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Science (New York, N.Y.) Mar 1997
Topics: Alkyl and Aryl Transferases; Animals; Cell Membrane; GTP-Binding Proteins; Methylation; Palmitic Acid; Protein Prenylation; Signal Transduction; Transferases; ras Proteins
PubMed: 9122679
DOI: 10.1126/science.275.5307.1750 -
FEBS Letters Feb 1993The antibiotic patulin was found to inhibit protein prenylation in mouse FM3A cells. Thus, the agent reduced incorporation of [3H]mevalonate into proteins by 50% at a...
The antibiotic patulin was found to inhibit protein prenylation in mouse FM3A cells. Thus, the agent reduced incorporation of [3H]mevalonate into proteins by 50% at a concentration of 7 microM. In a cell-free assay, patulin inhibited rat brain farnesyl:protein transferase, one of the enzymes responsible for protein prenylation. The inhibition was 50% at a concentration of 290 microM.
Topics: Alkyl and Aryl Transferases; Animals; Brain; Cells, Cultured; Cycloheximide; Leucine; Mevalonic Acid; Mice; Patulin; Protein Prenylation; Rats; Transferases; Trichothecenes
PubMed: 8436232
DOI: 10.1016/0014-5793(93)81334-v -
Biochemical Pharmacology Apr 1999The monoterpenes limonene and perillyl alcohol are undergoing clinical evaluation in cancer patients. In this paper, we report the chemical synthesis, characterisation,...
The monoterpenes limonene and perillyl alcohol are undergoing clinical evaluation in cancer patients. In this paper, we report the chemical synthesis, characterisation, and quantitation in patients' plasma of a novel human metabolite of limonene, which is identified as an isomer of perillic acid. The synthesis of R-perillic acid is also described, because previous reports on the activity of perillic acid against isoprenylation enzymes refer to the S-enantiomer, although it is the R-enantiomer which is the metabolite of R-limonene. The above monoterpenes, with several related compounds, were assayed for inhibitory activity towards the isoprenylation enzymes in rat brain cytosol. Although R- and S-limonene are only weak inhibitors of the isoprenylation enzymes, their major metabolites, perillic acid and perillyl alcohol, are more potent inhibitors, with IC50 values in the low mM range. The metabolites possess greater activity towards the geranylgeranyltransferase type I enzyme than farnesyltransferase, while the novel metabolite displays IC50 values similar to those of perillic acid suggesting that it may contribute to the in vivo activity of limonene.
Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents, Phytogenic; Brain; Chromatography, High Pressure Liquid; Cyclohexane Monoterpenes; Cyclohexenes; Cytosol; Enzyme Inhibitors; Farnesyltranstransferase; Humans; In Vitro Techniques; Limonene; Mass Spectrometry; Monoterpenes; Nerve Tissue Proteins; Protein Prenylation; Rats; Terpenes
PubMed: 10075086
DOI: 10.1016/s0006-2952(98)00349-9 -
Molecular Reproduction and Development Oct 2006Progesterone receptor (PR) stimulation promotes survival in human and rat periovulatory granulosa cells. PR antagonists, Org 31710 and RU 486, both increase apoptosis...
Progesterone receptor (PR) stimulation promotes survival in human and rat periovulatory granulosa cells. PR antagonists, Org 31710 and RU 486, both increase apoptosis and decrease cholesterol synthesis in these cells. The decrease in cholesterol synthesis also causes decreased synthesis of other products branching from the cholesterol synthesis pathway, including substrates for protein prenylation. In this study we focus on the link between apoptosis and prenylation in human periovulatory granulosa cells. A decreased cholesterol synthesis and increased apoptosis was verified in experiments with human periovulatory granulosa cells treated with the PR antagonists Org 31710 or RU 486 by measuring caspase-3/7 activity and incorporation of 14C-acetate into cholesterol and progesterone. Correspondingly, specific inhibition of cholesterol synthesis in periovulatory human granulosa cells using HMG-CoA reductase inhibitors (lovastatin or simvastatin) increased apoptosis, measured as caspase-3/7 activity. The increase in apoptosis caused by simvastatin or Org 31710 was partially reversed by addition of the protein prenylation precursors farnesol or geranylgeraniol. In addition, the prenylation inhibitors FTI R115777 and GGTI 2147 increased apoptosis in these cells. In conclusion our data suggest that PR antagonists increase apoptosis and reduce cholesterol synthesis in periovulatory granulosa cells and that the resulting depletion of substrates for protein prenylation may contribute to the increased apoptosis sensitivity.
Topics: Apoptosis; Cells, Cultured; Cholesterol; Diterpenes; Estrenes; Farnesol; Farnesyltranstransferase; Female; Furans; Granulosa Cells; Hormone Antagonists; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Imidazoles; Leucine; Mifepristone; Ovulation; Protein Prenylation; Quinolones; Receptors, Progesterone
PubMed: 16868926
DOI: 10.1002/mrd.20551 -
Current Opinion in Investigational... Aug 2005Protein farnesyl transferase inhibitors (PFTIs) have been developed as oncology therapeutics but recent studies have supported the use of PFTIs for the treatment of... (Review)
Review
Protein farnesyl transferase inhibitors (PFTIs) have been developed as oncology therapeutics but recent studies have supported the use of PFTIs for the treatment of eukaryotic pathogens. Data supporting PFTIs for the treatment of African sleeping sickness caused by Trypanosoma brucei sp, and for the therapy of malaria caused by Plasmodium spp is reviewed. Protein prenylation in T. brucei and P. falciparum has been studied using a variety of techniques, including recombinant and native enzyme assays. Studies have demonstrated farnesylation and geranylgeranylation in these parasites. A variety of PFTIs have shown growth inhibition activity and killing of T. brucei and P. falciparum, yet not all mammalian PFTIs are active on parasitic PFTs. Protein farnesyl transferase as well as protein geranylgeranyl transferase type II enzymatic activities have been demonstrated in T brucei and P. falciparum, but protein geranylgeranyl transferase type I activity may be lacking from these parasites, perhaps explaining the extreme sensitivity of these organisms to PFTIs compared with mammalian cells. Given that PFTIs are relatively non-toxic in short-term administration to humans, PFTIs specific to parasites are not required for therapy. Thus, the challenge in PFTI drug development is not to identify selective antiparasite compounds, but to identify compounds with sufficient potency and pharmacokinetic properties to produce satisfactory drugs for malaria and African sleeping sickness.
Topics: Alkyl and Aryl Transferases; Animals; Antimalarials; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Malaria; Plasmodium; Protein Prenylation; Trypanocidal Agents; Trypanosomiasis, African
PubMed: 16121685
DOI: No ID Found -
Biochemical Society Transactions Aug 1996
Review
Topics: Animals; Biological Transport, Active; GTP-Binding Proteins; Guanine Nucleotide Dissociation Inhibitors; Intracellular Membranes; Models, Biological; Molecular Structure; Protein Conformation; Protein Prenylation; Subcellular Fractions; rab1 GTP-Binding Proteins
PubMed: 8878830
DOI: 10.1042/bst0240703 -
Molecular Brain Feb 2023The prenylation of proteins is involved in a variety of biological functions. However, it remains unknown whether it plays an important role in the morphogenesis of the...
The prenylation of proteins is involved in a variety of biological functions. However, it remains unknown whether it plays an important role in the morphogenesis of the cerebellum. To address this question, we generated a mouse model, in which the geranylgeranyl pyrophosphate synthase (Ggps1) gene is inactivated in neural progenitor cells in the developing cerebellum. We report that conditional knockout (cKO) of Ggps1 leads to severe ataxia and deficient locomotion. To identify the underlying mechanisms, we completed a series of cellular and molecular experiments. First, our morphological analysis revealed significantly decreased population of granule cell progenitors (GCPs) and impaired proliferation of GCPs in the developing cerebellum of Ggps1 cKO mice. Second, our molecular analysis showed increased expression of p21, an important cell cycle regulator in Ggps1 cKO mice. Together, this study highlights a critical role of Ggpps-dependent protein prenylation in the proliferation of cerebellar GCPs during cerebellar development.
Topics: Mice; Animals; Protein Prenylation; Cerebellum; Neural Stem Cells; Ataxia; Cell Proliferation; Mice, Knockout
PubMed: 36782228
DOI: 10.1186/s13041-023-01010-4 -
Archivum Immunologiae Et Therapiae... Apr 2021The review discusses a new approach to the prevention and treatment of viral infections based on the use of pine needles polyprenyl phosphate (PPP) and associated with... (Review)
Review
The review discusses a new approach to the prevention and treatment of viral infections based on the use of pine needles polyprenyl phosphate (PPP) and associated with the infringement of prenylation process-the attachment of farnesol or geranyl geraniol to the viral protein. Currently, prenylation has been detected in type 1 adenovirus, hepatitis C virus, several herpes viruses, influenza virus, HIV. However, this list is far from complete, given that prenylated proteins play an extremely important role in the activity of the virus. We assume that the interferon produced in response to PPP may suppress expression of the SREBP2 transcription factor. As a result, the mevalonic acid pathway is violated and, as a result, the formation of early polyprenols precursors (geraniol, geranyl geraniol, farnesol), which are necessary for the prenylation of viral proteins, is blocked and the formation of mature, virulent virus particles is broken. As a consequence, the maturation of viral particles is inhibited, and defective particles are formed. Polyprenol was extracted from greenery (pine, fir and spruce needles, mulberry leaves, etc.), purified by chromatography, phosphorylated and identified by HPLC and NMR. Obtained PPP was used as antiviral in some experimental models in vitro and in vivo. During numerous studies, it was found that PPP manifested versatile antiviral effects, both in vitro and in vivo. The maximum effect was observed with viruses in which the presence of prenylated proteins was established, namely influenza A virus, HIV-1, tick-borne encephalitis virus, hepatitis A and C viruses, herpes simplex viruses type 1 and 2, some coronavirus. The available data obtained both in the experimental conditions and during clinical trials allow us to regard PPPs as safe and effective medicine for prevention and treatment of viral diseases.
Topics: Animals; Antiviral Agents; Clinical Trials as Topic; Disease Models, Animal; Gene Expression Regulation; Humans; Interferons; Microscopy, Electron; Pinus; Polyisoprenyl Phosphates; Protein Prenylation; Sterol Regulatory Element Binding Protein 2; Treatment Outcome; Viral Proteins; Virion; Virus Diseases; Virus Replication
PubMed: 33811524
DOI: 10.1007/s00005-021-00613-w -
Cancer Cell Apr 2005Protein farnesylation is a lipid posttranslational modification required for the cancer-causing activity of proteins such as the GTPase Ras. Although farnesyltransferase... (Review)
Review
Protein farnesylation is a lipid posttranslational modification required for the cancer-causing activity of proteins such as the GTPase Ras. Although farnesyltransferase inhibitors (FTIs) are in clinical trials, their mechanism of action and the role of protein farnesylation in normal physiology are ill understood. In this issue of Cancer Cell, two articles shed light on these important issues. Protein farnesylation was found to be essential for early embryogenesis, dispensable for adult homeostasis, and critical for progression but not initiation of tumorigenesis. Furthermore, Rab geranylgeranyltransferase was identified as a target for some FTIs. This minireview discusses the implications of these findings on normal physiology, malignant transformation, and cancer therapy.
Topics: Alkyl and Aryl Transferases; Animals; Caenorhabditis elegans; Cell Proliferation; Cell Transformation, Neoplastic; Embryonic Development; Enzyme Inhibitors; Homeostasis; Humans; Mice; Neoplasms; Protein Prenylation; Protein Processing, Post-Translational; rab GTP-Binding Proteins; ras Proteins; rho GTP-Binding Proteins
PubMed: 15837619
DOI: 10.1016/j.ccr.2005.04.005 -
Expert Opinion on Therapeutic Patents May 2019Bisphosphonates (BPs) are widely used to manage a variety of bone disorders, including osteoporosis, metastatic bone disease and myeloma bone disease. The... (Review)
Review
INTRODUCTION
Bisphosphonates (BPs) are widely used to manage a variety of bone disorders, including osteoporosis, metastatic bone disease and myeloma bone disease. The nitrogen-containing BPs (NBPs) target osteoclast activity by disrupting protein prenylation via inhibition of farnesyl diphosphate synthase (FDPS).
AREAS COVERED
This review summarizes the recent advances in BPs with a focus on the latest patents (2015-2018). Patents involving novel BPs, new modes of BP delivery, as well as use of BPs to deliver other drugs to bone are discussed. A review of phosphonate-based drugs targeting geranylgeranyl diphosphate synthase (GGDPS) or geranylgeranyl transferase II (GGTase II) as alternative strategies to disrupt protein geranylgeranylation is provided.
EXPERT OPINION
While the NBPs remain the mainstay of treatment for most bone disorders, further understanding of their pharmacological properties could lead to further refinement of their chemical structures and optimization of efficacy and safety profiles. In addition, the development of NBP analogs or drug delivery mechanisms that allow for nonbone tissue exposure could allow for the use of these drugs as direct anticancer agents. The development of GGDPS and GGTase II inhibitors represents alternative heterocycle phosphonate-based strategies to disrupt protein geranylgeranylation and may have potential as anticancer agents and/or as bone-targeted therapies.
Topics: Animals; Bone Diseases; Diphosphonates; Drug Delivery Systems; Drug Development; Farnesyltranstransferase; Geranyltranstransferase; Humans; Osteoclasts; Patents as Topic; Protein Prenylation; Transferases
PubMed: 31023104
DOI: 10.1080/13543776.2019.1608180