-
Expert Review of Proteomics Jun 2017Protein prenylation is a ubiquitous covalent post-translational modification characterized by the addition of farnesyl or geranylgeranyl isoprenoid groups to a cysteine... (Review)
Review
Protein prenylation is a ubiquitous covalent post-translational modification characterized by the addition of farnesyl or geranylgeranyl isoprenoid groups to a cysteine residue located near the carboxyl terminal of a protein. It is essential for the proper localization and cellular activity of numerous proteins, including Ras family GTPases and G-proteins. In addition to its roles in cellular physiology, the prenylation process has important implications in human diseases and in the recent years, it has become attractive target of inhibitors with therapeutic potential. Areas covered: This review attempts to summarize the basic aspects of prenylation integrating them with biological functions in diseases and giving an account of the current status of prenylation inhibitors as potential therapeutics. We also summarize the methodologies for the characterization of this modification. Expert commentary: The growing body of evidence suggesting an important role of prenylation in diseases and the subsequent development of inhibitors of the enzymes responsible for this modification lead to the urgent need to identify the full spectrum of prenylated proteins that are altered in the disease or affected by drugs. Proteomic tools to analyze prenylated proteins are recently emerging, thanks to the advancement in the field of mass spectrometry coupled to enrichment strategies.
Topics: Cysteine; Humans; Protein Prenylation; Protein Processing, Post-Translational; Proteins; Proteomics
PubMed: 28521569
DOI: 10.1080/14789450.2017.1332998 -
Journal of Medicinal Chemistry Apr 2018Post-translational modifications (PTMs) allot versatility to the biological functions of highly conserved proteins. Recently, modifications to non-histone proteins such... (Review)
Review
Post-translational modifications (PTMs) allot versatility to the biological functions of highly conserved proteins. Recently, modifications to non-histone proteins such as methylation, acetylation, phosphorylation, glycosylation, ubiquitination, and many more have been linked to the regulation of pivotal pathways related to cellular response and stability. Due to the roles these dynamic modifications assume, their dysregulation has been associated with cancer and many other important diseases such as inflammatory disorders and neurodegenerative diseases. For this reason, we present a review and perspective on important post-translational modifications on non-histone proteins, with emphasis on their roles in diseases and small molecule inhibitors developed to target PTM writers. Certain PTMs' contribution to epigenetics has been extensively expounded; yet more efforts will be needed to systematically dissect their roles on non-histone proteins, especially for their relationships with nononcological diseases. Finally, current research approaches for PTM study will be discussed and compared, including limitations and possible improvements.
Topics: Acetylation; Animals; Citrullination; Enzyme Inhibitors; Glycosylation; Humans; Methylation; Phosphorylation; Protein Prenylation; Protein Processing, Post-Translational; Proteins; Ubiquitination
PubMed: 28505447
DOI: 10.1021/acs.jmedchem.6b01817 -
Science Signaling Mar 2015Whereas resting T cells, which have low metabolic requirements, use oxidative phosphorylation (OXPHOS) to maximize their generation of ATP, activated T cells, similar to... (Review)
Review
Whereas resting T cells, which have low metabolic requirements, use oxidative phosphorylation (OXPHOS) to maximize their generation of ATP, activated T cells, similar to tumor cells, shift metabolic activity to aerobic glycolysis, which also fuels mevalonate metabolism. Both sterol and nonsterol derivatives of mevalonate affect T cell function. The intracellular availability of sterols, which is dynamically regulated by different classes of transcription factors, represents a metabolic checkpoint that modulates T cell responses. The electron carrier ubiquinone, which is modified with an isoprenoid membrane anchor, plays a pivotal role in OXPHOS, which supports the proliferation of T cells. Isoprenylation also mediates the plasma membrane attachment of the Ras, Rho, and Rab guanosine triphosphatases, which are involved in T cell immunological synapse formation, migration, proliferation, and cytotoxic effector responses. Finally, multiple phosphorylated mevalonate derivatives can act as danger signals for innate-like γδ T cells, thus contributing to the immune surveillance of stress, pathogens, and tumors. We highlight the importance of the mevalonate pathway in the metabolic reprogramming of effector and regulatory T cells.
Topics: Cholesterol; Glycolysis; Gonadal Steroid Hormones; Homeostasis; Humans; Lymphocyte Activation; Metabolic Networks and Pathways; Mevalonic Acid; Models, Immunological; Oxidative Phosphorylation; Protein Prenylation; T-Lymphocytes; Ubiquinone
PubMed: 25829448
DOI: 10.1126/scisignal.2005970 -
BioRxiv : the Preprint Server For... Jul 2023Prenylation is a universal and irreversible post-translational modification that supports membrane interactions of proteins involved in various cellular processes,...
Prenylation is a universal and irreversible post-translational modification that supports membrane interactions of proteins involved in various cellular processes, including migration, proliferation, and survival. Thus, dysregulation of prenylation contributes to multiple disorders, including cancers, vascular diseases, and neurodegenerative diseases. During prenylation, prenyltransferase enzymes tether metabolically produced isoprenoid lipids to proteins via a thioether linkage. Pharmacological inhibition of the lipid synthesis pathway by statins has long been a therapeutic approach to control hyperlipidemia. Building on our previous finding that statins inhibit membrane association of G protein γ (Gγ) in a subtype-dependent manner, we investigated the molecular reasoning for this differential. We examined the prenylation efficacy of carboxy terminus (Ct) mutated Gγ in cells exposed to Fluvastatin and prenyl transferase inhibitors and monitored the subcellular localization of fluorescently tagged Gγ subunits and their mutants using live-cell confocal imaging. Reversible optogenetic unmasking-masking of Ct residues was used to probe their contribution to the prenylation process and membrane interactions of the prenylated proteins. Our findings suggest that specific Ct residues regulate membrane interactions of the Gγ polypeptide statin sensitivity, and prenylation efficacy. Our results also show that a few hydrophobic and charged residues at the Ct are crucial determinants of a protein's prenylation ability, especially under suboptimal conditions. Given the cell and tissue-specific expression of different Gγ subtypes, our findings explain how and why statins differentially perturb heterotrimeric G protein signaling in specific cells and tissues. Our results may provide molecular reasoning for repurposing statins as Ras oncogene inhibitors and the failure of using prenyltransferase inhibitors in cancer treatment.
PubMed: 37461501
DOI: 10.1101/2023.07.04.547731 -
Frontiers in Oncology 2021Cholesterol is a ubiquitous sterol with many biological functions, which are crucial for proper cellular signaling and physiology. Indeed, cholesterol is essential in... (Review)
Review
Cholesterol is a ubiquitous sterol with many biological functions, which are crucial for proper cellular signaling and physiology. Indeed, cholesterol is essential in maintaining membrane physical properties, while its metabolism is involved in bile acid production and steroid hormone biosynthesis. Additionally, isoprenoids metabolites of the mevalonate pathway support protein-prenylation and dolichol, ubiquinone and the heme biosynthesis. Cancer cells rely on cholesterol to satisfy their increased nutrient demands and to support their uncontrolled growth, thus promoting tumor development and progression. Indeed, transformed cells reprogram cholesterol metabolism either by increasing its uptake and biosynthesis, or deregulating the efflux. Alternatively, tumor can efficiently accumulate cholesterol into lipid droplets and deeply modify the activity of key cholesterol homeostasis regulators. In light of these considerations, altered pathways of cholesterol metabolism might represent intriguing pharmacological targets for the development of exploitable strategies in the context of cancer therapy. Thus, this work aims to discuss the emerging evidence of and studies, as well as clinical trials, on the role of cholesterol pathways in the treatment of cancer, starting from already available cholesterol-lowering drugs (statins or fibrates), and moving towards novel potential pharmacological inhibitors or selective target modulators.
PubMed: 34109128
DOI: 10.3389/fonc.2021.682911 -
Drug Discovery Today Oct 2022Inhibition of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase by statins is affected by inhibiting the active site of the enzyme in a competitive manner. Statins... (Review)
Review
Inhibition of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase by statins is affected by inhibiting the active site of the enzyme in a competitive manner. Statins reduce plasma cholesterol by inhibiting its de novo synthesis. In addition, statins impart 'pleiotropic' activities that do not directly relate to their ability to decrease cholesterol. The proangiogenic and antiangiogenic characteristics of statins are among these pleiotropic effects. These angiogenic-modifying properties could offer new therapeutic applications. Statins stimulate or suppress angiogenesis in a biphasic manner. Whereas low doses of statin stimulate angiogenesis, high doses reduce protein prenylation and limit cell development and angiogenesis. In this review, we discuss how statins impact angiogenesis, with a particular focus on angiogenesis in stroke and cardiovascular disease (CVD).
Topics: Cardiovascular Diseases; Cholesterol; Coenzyme A; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Neovascularization, Pathologic; Oxidoreductases
PubMed: 35872297
DOI: 10.1016/j.drudis.2022.07.010 -
Molecular Neurobiology Mar 2021Protein prenylation is a post-translational lipid modification that governs a variety of important cellular signaling pathways, including those regulating synaptic...
Protein prenylation is a post-translational lipid modification that governs a variety of important cellular signaling pathways, including those regulating synaptic functions and cognition in the nervous system. Two enzymes, farnesyltransferase (FT) and geranylgeranyltransferase type I (GGT), are essential for the prenylation process. Genetic reduction of FT or GGT ameliorates neuropathology but only FT haplodeficiency rescues cognitive function in transgenic mice of Alzheimer's disease. A follow-up study showed that systemic or forebrain neuron-specific deficiency of GGT leads to synaptic and cognitive deficits under physiological conditions. Whether FT plays different roles in shaping neuronal functions and cognition remains elusive. This study shows that in contrast to the detrimental effects of GGT reduction, systemic haplodeficiency of FT has little to no impact on hippocampal synaptic plasticity and cognition. However, forebrain neuron-specific FT deletion also leads to reduced synaptic plasticity, memory retention, and hippocampal dendritic spine density. Furthermore, a novel prenylomic analysis identifies distinct pools of prenylated proteins that are affected in the brain of forebrain neuron-specific FT and GGT knockout mice, respectively. Taken together, this study uncovers that physiological levels of FT and GGT in neurons are essential for normal synaptic/cognitive functions and that the prenylation status of specific signaling molecules regulates neuronal functions.
Topics: Alkyl and Aryl Transferases; Animals; Cognition; Dendritic Spines; Hippocampus; Long-Term Potentiation; Maze Learning; Mice; Neuronal Plasticity; Neurons; Protein Prenylation; Spatial Learning; Spatial Memory; Synapses
PubMed: 33098528
DOI: 10.1007/s12035-020-02169-w -
Mycopathologia Dec 2014Pathogenic fungi employ numerous mechanisms to flourish in the stressful environment encountered within their mammalian hosts. Central to this arsenal for filamentous... (Review)
Review
Pathogenic fungi employ numerous mechanisms to flourish in the stressful environment encountered within their mammalian hosts. Central to this arsenal for filamentous fungi is invasive growth within the host microenvironment, mediated by establishment and maintenance of polarized hyphal morphogenesis. In Aspergillus fumigatus, the RasA signal transduction pathway has emerged as a significant regulator of hyphal morphogenesis and virulence, among other processes. The factors contributing to the regulation of RasA itself are not as thoroughly understood, although proper temporal activation of RasA and spatial localization of RasA to the plasma membrane are known to play major roles. Interference with RasA palmitoylation or prenylation results in mislocalization of RasA and is associated with severe growth deficits. In addition, dysregulation of RasA activation results in severe morphologic aberrancies and growth deficits. This review highlights the relationship between RasA signaling, hyphal morphogenesis, and virulence in A. fumigatus and focuses on potential determinants of spatial and temporal RasA regulation.
Topics: Aspergillus fumigatus; Gene Expression Regulation, Fungal; Hyphae; Lipoylation; Protein Prenylation; Signal Transduction; Virulence; ras Proteins
PubMed: 24952717
DOI: 10.1007/s11046-014-9765-1 -
Frontiers in Chemistry 2014In the human body, the complex biochemical network known as the mevalonate pathway is responsible for the biosynthesis of all isoprenoids, which consists of a vast array... (Review)
Review
In the human body, the complex biochemical network known as the mevalonate pathway is responsible for the biosynthesis of all isoprenoids, which consists of a vast array of metabolites that are vital for proper cellular functions. Two key isoprenoids, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are responsible for the post-translational prenylation of small GTP-binding proteins, and serve as the biosynthetic precursors to numerous other biomolecules. The down-stream metabolite of FPP and GGPP is squalene, the precursor to steroids, bile acids, lipoproteins, and vitamin D. In the past, interest in prenyl synthase inhibitors focused mainly on the role of the FPP in lytic bone diseases. More recently pre-clinical and clinical studies have strongly implicated high levels of protein prenylation in a plethora of human diseases, including non-skeletal cancers, the progression of neurodegenerative diseases and cardiovascular diseases. In this review, we focus mainly on the potential therapeutic value of down-regulating the biosynthesis of FPP, GGPP, and squalene. We summarize the most recent drug discovery efforts and the structural data available that support the current on-going studies.
PubMed: 25101260
DOI: 10.3389/fchem.2014.00050 -
Bioorganic & Medicinal Chemistry May 2018Prenylation is a post-translational modification that increases the affinity of proteins for membranes and mediates protein-protein interactions. The retinal rod...
Prenylation is a post-translational modification that increases the affinity of proteins for membranes and mediates protein-protein interactions. The retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDEδ) is a prenyl binding protein that is essential for the shuttling of small GTPases between different membrane compartments and, thus, for their proper functioning. Although the prenylome comprises up to 2% of the mammalian proteome, only few prenylated proteins are known to interact with PDEδ. A proteome-wide approach was employed to map the PDEδ interactome among the prenylome and revealed RAB23, CDC42 and CNP as novel PDEδ interacting proteins. Moreover, PDEδ associates with the lamin A mutant progerin in a prenyl-dependent manner. These findings shed new light on the role of PDEδ in binding (and regulating) prenylated proteins in cells.
Topics: Carrier Proteins; Cells, Cultured; Cyclic Nucleotide Phosphodiesterases, Type 6; Dose-Response Relationship, Drug; Humans; Molecular Structure; Protein Binding; Structure-Activity Relationship
PubMed: 28935183
DOI: 10.1016/j.bmc.2017.08.033