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Biomedicine & Pharmacotherapy =... Aug 2023Prenyltransferases (PTases) are known to play a role in embryonic development, normal tissue homeostasis and cancer by posttranslationally modifying proteins involved in... (Review)
Review
Prenyltransferases (PTases) are known to play a role in embryonic development, normal tissue homeostasis and cancer by posttranslationally modifying proteins involved in these processes. They are being discussed as potential drug targets in an increasing number of diseases, ranging from Alzheimer's disease to malaria. Protein prenylation and the development of specific PTase inhibitors (PTIs) have been subject to intense research in recent decades. Recently, the FDA approved lonafarnib, a specific farnesyltransferase inhibitor that acts directly on protein prenylation; and bempedoic acid, an ATP citrate lyase inhibitor that might alter intracellular isoprenoid composition, the relative concentrations of which can exert a decisive influence on protein prenylation. Both drugs represent the first approved agent in their respective substance class. Furthermore, an overwhelming number of processes and proteins that regulate protein prenylation have been identified over the years, many of which have been proposed as molecular targets for pharmacotherapy in their own right. However, certain aspects of protein prenylation, such as the regulation of PTase gene expression or the modulation of PTase activity by phosphorylation, have attracted less attention, despite their reported influence on tumor cell proliferation. Here, we want to summarize the advances regarding our understanding of the regulation of protein prenylation and the potential implications for drug development. Additionally, we want to suggest new lines of investigation that encompass the search for regulatory elements for PTases, especially at the genetic and epigenetic levels.
Topics: Protein Prenylation; Proteins; Dimethylallyltranstransferase; Enzyme Inhibitors; Terpenes; Prenylation
PubMed: 37236024
DOI: 10.1016/j.biopha.2023.114915 -
Molecules (Basel, Switzerland) Oct 2019Protein prenylation is one of the most important posttranslational modifications of proteins. Prenylated proteins play important roles in different developmental... (Review)
Review
Protein prenylation is one of the most important posttranslational modifications of proteins. Prenylated proteins play important roles in different developmental processes as well as stress responses in plants as the addition of hydrophobic prenyl chains (mostly farnesyl or geranyl) allow otherwise hydrophilic proteins to operate as peripheral lipid membrane proteins. This review focuses on selected aspects connecting protein prenylation with plant responses to both abiotic and biotic stresses. It summarizes how changes in protein prenylation impact plant growth, deals with several families of proteins involved in stress response and highlights prominent regulatory importance of prenylated small GTPases and chaperons. Potential possibilities of these proteins to be applicable for biotechnologies are discussed.
Topics: Biotechnology; Plant Proteins; Plants; Protein Prenylation; Stress, Physiological; Substrate Specificity
PubMed: 31671559
DOI: 10.3390/molecules24213906 -
International Journal of Environmental... Jul 2022The cholesterol biosynthesis represents a crucial metabolic pathway for cellular homeostasis. The end products of this pathway are sterols, such as cholesterol, which... (Review)
Review
The cholesterol biosynthesis represents a crucial metabolic pathway for cellular homeostasis. The end products of this pathway are sterols, such as cholesterol, which are essential components of cell membranes, precursors of steroid hormones, bile acids, and other molecules such as ubiquinone. Furthermore, some intermediates of this metabolic system perform biological activity in specific cellular compartments, such as isoprenoid molecules that can modulate different signal proteins through the prenylation process. The defects of prenylation represent one of the main causes that promote the activation of inflammation. In particular, this mechanism, in association with oxidative stress, induces a dysfunction of the mitochondrial activity. The purpose of this review is to describe the pleiotropic role of prenylation in neuroinflammation and to highlight the consequence of the defects of prenylation.
Topics: Cholesterol; Humans; Mevalonic Acid; Neuroinflammatory Diseases; Oxidative Stress; Prenylation
PubMed: 35897423
DOI: 10.3390/ijerph19159061 -
Journal of Agricultural and Food... Feb 2023Prenylated aromatic natural products (PANPs) have received much attention due to their biomedical benefits for human health. The prenylation of aromatic natural products... (Review)
Review
Prenylated aromatic natural products (PANPs) have received much attention due to their biomedical benefits for human health. The prenylation of aromatic natural products (ANPs), which is mainly catalyzed by aromatic prenyltransferases (aPTs), contributes significantly to their structural and functional diversity by providing higher lipophilicity and enhanced bioactivity. aPTs are widely distributed in bacteria, fungi, animals, and plants and play a key role in the regiospecific prenylation of ANPs. Recent studies have greatly advanced our understanding of the characteristics and application of aPTs. In this review, we comment on research progress regarding sources, evolutionary relationships, structural features, reaction mechanism, engineering modification, and application of aPTs. Particular emphasis is also placed on recent advances, challenges, and prospects about applications of aPTs in microbial cell factories for producing PANPs. Generally, this review could provide guidance for using aPTs as robust biocatalytic tools to produce various PANPs with high efficiency.
Topics: Humans; Bacteria; Biological Products; Dimethylallyltranstransferase; Fungi; Prenylation; Substrate Specificity
PubMed: 36716399
DOI: 10.1021/acs.jafc.2c07287 -
Molecular Neurobiology May 2020Mevalonate pathway inhibitors have been extensively studied for their roles in cholesterol depletion and for inhibiting the prenylation and activation of various... (Review)
Review
Mevalonate pathway inhibitors have been extensively studied for their roles in cholesterol depletion and for inhibiting the prenylation and activation of various proteins. Inhibition of protein prenylation has potential therapeutic uses against neurological disorders, like neural cancers, neurodegeneration, and neurotramatic lesions. Protection against neurodegeneration and promotion of neuronal regeneration is regulated in large part by Ras superfamily small guanosine triphosphatases (GTPases), particularly the Ras, Rho, and Rab subfamilies. These proteins are prenylated to target them to cellular membranes. Prenylation can be specifically inhibited through altering the function of enzymes of the mevalonate pathway necessary for isoprenoid production and attachment to target proteins to elicit a variety of effects on neural cells. However, this approach does not address how prenylation affects a specific protein. This review focuses on the regulation of small GTPase prenylation, the different techniques to inhibit prenylation, and how this inhibition has affected neural cell processes.
Topics: Acyl Coenzyme A; Amino Acid Motifs; Animals; Biosynthetic Pathways; Cell Membrane; Dimethylallyltranstransferase; Enzyme Activation; GTP Phosphohydrolases; Humans; Methylation; Mevalonic Acid; Nerve Tissue Proteins; Protein Binding; Protein Prenylation; Terpenes
PubMed: 31989383
DOI: 10.1007/s12035-020-01870-0 -
Bioscience, Biotechnology, and... Feb 2018Flavonoids are distributed across the plant kingdom and have attracted substantial attention owing to their potential benefits for human health. Several studies have... (Review)
Review
Flavonoids are distributed across the plant kingdom and have attracted substantial attention owing to their potential benefits for human health. Several studies have demonstrated that flavonoids prenylation enhances various biological activities, suggesting an attractive tool for developing functional foods. This review provides an overview of the current knowledge on how prenylation influences the biological activity and bioavailability of flavonoids. The enhancement effect of prenylation on the biological activities of dietary flavonoids in mammals was demonstrated by comparing the effect of 8-prenyl naringenin (8PN) with that of parent naringenin in the prevention of disuse muscle atrophy in mice. This enhancement results from higher muscular accumulation of 8PN than naringenin. As to bioavailability, despite the lower absorption of 8-prenyl quercetin (8PQ) compared with quercetin, higher 8PQ accumulation was found in the liver and kidney. These data imply that prenylation interferes with the elimination of flavonoids from tissues.
Topics: Animals; Biological Availability; Diet; Flavonoids; Humans; Intestinal Absorption; Prenylation; Tissue Distribution
PubMed: 29307271
DOI: 10.1080/09168451.2017.1415750 -
Journal of Medical Genetics Mar 2014Many proteins depend on post-translational prenylation for a correct subcellular localisation and membrane anchoring. This involves the covalent attachment of farnesyl... (Review)
Review
Many proteins depend on post-translational prenylation for a correct subcellular localisation and membrane anchoring. This involves the covalent attachment of farnesyl or geranylgeranyl residues to cysteines residing in consensus motifs at the C-terminal parts of proteins. Retinal photoreceptor cells are highly compartmentalised and membranous structures, and therefore it can be expected that the proper function of many retinal proteins depends on prenylation, which has been proven for several proteins that are absent or defective in different inherited retinal diseases (IRDs). These include proteins involved in the phototransduction cascade, such as GRK1, the phosphodiesterase 6 subunits and the transducin γ subunit, or proteins involved in transport processes, such as RAB28 and retinitis pigmentosa GTPase regulator (RPGR). In addition, there is another class of general prenylation defects due to mutations in proteins such as AIPL1, PDE6D and rab escort protein-1 (REP-1), which can act as chaperones for subsets of prenylated retinal proteins that are associated with IRDs. REP-1 also is a key accessory protein of geranylgeranyltransferase II, an enzyme involved in the geranylgeranylation of almost all members of a large family of Rab GTPases. Finally, mutations in the mevalonate kinase (MVK) gene, which were known to be principally associated with mevalonic aciduria, were recently associated with non-syndromic retinitis pigmentosa. We hypothesise that MVK deficiency results in a depletion of prenyl moieties that affects the prenylation of many proteins synthesised specifically in the retina, including Rabs. In this review, we discuss the entire spectrum of prenylation defects underlying progressive degeneration of photoreceptors, the retinal pigment epithelium and the choroid.
Topics: Animals; Humans; Mice; Protein Prenylation; Retinal Diseases
PubMed: 24401286
DOI: 10.1136/jmedgenet-2013-102138 -
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 -
Current Opinion in Cell Biology Dec 1992As with other lipid modifications of proteins, prenylation now appears to be critically important in the regulation of protein function. Recent research has led to an... (Comparative Study)
Comparative Study Review
As with other lipid modifications of proteins, prenylation now appears to be critically important in the regulation of protein function. Recent research has led to an explosion of information concerning prenylation signals, prenyl transferase enzymes and the role of prenylation in protein-membrane interactions. Experiments have examined the role of prenylation in protein function and the results suggest that protein prenylation may be involved in facilitating proper subcellular localization, promoting protein-protein and protein-membrane interactions and regulating protein function.
Topics: Amino Acid Sequence; Animals; Cell Membrane; Dimethylallyltranstransferase; Molecular Sequence Data; Oncogene Proteins; Protein Prenylation
PubMed: 1485954
DOI: 10.1016/0955-0674(92)90133-w -
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