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Natural Product Reports Apr 2000
Review
Topics: Enzymes; Kinetics; Mutagenesis, Site-Directed; Protein Binding; Protein Prenylation; Protein Processing, Post-Translational; Substrate Specificity
PubMed: 10821108
DOI: 10.1039/a904110i -
Proteomics Mar 2016Covalent lipid modifications of proteins are crucial for regulation of cellular plasticity, since they affect the chemical and physical properties and therefore protein... (Review)
Review
Covalent lipid modifications of proteins are crucial for regulation of cellular plasticity, since they affect the chemical and physical properties and therefore protein activity, localization, and stability. Most recently, lipid modifications on proteins are increasingly attracting important regulatory entities in diverse signaling events and diseases. In all cases, the lipid moiety of modified proteins is essential to allow water-soluble proteins to strongly interact with membranes or to induce structural changes in proteins that are critical for elemental processes such as respiration, transport, signal transduction, and motility. Until now, roughly about ten lipid modifications on different amino acid residues are described at the UniProtKB database and even well-known modifications are underrepresented. Thus, it is of fundamental importance to develop a better understanding of this emerging and so far under-investigated type of protein modification. Therefore, this review aims to give a comprehensive and detailed overview about enzymatic and nonenzymatic lipidation events, will report their role in cellular biology, discuss their relevancy for diseases, and describe so far available bioanalytical strategies to analyze this highly challenging type of modification.
Topics: Humans; Lipid Metabolism; Lipids; Lipoylation; Protein Prenylation; Proteins
PubMed: 26683279
DOI: 10.1002/pmic.201500353 -
Trends in Molecular Medicine Apr 2012Fatty acids and/or isoprenoids are covalently attached to a variety of disease-related proteins. The distinct chemical properties of each of these hydrophobic moieties... (Review)
Review
Fatty acids and/or isoprenoids are covalently attached to a variety of disease-related proteins. The distinct chemical properties of each of these hydrophobic moieties allow lipid modification to serve as a mechanism to regulate protein structure, localization and function. This review highlights recent progress in identifying inhibitors of protein lipidation and their effects on human disease. Myristoylation inhibitors have shown promise in blocking the action of human pathogens. Although inhibitors that block prenylation of Ras proteins have not yet been successful for cancer treatment, they may be efficacious in the rare premature aging syndrome progeria. Agents that alter the palmitoylation status of Ras, Wnt and Hh proteins have recently been discovered, and represent the next generation of potential chemotherapeutics.
Topics: Animals; Disease; Fatty Acids; Humans; Lipid Metabolism; Protein Prenylation; Protein Processing, Post-Translational; Proteins
PubMed: 22342806
DOI: 10.1016/j.molmed.2012.01.007 -
Current Topics in Microbiology and... 2006Hepatitis delta virus (HDV) is an important cause of acute and chronic liver disease. Current medical therapies are unable to effectively eradicate HDV infections.... (Review)
Review
Hepatitis delta virus (HDV) is an important cause of acute and chronic liver disease. Current medical therapies are unable to effectively eradicate HDV infections. Research into the molecular virology of the HDV life cycle has revealed a fascinating collection of biology. These insights are now beginning to be translated into new potential treatment strategies. For example, an essential step in the virus assembly process involves the post-translational lipid modification of a specific HDV protein, namely prenylation of large delta antigen. Preventing prenylation abolishes virus particle formation. Drugs capable of specifically inhibiting prenylation have been developed for use in humans. These agents represent a new class of antiviral agents, with HDV as a first target. Here, a brief review of the HDV life cycle emphasizing the role of prenylation is presented along with implications for drug development and therapy.
Topics: Antiviral Agents; Drug Design; Hepatitis D; Hepatitis Delta Virus; Hepatitis delta Antigens; Humans; Protein Prenylation; Virion; Virus Assembly
PubMed: 16903224
DOI: 10.1007/3-540-29802-9_7 -
Nature Chemistry Jun 2019Post-translational farnesylation or geranylgeranylation at a C-terminal cysteine residue regulates the localization and function of over 100 proteins, including the Ras...
Post-translational farnesylation or geranylgeranylation at a C-terminal cysteine residue regulates the localization and function of over 100 proteins, including the Ras isoforms, and is a therapeutic target in diseases including cancer and infection. Here, we report global and selective profiling of prenylated proteins in living cells enabled by the development of isoprenoid analogues YnF and YnGG in combination with quantitative chemical proteomics. Eighty prenylated proteins were identified in a single human cell line, 64 for the first time at endogenous abundance without metabolic perturbation. We further demonstrate that YnF and YnGG enable direct identification of post-translationally processed prenylated peptides, proteome-wide quantitative analysis of prenylation dynamics and alternative prenylation in response to four different prenyltransferase inhibitors, and quantification of defective Rab prenylation in a model of the retinal degenerative disease choroideremia.
Topics: Adaptor Proteins, Signal Transducing; Alkynes; Animals; Cell Line; Gene Knockout Techniques; Humans; Mass Spectrometry; Mice, Knockout; Molecular Probes; Protein Prenylation; Proteins; Proteome; Proteomics
PubMed: 30936521
DOI: 10.1038/s41557-019-0237-6 -
The Journal of Neuroscience : the... May 2012Accumulation of β-amyloid (Aβ) inside brain neurons is an early and crucial event in Alzheimer's disease (AD). Studies in brains of AD patients and mice models of AD... (Comparative Study)
Comparative Study
Accumulation of β-amyloid (Aβ) inside brain neurons is an early and crucial event in Alzheimer's disease (AD). Studies in brains of AD patients and mice models of AD suggested that cholesterol homeostasis is altered in neurons that accumulate Aβ. Here we directly investigated the role of intracellular oligomeric Aβ(42) (oAβ(42)) in neuronal cholesterol homeostasis. We report that oAβ(42) induces cholesterol sequestration without increasing cellular cholesterol mass. Several features of AD, such as endosomal abnormalities, brain accumulation of Aβ and neurofibrillary tangles, and influence of apolipoprotein E genotype, are also present in Niemann-Pick type C, a disease characterized by impairment of intracellular cholesterol trafficking. These common features and data presented here suggest that a pathological mechanism involving abnormal cholesterol trafficking could take place in AD. Cholesterol sequestration in Aβ-treated neurons results from impairment of intracellular cholesterol trafficking secondary to inhibition of protein prenylation. oAβ(42) reduces sterol regulatory element-binding protein-2 (SREBP-2) cleavage, causing decrease of protein prenylation. Inhibition of protein prenylation represents a mechanism of oAβ(42)-induced neuronal death. Supply of the isoprenoid geranylgeranyl pyrophosphate to oAβ(42)-treated neurons recovers normal protein prenylation, reduces cholesterol sequestration, and prevents Aβ-induced neurotoxicity. Significant to AD, reduced levels of protein prenylation are present in the cerebral cortex of the TgCRND8 mouse model. In conclusion, we demonstrate a significant inhibitory effect of Aβ on protein prenylation and identify SREBP-2 as a target of oAβ(42), directly linking Aβ to cholesterol homeostasis impairment.
Topics: Amyloid beta-Peptides; Animals; Anticholesteremic Agents; Biological Transport; Cell Death; Cells, Cultured; Cholesterol; Female; Intracellular Space; Male; Mice; Mice, Transgenic; Neurons; Peptide Fragments; Protein Prenylation; Rats; Rats, Sprague-Dawley; Sterol Regulatory Element Binding Protein 2
PubMed: 22573671
DOI: 10.1523/JNEUROSCI.0630-12.2012 -
Lancet (London, England) Feb 2000Members of the superfamily of Ras GTPase signalling proteins (monomeric G proteins) require post-translational carboxy-terminal prenylation to function. Prenylation is... (Review)
Review
Members of the superfamily of Ras GTPase signalling proteins (monomeric G proteins) require post-translational carboxy-terminal prenylation to function. Prenylation is the covalent attachment of a hydrophobic prenyl group (either farnesyl or geranylgeranyl), which localises the GTPase to cell membranes. Ras proteins exert substantial control on cell proliferation and gene-transcription events, and prenylation inhibitors are now included in clinical trials for cancer. Many renal diseases are highly proliferative and are driven by a range of profibrotic cytokines. We hypothesise that inhibition of prenylation could be of substantial therapeutic benefit in such diseases, providing greater selectivity against abnormal cytokine-driven proliferation and fibrogenesis than current treatments available to nephrologists.
Topics: Animals; Cell Division; GTP Phosphohydrolases; Humans; Kidney Diseases; Protein Prenylation; ras Proteins
PubMed: 10703816
DOI: 10.1016/s0140-6736(99)08347-6 -
Current Opinion in Plant Biology Dec 2009Classically perceived as means for recruiting proteins to the membranes, protein lipid modifications are known today to play diverse roles in subcellular targeting,... (Review)
Review
Classically perceived as means for recruiting proteins to the membranes, protein lipid modifications are known today to play diverse roles in subcellular targeting, protein-protein interactions and signaling. This review focuses on three protein lipid modifications: prenylation, S-acylation and N-myristoylation and attempts to provide an up-to-date view of their function by focusing on several model proteins.
Topics: Acylation; Lipoylation; Plant Proteins; Protein Prenylation; Signal Transduction
PubMed: 19796984
DOI: 10.1016/j.pbi.2009.09.003 -
Molecular BioSystems Jan 2011Protein S-prenylation is a lipid modification that regulates membrane-protein and protein-protein interactions in cell signaling. Though sites of protein S-prenylation...
Protein S-prenylation is a lipid modification that regulates membrane-protein and protein-protein interactions in cell signaling. Though sites of protein S-prenylation can be predicted based upon conserved C-terminal CaaX or CC/CXC motifs, biochemical detection of protein S-prenylation in cells is still challenging. Herein, we report an alkynyl-isoprenol chemical reporter (alk-FOH) as an efficient substrate for prenyltransferases in mammalian cells that enables sensitive detection of S-farnesylated and S-geranylgeranylated proteins using bioorthogonal ligation methods. Fluorescent detection alleviates the need to deplete cellular isoprenoids for biochemical analysis of S-prenylated proteins and enables robust characterization of S-prenylated proteins, such as effectors that are injected into host cells by bacterial pathogens. This alkynyl-prenylation reporter provides a sensitive tool for biochemical analysis and rapid profiling of prenylated proteins in cells.
Topics: Animals; Cell Line; Dimethylallyltranstransferase; Electrophoresis, Polyacrylamide Gel; Farnesol; HeLa Cells; Humans; Immunoblotting; Immunoprecipitation; Mice; Models, Biological; Protein Prenylation
PubMed: 21107478
DOI: 10.1039/c0mb00183j -
Bioorganic & Medicinal Chemistry Letters Dec 2019Benzimidazole carboxyphosphonates and bisphosphonates have been prepared and evaluated for their activity as inhibitors of protein prenylation or isoprenoid...
Benzimidazole carboxyphosphonates and bisphosphonates have been prepared and evaluated for their activity as inhibitors of protein prenylation or isoprenoid biosynthesis. The nature of the phosphonate head group was found to dictate enzyme specificity. The lead carboxyphosphonate inhibits geranylgeranyl transferase II while its corresponding bisphosphonate analogue potently inhibits farnesyl diphosphate synthase. The most active inhibitors effectively disrupted protein prenylation in human multiple myeloma cells.
Topics: Benzimidazoles; Humans; Organophosphonates; Protein Prenylation
PubMed: 31699606
DOI: 10.1016/j.bmcl.2019.126757