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BioEssays : News and Reviews in... Oct 2017Intracellular bacteria were recently shown to employ eukaryotic prenylation system for modifying activity and ensuring proper intracellular localization of their own... (Review)
Review
Intracellular bacteria were recently shown to employ eukaryotic prenylation system for modifying activity and ensuring proper intracellular localization of their own proteins. Following the same logic, the proteins of viruses may also serve as prenylation substrates. Using extensively validated high-confidence prenylation predictions by PrePS with a cut-off for experimentally confirmed farnesylation of hepatitis delta virus antigen, we compiled in silico evidence for several new prenylation candidates, including IRL9 (CMV) and few other proteins encoded by Herpesviridae, Nef (HIV-1), E1A (human adenovirus 1), NS5A (HCV), PB2 (influenza), HN (human parainfluenza virus 3), L83L (African swine fever), MC155R (molluscum contagiosum virus), other Poxviridae proteins, and some bacteriophages of human associated bacteria. If confirmed experimentally, these findings may aid in dissection of molecular functions of uncharacterized viral proteins and provide a novel rationale for statin and FT/GGT1-based inhibition of viral infections. Prenylation of bacteriophage proteins may aid in moderation of microbial infections.
Topics: Adenoviridae; Bacteriophages; Herpesviridae; Humans; Prenylation; Viral Proteins
PubMed: 28885709
DOI: 10.1002/bies.201700014 -
Phytotherapy Research : PTR Mar 2019The genus Sophora (Fabaceae) has been used in traditional medicine for years. Prenylated flavonoids are one of the constituents of Sophora species that play important... (Review)
Review
The genus Sophora (Fabaceae) has been used in traditional medicine for years. Prenylated flavonoids are one of the constituents of Sophora species that play important roles in their biological properties. Different classes of prenylated flavonoids are produced by Sophora spp. including prenylated flavonol (e.g., sophoflavescenol), prenylated flavanone (e.g., sophoraflavanone G), prenylated flavonostilbene (e.g., alopecurones A and B), and prenylated chalcone (kuraridin). Prenylated flavonoids have a more lipophilic structure, which leads to its high affinity to the cell membranes and enhancement of the biological activity, which includes cytotoxicity, antibacterial, anti-inflammatory, and estrogenic activities. However, it is reported that prenylation decreases the plasma absorption but increases the tissue accumulation. The presence of the prenyl or lavandulyl groups on C8 position of flavonoids plays an important role in the biological activity. It seems that prenylated flavonoids have the potential to be developed as new drugs or supplements for human health.
Topics: Biological Products; Chalcones; Flavanones; Flavonoids; Humans; Medicine, Traditional; Monoterpenes; Plant Extracts; Prenylation; Sophora; Structure-Activity Relationship
PubMed: 30652369
DOI: 10.1002/ptr.6265 -
Current Medicinal Chemistry 2018O-Prenyl coumarins (3,3-dimethylallyl, geranyl-, farnesyl- and related biosynthetic derivatives) represent a class of rarely occurring natural products. In the last two... (Review)
Review
O-Prenyl coumarins (3,3-dimethylallyl, geranyl-, farnesyl- and related biosynthetic derivatives) represent a class of rarely occurring natural products. In the last two decades, such secondary metabolites have been found to possess promising and effective pharmacological properties, mainly in terms of anti-cancer and anti-inflammatory properties. To date, about 160 oxyprenylated coumarins have been extracted from plants, fungi, and bacteria. The genus Citrus has been demonstrated to be among the richest source of the title products. The aim of this comprehensive review is to make a survey of the so far reported literature citations about the main O-prenyl coumarins found in this genus from phytochemical and pharmacological point of views and for which no surveys of the in so far reported literature have been made.
Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Citrus; Coumarins; Humans; Molecular Structure; Plant Extracts; Prenylation
PubMed: 29303071
DOI: 10.2174/0929867325666180104154443 -
Methods in Enzymology 2019Prenylated flavin mononucleotide (prFMN) is a recently discovered flavin cofactor produced by the UbiX family of FMN prenyltransferases, and is required for the activity...
Prenylated flavin mononucleotide (prFMN) is a recently discovered flavin cofactor produced by the UbiX family of FMN prenyltransferases, and is required for the activity of UbiD-like reversible decarboxylases. The latter enzymes are known to be involved in ubiquinone biosynthesis and biotransformation of lignin, aromatic compounds, and unsaturated aliphatic acids. However, exploration of uncharacterized UbiD proteins for biotechnological applications is hindered by our limited knowledge about the biochemistry of prFMN and prFMN-dependent enzymes. Here, we describe experimental protocols and considerations for the biosynthesis of prFMN in vivo and in vitro, in addition to cofactor extraction and application for activation of UbiD proteins.
Topics: Aspergillus niger; Carboxy-Lyases; Enzyme Assays; Escherichia coli; Flavin Mononucleotide; Models, Molecular; Prenylation; Recombinant Proteins
PubMed: 31072498
DOI: 10.1016/bs.mie.2019.03.021 -
Life Sciences Jan 2020Thymic carcinoma is a rare epithelial tumor, for which, optimal pharmacotherapeutic methods have not yet been established. To develop new drug treatments for thymic...
AIMS
Thymic carcinoma is a rare epithelial tumor, for which, optimal pharmacotherapeutic methods have not yet been established. To develop new drug treatments for thymic carcinoma, we investigated the effects of fluvastatin-mediated pharmacological inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) on thymic carcinoma.
MAIN METHODS
Thymic carcinoma tissue was surgically excised and HMGCR expression was assessed by immunohistochemistry. Ty82 human thymic carcinoma cells were treated with fluvastatin (1-10 μM) and their growth was monitored.
KEY FINDINGS
HMGCR was expressed on carcinoma cells but not on normal epithelial cells in thymic tissue. Inhibition of HMGCR by fluvastatin suppressed cell proliferation and induced the death of Ty-82 human thymic carcinoma cells. Fluvastatin mediated its antitumor effects by blocking the production of geranylgeranyl-pyrophosphate (GGPP), an isoprenoid that is produced from mevalonate and binds to small GTPases, which promotes cell proliferation.
SIGNIFICANCE
Fluvastatin showed marked antitumor effects on thymic carcinoma. The results suggest that the statin has clinical benefits in thymic carcinoma management.
Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Fluvastatin; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; MAP Kinase Signaling System; Polyisoprenyl Phosphates; Prenylation; Thymoma; Thymus Neoplasms
PubMed: 31786191
DOI: 10.1016/j.lfs.2019.117110 -
Cardiovascular Research Mar 2017
Topics: Humans; Hypertension, Pulmonary; Hypoxia; Neoplasms; Prenylation; Quinolones; rhoB GTP-Binding Protein
PubMed: 28395024
DOI: 10.1093/cvr/cvx010 -
ACS Chemical Biology Dec 2019Prenylation is a common step in the biosynthesis of many natural products and plays an important role in increasing their structural diversity and enhancing biological...
Prenylation is a common step in the biosynthesis of many natural products and plays an important role in increasing their structural diversity and enhancing biological activity. Muscoride A is a linear peptide alkaloid that contain two contiguous oxazoles and unusual prenyl groups that protect the amino- and carboxy-termini. Here we identified the 12.7 kb muscoride () biosynthetic gene clusters from spp. PCC 7906 and UHCC 0398. The biosynthetic gene clusters encode enzymes for the heterocyclization, oxidation, and prenylation of the MusE precursor protein. The biosynthetic gene clusters encode two copies of the cyanobactin prenyltransferase, MusF1 and MusF2. The predicted tetrapeptide substrate of MusF1 and MusF2 was synthesized through a novel tandem cyclization route in only eight steps. Biochemical assays demonstrated that MusF1 acts on the carboxy-terminus while MusF2 acts on the amino-terminus of the tetrapeptide substrate. We show that the MusF2 enzyme catalyzes the reverse or forward prenylation of amino-termini from spp. PCC 7906 and UHCC 0398, respectively. This finding expands the regiospecific chemical functionality of cyanobactin prenyltransferases and the chemical diversity of the cyanobactin family of natural products to include bis-prenylated polyoxazole linear peptides.
Topics: Biosynthetic Pathways; Dimethylallyltranstransferase; Multigene Family; Oxazoles; Peptides, Cyclic; Prenylation; Pyrrolidines
PubMed: 31674754
DOI: 10.1021/acschembio.9b00620 -
Nature Methods Jun 2019
Topics: Protein Prenylation
PubMed: 31147650
DOI: 10.1038/s41592-019-0446-3 -
Drug Discovery Today Nov 2016Prenylated xanthones are secondary metabolites that are particularly common in plants belonging to the Clusiaceae family. Such compounds have been the focus intensive... (Review)
Review
Prenylated xanthones are secondary metabolites that are particularly common in plants belonging to the Clusiaceae family. Such compounds have been the focus intensive research because of their potential as biologically active agents. Here, we survey data published over the past decade relating to the properties of prenylated xanthones to provide a more detailed view of the potential of these naturally occurring compounds as therapeutic agents.
Topics: Animals; Humans; Magnoliopsida; Prenylation; Xanthones
PubMed: 27596926
DOI: 10.1016/j.drudis.2016.06.033 -
PloS One 2017RAS mutations lead to a constitutively active oncogenic protein that signals through multiple effector pathways. In this chemical biology study, we describe a novel...
RAS mutations lead to a constitutively active oncogenic protein that signals through multiple effector pathways. In this chemical biology study, we describe a novel coupled biochemical assay that measures activation of the effector BRAF by prenylated KRASG12V in a lipid-dependent manner. Using this assay, we discovered compounds that block biochemical and cellular functions of KRASG12V with low single-digit micromolar potency. We characterized the structural basis for inhibition using NMR methods and showed that the compounds stabilized the inactive conformation of KRASG12V. Determination of the biophysical affinity of binding using biolayer interferometry demonstrated that the potency of inhibition matches the affinity of binding only when KRAS is in its native state, namely post-translationally modified and in a lipid environment. The assays we describe here provide a first-time alignment across biochemical, biophysical, and cellular KRAS assays through incorporation of key physiological factors regulating RAS biology, namely a negatively charged lipid environment and prenylation, into the in vitro assays. These assays and the ligands we discovered are valuable tools for further study of KRAS inhibition and drug discovery.
Topics: Animals; Cell Line; Cell Line, Tumor; Humans; Lipids; Magnetic Resonance Spectroscopy; Prenylation; Proto-Oncogene Proteins p21(ras)
PubMed: 28384226
DOI: 10.1371/journal.pone.0174706