential possibilities of these proteins to be applicable for biotechnologies are discussed.
Topics: Biotechnology; Plant Proteins; Plants; Protein Prenylation; Stress, Physiological; Substrate Specificity
PubMed: 31671559
DOI: 10.3390/molecules24213906 -
Molecular Neurobiology Aug 2014Protein prenylation is an important lipid posttranslational modification of proteins. It includes protein farnesylation and geranylgeranylation, in which the 15-carbon... (Review)
Review
Protein prenylation is an important lipid posttranslational modification of proteins. It includes protein farnesylation and geranylgeranylation, in which the 15-carbon farnesyl pyrophosphate or 20-carbon geranylgeranyl pyrophosphate is attached to the C-terminus of target proteins, catalyzed by farnesyl transferase or geranylgeranyl transferases, respectively. Protein prenylation facilitates the anchoring of proteins into the cell membrane and mediates protein-protein interactions. Among numerous proteins that undergo prenylation, small GTPases represent the largest group of prenylated proteins. Small GTPases are involved in regulating a plethora of cellular functions including synaptic plasticity. The prenylation status of small GTPases determines the subcellular locations and functions of the proteins. Dysregulation or dysfunction of small GTPases leads to the development of different types of disorders. Emerging evidence indicates that prenylated proteins, in particular small GTPases, may play important roles in the pathogenesis of Alzheimer's disease. This review focuses on the prenylation of Ras and Rho subfamilies of small GTPases and its relation to synaptic plasticity and Alzheimer's disease.
Topics: Alzheimer Disease; Animals; Humans; Neuronal Plasticity; Neurons; Protein Prenylation; Protein Processing, Post-Translational; ras Proteins; rho GTP-Binding Proteins
PubMed: 24390573
DOI: 10.1007/s12035-013-8627-z