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Cell Nov 2018Diseases leading to immune activation and autoinflammatory phenotypes may provide a reservoir of potentially druggable pathways for optimizing immune adjuvants or...
Diseases leading to immune activation and autoinflammatory phenotypes may provide a reservoir of potentially druggable pathways for optimizing immune adjuvants or boosting antitumor immune responses. Now, Xia et al. report that lipophilic statins or biphosphonates, targeting the mevalonate pathway, act as efficient vaccine adjuvants and synergize with anti-PD1 against cancer.
Topics: Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mevalonic Acid; Prenylation; Protein Processing, Post-Translational; Vaccines
PubMed: 30388448
DOI: 10.1016/j.cell.2018.10.032 -
Chembiochem : a European Journal of... Oct 2011Production of typical plant metabolites by a fungal enzyme: Fungal prenyltransferases of the DMATS superfamily are mainly involved in the biosynthesis of prenylated...
Production of typical plant metabolites by a fungal enzyme: Fungal prenyltransferases of the DMATS superfamily are mainly involved in the biosynthesis of prenylated indole alkaloids, but also catalyze the prenylation of tyrosine and naphthalene derivatives. In this study, nine prenylated flavonoids were produced by using the recombinant dimethylallyltryptophan synthase 7-DMATS from Aspergillus fumigatus.
Topics: Alkyl and Aryl Transferases; Aspergillus fumigatus; Flavonoids; Prenylation; Recombinant Proteins
PubMed: 23106077
DOI: 10.1002/cbic.201100413 -
Journal of Bioscience and Bioengineering Oct 2022The prenylation of compounds has attracted much attention, since it often adds bioactivity to non-prenylated compounds. We employed an enzyme assay with CdpNPT, an...
The prenylation of compounds has attracted much attention, since it often adds bioactivity to non-prenylated compounds. We employed an enzyme assay with CdpNPT, an indole prenyltransferase from Aspergillus fumigatus with two naturally occurring β-carbolines, harmine (3) and harman (4) as prenyl acceptors, in the presence of dimethylallyl diphosphate (DMAPP) as the prenyl donor. The enzyme accepted these two prenyl acceptor substrates to produce 6-(3',3'-dimethylallyl)harmine (5) from 3 and 9-(3',3'-dimethylallyl)harman (6) and 6-(3',3'-dimethylallyl)harman (7) from 4. The X-ray crystal structure analysis of the CdpNPT (38-440) truncated mutant complexed with 4, and docking simulation studies of DMAPP to the crystal structure of the CdpNPT (38-440) mutant, suggested that CdpNPT could employ the two-step prenylation mechanism to produce 7, while the enzyme produced 6 with either one- or two-step prenylation mechanisms. Furthermore, the antibacterial assays revealed that the 3',3'-dimethylallylation of 3 and 4, as well as harmol (1), at C-6 enhanced the activities against Staphylococcus aureus and Bacillus subtilis.
Topics: Anti-Bacterial Agents; Carbolines; Dimethylallyltranstransferase; Harmine; Hemiterpenes; Indoles; Organophosphorus Compounds; Prenylation; Substrate Specificity
PubMed: 35931602
DOI: 10.1016/j.jbiosc.2022.07.004 -
Journal of Inherited Metabolic Disease Sep 2012Prenylation consists of the addition of an isoprenoid group to a cysteine residue located near the carboxyl terminal of a protein. This enzymatic posttranslational... (Review)
Review
Prenylation consists of the addition of an isoprenoid group to a cysteine residue located near the carboxyl terminal of a protein. This enzymatic posttranslational modification is important for the maturation and processing of proteins. Both processes are necessary to mediate protein-protein and membrane-protein associations, in addition to regulating the localisation and function of proteins. The severe phenotype of animals deficient in enzymes involved in both prenylation and maturation highlights the significance of these processes. Moreover, alterations in the genes coding for isoprenylated proteins or enzymes that are involved in both prenylation and maturation processes have been found to be the basis of severe human diseases, such as cancer, neurodegenerative disorders, retinitis pigmentosa, and premature ageing syndromes. Recent studies on isoprenylation and postprenylation processing in pathological conditions have unveiled surprising aspects of these modifications and their roles in different cellular pathways. The identification of these enzymes as therapeutic targets has led researchers to validate their effects in vitro and in vivo as antitumour or antiageing agents. This review attempts to summarise the basic aspects of protein isoprenylation and postprenylation, integrating our data with that observed in other studies to provide a comprehensive scenario of progeroid syndromes and the therapeutic avenues.
Topics: Animals; Disease; Humans; Protein Prenylation; Proteins
PubMed: 22307208
DOI: 10.1007/s10545-011-9445-y -
PloS One 2013The bacterium Micromonospora sp. RV115, isolated from a marine sponge, produces the unusual metabolite diazepinomicin, a prenylated benzodiazepine derivative. We have...
Unusual N-prenylation in diazepinomicin biosynthesis: the farnesylation of a benzodiazepine substrate is catalyzed by a new member of the ABBA prenyltransferase superfamily.
The bacterium Micromonospora sp. RV115, isolated from a marine sponge, produces the unusual metabolite diazepinomicin, a prenylated benzodiazepine derivative. We have cloned the prenyltransferase gene dzmP from this organism, expressed it in Escherichia coli, and the resulting His8-tagged protein was purified and investigated biochemically. It was found to catalyze the farnesylation of the amide nitrogen of dibenzodiazepinone. DzmP belongs to the ABBA prenyltransferases and is the first member of this superfamily which utilizes farnesyl diphosphate as genuine substrate. All previously discovered members utilize either dimethylallyl diphosphate (C5) or geranyl diphosphate (C10). Another putative diazepinomicin biosynthetic gene cluster was identified in the genome of Streptomyces griseoflavus Tü4000, suggesting that the formation of diazepinomicin is not restricted to the genus Micromonospora. The gene cluster contains a gene ssrg_00986 with 61.4% identity (amino acid level) to dzmP. The gene was expressed in E. coli, and the purified protein showed similar catalytic properties as DzmP. Both enzymes also accepted other phenolic or phenazine substrates. ABBA prenyltransferases are useful tools for chemoenzymatic synthesis, due to their nature as soluble, stable biocatalysts. The discovery of DzmP and Ssrg_00986 extends the isoprenoid substrate range of this superfamily. The observed prenylation of an amide nitrogen is an unusual biochemical reaction.
Topics: Amino Acid Sequence; Animals; Benzodiazepines; Biosynthetic Pathways; Catalysis; Cluster Analysis; Computational Biology; Dibenzazepines; Dimethylallyltranstransferase; Escherichia coli; Micromonospora; Molecular Sequence Data; Molecular Structure; Multigene Family; Phylogeny; Prenylation; Sequence Alignment; Streptomyces
PubMed: 24376894
DOI: 10.1371/journal.pone.0085707 -
Journal of Leukocyte Biology Sep 1996Interferons (IFN) and lipopolysaccharide (LPS) cause multiple changes in isoprenoid-modified proteins in murine macrophages, the most dramatic being the expression of a...
Interferons (IFN) and lipopolysaccharide (LPS) cause multiple changes in isoprenoid-modified proteins in murine macrophages, the most dramatic being the expression of a prenyl protein of 65 kDa. The guanylate binding proteins (GBPs) are IFN-inducible GTP-binding proteins of approximately 65 kDa that possess a CaaX motif at their C-terminus, indicating that they might be substrates for prenyltransferases. The human GBP1 protein, when expressed in transfected COS-1 cells, incorporates radioactivity from the isoprenoid precursor [3H]mevalonate. In addition, huGBPs expressed from the endogenous genes in IFN-gamma-treated human fibroblasts or monocytic cells were also found to be isoprenoid modified. IFN-gamma-induced huGBPs in HL-60 cells were not labeled by the specific C20 isoprenoid, [3H]geranylgeraniol, but did show decreased isoprenoid incorporation in cells treated with the farnesyl transferase inhibitor BZA-5B, indicating that huGBPs in HL-60 cells are probably modified by a C15 farnesyl rather than the more common C20 lipid. Differentiated HL-60 cells treated with IFN-gamma/LPS showed no change in the profile of constitutive isoprenylated proteins and the IFN-gamma/LPS-induced huGBPs remained prenylated. Despite being prenylated, huGBP1 in COS cells and endogenous huGBPs in HL-60 cells were primarily (approximately 85%) cytosolic. Human GBPs are thus among the select group of prenyl proteins whose synthesis is tightly regulated by a cytokine. HuGBP1 is an abundant protein whose prenylation may be vulnerable to farnesyl transferase inhibitors that are designed to prevent farnesylation of Ras proteins.
Topics: Animals; Benzodiazepines; COS Cells; Enzyme Inhibitors; GTP-Binding Proteins; HL-60 Cells; Humans; Interferon-gamma; Mevalonic Acid; Oligopeptides; Protein Prenylation; Transfection; Tritium
PubMed: 8830800
DOI: 10.1002/jlb.60.3.423 -
Nature Chemical Biology Apr 2009
Topics: Animals; Mammals; Prenylation; Protein Transport; Proteins; Proteome
PubMed: 19295521
DOI: 10.1038/nchembio0409-197 -
The Journal of Biological Chemistry Nov 1997We recently identified a prenyl peptide-binding protein in microsomal membranes from bovine brain (Thissen, J. A., and Casey, P. J. (1993) J. Biol. Chem. 268,...
We recently identified a prenyl peptide-binding protein in microsomal membranes from bovine brain (Thissen, J. A., and Casey, P. J. (1993) J. Biol. Chem. 268, 13780-13783). Through a variety of approaches, this binding protein has been identified as the cytoskeletal protein tubulin. Prenyl peptides bind to purified tubulin with a Kd of 40 nM and also bind to tubulin polymerized into microtubules. Microtubule affinity chromatography of extracts from cells in which the prenyl protein pool was metabolically labeled revealed that prenyl proteins bound to the immobilized microtubules; one, a 24-kDa protein, was tentatively identified as a GTP-binding protein. Of several prenylated GTP-binding proteins tested, including Ki-Ras4B, Ha-Ras, RhoB, RhoA, and Rap1B, only Ki-Ras was found to bind significantly to microtubules, and this was in a prenylation-dependent fashion. A potential significance of the interaction of Ki-Ras4B with microtubules was indicated from analysis of the localization of newly synthesized Ki-Ras4B and Ha-Ras, each tagged with green fluorescence protein (GFP). Treatment of NIH-3T3 cells expressing GFP-Ki-Ras with Taxol (paclitaxel) resulted in accumulation of the expressed protein in intracellular locations, whereas in control cells the protein was correctly targeted to the plasma membrane. Importantly, such treatment with paclitaxel did not affect the cellular localization of expressed GFP-Ha-Ras. These results indicate that an intact microtubule network may be directly involved in Ki-Ras processing and/or targeting and provide direct evidence for a physiological distinction between Ki-Ras and Ha-Ras in cells. Additionally, the finding that paclitaxel treatment of cells disrupts Ki-Ras trafficking suggests an additional mechanism for the anti-proliferative effects of this drug.
Topics: Animals; Brain; Cattle; Cell Compartmentation; Chromatography, Affinity; Microtubule-Associated Proteins; Microtubules; Paclitaxel; Protein Binding; Protein Prenylation; Proto-Oncogene Proteins p21(ras); Tubulin
PubMed: 9374526
DOI: 10.1074/jbc.272.48.30362 -
PloS One 2013Protein prenylation is a widespread post-translational modification in eukaryotes that plays a crucial role in membrane targeting and signal transduction. RabGTPases is...
Protein prenylation is a widespread post-translational modification in eukaryotes that plays a crucial role in membrane targeting and signal transduction. RabGTPases is the largest group of post-translationally C-terminally geranylgeranylated. All Rabs are processed by Rab geranylgeranyl-transferase and Rab escort protein (REP). Human genetic defects resulting in the loss one of two REP isoforms REP-1, lead to underprenylation of RabGTPases that manifests in retinal degradation and blindness known as choroideremia. In this study we used a combination of microinjections and chemo-enzymatic tagging to establish whether Rab GTPases are prenylated and delivered to their target cellular membranes with the same rate. We demonstrate that although all tested Rab GTPases display the same rate of membrane delivery, the extent of Rab prenylation in 5 hour time window vary by more than an order of magnitude. We found that Rab27a, Rab27b, Rab38 and Rab42 display the slowest prenylation in vivo and in the cell. Our work points to possible contribution of Rab38 to the emergence of choroideremia in addition to Rab27a and Rab27b.
Topics: Choroideremia; Escherichia coli; Humans; Prenylation; Time Factors; rab GTP-Binding Proteins
PubMed: 24358126
DOI: 10.1371/journal.pone.0081758 -
Natural Product Reports Jan 2015Covering: up to 2014. Prenylated indole alkaloids comprise a large and structurally diverse family of natural products that often display potent biological activities.... (Review)
Review
Covering: up to 2014. Prenylated indole alkaloids comprise a large and structurally diverse family of natural products that often display potent biological activities. In recent years a large family of prenyltransferases that install prenyl groups onto the indole core have been discovered. While the vast majority of these enzymes are evolutionarily related and share a common protein fold, they are remarkably versatile in their ability to catalyze reverse and normal prenylations at all positions on the indole ring. This highlight article will focus on recent studies of the mechanisms utilized by indole prenyltransferases. While all of the prenylation reactions may follow a direct electrophilic aromatic substitution mechanism, studies of structure and reactivity suggest that in some cases prenylation may first occur at the nucleophilic C-3 position, and subsequent rearrangements then generate the final product.
Topics: Biological Products; Dimethylallyltranstransferase; Indole Alkaloids; Molecular Structure; Prenylation
PubMed: 25270661
DOI: 10.1039/c4np00099d