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Trends in Biochemical Sciences Apr 2023Prenylation is a post-translational modification (PTM) widely found in primary and secondary metabolism. This modification can enhance the lipophilicity of molecules,... (Review)
Review
Prenylation is a post-translational modification (PTM) widely found in primary and secondary metabolism. This modification can enhance the lipophilicity of molecules, enabling them to interact with lipid membranes more effectively. The prenylation of peptides is often carried out by cyanobactin prenyltransferases (PTases) from cyanobacteria. These enzymes are of interest due to their ability to add prenyl groups to unmodified peptides, thus making them more effective therapeutics through the subsequent acquisition of increased membrane permeability and bioavailability. Herein we review the current knowledge of cyanobactin PTases, focusing on their discovery, biochemistry, and bioengineering, and highlight the potential application of them as peptide alkylation biocatalysts to generate peptide therapeutics.
Topics: Dimethylallyltranstransferase; Peptides, Cyclic; Peptides; Bioengineering
PubMed: 36564250
DOI: 10.1016/j.tibs.2022.11.002 -
International Journal of Molecular... Dec 2022Multiple myeloma (MM) is a plasma cell malignancy for which there is currently no cure. While treatment options for MM have expanded over the last two decades, all... (Review)
Review
Multiple myeloma (MM) is a plasma cell malignancy for which there is currently no cure. While treatment options for MM have expanded over the last two decades, all patients will eventually become resistant to current therapies. Thus, there is an urgent need for novel therapeutic strategies to treat MM. The isoprenoid biosynthetic pathway (IBP) is responsible for the post-translational modification of proteins belonging to the Ras small GTPase superfamily, such as Ras, Rho and Rab family members. Given the important roles these GTPase proteins play in various cellular processes, there is significant interest in the development of inhibitors that disturb their prenylation and consequently their activity in MM cells. Numerous preclinical studies have demonstrated that IBP inhibitors have anti-MM effects, including the induction of apoptosis in MM cells and inhibition of osteoclast activity. Some IBP inhibitors have made their way into the clinic. For instance, nitrogenous bisphosphonates are routinely prescribed for the management MM bone disease. Other IBP inhibitors, including statins and farnesyltransferase inhibitors, have been evaluated in clinical trials for MM, while there is substantial preclinical investigation into geranylgeranyl diphosphate synthase inhibitors. Here we discuss recent advances in the development of IBP inhibitors, assess their mechanism of action and evaluate their potential as anti-MM agents.
Topics: Humans; Multiple Myeloma; Biosynthetic Pathways; Diphosphonates; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Terpenes; Protein Prenylation
PubMed: 36613550
DOI: 10.3390/ijms24010111 -
Chemistry and Physics of Lipids Oct 2021Flavonoids are a huge class of polyphenolic compounds ubiquitous in higher plants, in most food and beverages of natural origin. They could be considered as dietary...
Flavonoids are a huge class of polyphenolic compounds ubiquitous in higher plants, in most food and beverages of natural origin. They could be considered as dietary phenols, which exert many health-promoting effects on human and animal physiology with a wide range of biomedical and nutritional functions such as activation or inhibition of enzymes like lipoxygenase and cyclooxygenase, the detoxification of carcinogens and chemoprevention. From a chemical point of view, these aromatic compounds can be divided in six subgroups depending on the position of aromatic B ring on C ring, the degree of unsaturation and oxidation, the position of hydroxyl groups and their functionalization. Between flavonoids, the prenylated ones represent a unique class occurring in nature where the C-prenylation is the most common, whereas O-prenylation is rarely present. The presence of this lipophilic functional group in different positions on the scaffold of flavonoids can sometimes lead to relevant changes in their biological activity due to an increased bioavailability. Capitalizing on the restricted incidence in nature of prenylated flavonoids, we have assessed the synthesis of C- and O-prenylated derivatives starting from two flavonoids, quercetin and artemetin, aimed at the exploration of structure-activity relationships. Results showed that prenylation significantly increased the cytotoxic effect of flavonoids in cancer HeLa cells, also improving their capacity to affect cell phospholipid and fatty acid composition. A marked cell bioavailability increase was demonstrated for the artemetin C-prenylated derivative.
Topics: Antineoplastic Agents; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Flavonoids; HeLa Cells; Humans; Prenylation; Quercetin
PubMed: 34529978
DOI: 10.1016/j.chemphyslip.2021.105137 -
The Journal of Biological Chemistry Jun 2023Identifying events that regulate the prenylation and localization of small GTPases will help define new strategies for therapeutic targeting of these proteins in...
Identifying events that regulate the prenylation and localization of small GTPases will help define new strategies for therapeutic targeting of these proteins in disorders such as cancer, cardiovascular disease, and neurological deficits. Splice variants of the chaperone protein SmgGDS (encoded by RAP1GDS1) are known to regulate prenylation and trafficking of small GTPases. The SmgGDS-607 splice variant regulates prenylation by binding preprenylated small GTPases but the effects of SmgGDS binding to the small GTPase RAC1 versus the splice variant RAC1B are not well defined. Here we report unexpected differences in the prenylation and localization of RAC1 and RAC1B and their binding to SmgGDS. Compared to RAC1, RAC1B more stably associates with SmgGDS-607, is less prenylated, and accumulates more in the nucleus. We show that the small GTPase DIRAS1 inhibits binding of RAC1 and RAC1B to SmgGDS and reduces their prenylation. These results suggest that prenylation of RAC1 and RAC1B is facilitated by binding to SmgGDS-607 but the greater retention of RAC1B by SmgGDS-607 slows RAC1B prenylation. We show that inhibiting RAC1 prenylation by mutating the CAAX motif promotes RAC1 nuclear accumulation, suggesting that differences in prenylation contribute to the different nuclear localization of RAC1 versus RAC1B. Finally, we demonstrate RAC1 and RAC1B that cannot be prenylated bind GTP in cells, indicating that prenylation is not a prerequisite for activation. We report differential expression of RAC1 and RAC1B transcripts in tissues, consistent with these two splice variants having unique functions that might arise in part from their differences in prenylation and localization.
Topics: Protein Isoforms; Prenylation; Monomeric GTP-Binding Proteins; rac1 GTP-Binding Protein; Protein Prenylation
PubMed: 37059183
DOI: 10.1016/j.jbc.2023.104698 -
Phytochemistry Sep 2023Pharmacological studies on flavonoids have always drawn much interest for many years. Icaritin (ICT), a representative flavone containing an 8-prenyl group, is a... (Review)
Review
Pharmacological studies on flavonoids have always drawn much interest for many years. Icaritin (ICT), a representative flavone containing an 8-prenyl group, is a principal compound detected in medicinal plants of the genus Epimedum, the family Berberidaceae. Experimental results in the phytochemistry and pharmacology of this molecule are abundant now, but a deep overview has not been carried out. The goal of this review is to provide an insight into the natural observation, biosynthesis, biotransformation, synthesis, pharmacology, and pharmacokinetics of prenyl flavone ICT. The relevant data on ICT was collected from bibliographic sources, like Google Scholar, Web of Science, Sci-Finder, and various published journals. "Icaritin" alone or in combination is the main keyword to seek for references, and references have been updated till now. ICT is among the characteristic phytomolecules of Epimedum plants. Bacteria monitored its biosynthesis and biotransformation, while this agent was rapidly synthesized from phloroglucinol by microwave-assistance Claisen rearrangement. ICT is a potential agent in numerous in vitro and in vivo pharmacological records, which demonstrated its role in cancer treatments via apoptotic-related mechanisms. It also brings in various health benefits since it reduced harmful effects on the liver, lung, heart, bone, blood, and skin, and improved immune responses. Pharmacokinetic outcomes indicated that its metabolic pathway involved hydration, hydroxylation, dehydrogenation, glycosylation, and glucuronidation. Molecule mechanisms of action at a cellular level are predominant, but clinical studies are expected to get more. Structure-activity relationship records seem insufficient, and the studies on nano-combined approaches to improve its soluble property in living bodied medium are needed.
Topics: Flavonoids; Plants, Medicinal; Flavones
PubMed: 37356700
DOI: 10.1016/j.phytochem.2023.113772 -
ACS Omega Apr 2021Tryptophan-containing isoprenoid indole alkaloid natural products are well known for their intricate structural architectures and significant biological activities....
Tryptophan-containing isoprenoid indole alkaloid natural products are well known for their intricate structural architectures and significant biological activities. Nature employs dimethylallyl tryptophan synthases (DMATSs) or aromatic indole prenyltransferases (iPTs) to catalyze regio- and stereoselective prenylation of l-Trp. Regioselective synthetic routes that isoprenylate -Trp-Trp in a 2,5-diketopiperazine (DKP) core, in a desymmetrizing manner, are nonexistent and are highly desirable. Herein, we present an elaborate report on Brønsted acid-promoted regioselective tryptophan isoprenylation strategy, applicable to both the monomeric amino acid and its dimeric l-Trp DKP. This report outlines a method that regio- and stereoselectively increases sp centers of a privileged bioactive core. We report on conditions involving screening of Brønsted acids, their conjugate base as salt, solvent, temperature, and various substrates with diverse side chains. Furthermore, we extensively delineate effects on regio- and stereoselection of isoprenylation and their stereochemical confirmation NMR experiments. Regioselectively, the C3-position undergoes -isoprenylation or benzylation and forms -ring-fused pyrroloindolines selectively. Through appropriate prenyl group migrations, we report access to the bioactive tryprostatin alkaloids, and by C3--farnesylation, we access anticancer drimentines as direct targets of this method. The optimized strategy affords -tryprostatin B-type products and predrimentine C with 58 and 55% yields, respectively. The current work has several similarities to biosynthesis, such as-reactions can be performed on unprotected substrates, conditions that enable Brønsted acid promotion, and they are easy to perform under ambient conditions, without the need for stoichiometric levels of any transition metal or expensive ligands.
PubMed: 34056238
DOI: 10.1021/acsomega.1c00515 -
International Journal of Molecular... May 2022Protein prenylation is a post-translational modification controlling the localization, activity, and protein-protein interactions of small GTPases, including the Ras... (Review)
Review
Protein prenylation is a post-translational modification controlling the localization, activity, and protein-protein interactions of small GTPases, including the Ras superfamily. This covalent attachment of either a farnesyl (15 carbon) or a geranylgeranyl (20 carbon) isoprenoid group is catalyzed by four prenyltransferases, namely farnesyltransferase (FTase), geranylgeranyltransferase type I (GGTase-I), Rab geranylgeranyltransferase (GGTase-II), and recently discovered geranylgeranyltransferase type III (GGTase-III). Blocking small GTPase activity, namely inhibiting prenyltransferases, has been proposed as a potential disease treatment method. Inhibitors of prenyltransferase have resulted in substantial therapeutic benefits in various diseases, such as cancer, neurological disorders, and viral and parasitic infections. In this review, we overview the structure of FTase, GGTase-I, GGTase-II, and GGTase-III and summarize the current status of research on their inhibitors.
Topics: Carbon; Dimethylallyltranstransferase; Farnesyltranstransferase; Protein Prenylation; Terpenes
PubMed: 35628237
DOI: 10.3390/ijms23105424 -
PloS One 2022Protein prenylation by farnesyltransferase (FTase) is often described as the targeting of a cysteine-containing motif (CaaX) that is enriched for aliphatic amino acids...
Protein prenylation by farnesyltransferase (FTase) is often described as the targeting of a cysteine-containing motif (CaaX) that is enriched for aliphatic amino acids at the a1 and a2 positions, while quite flexible at the X position. Prenylation prediction methods often rely on these features despite emerging evidence that FTase has broader target specificity than previously considered. Using a machine learning approach and training sets based on canonical (prenylated, proteolyzed, and carboxymethylated) and recently identified shunted motifs (prenylation only), this study aims to improve prenylation predictions with the goal of determining the full scope of prenylation potential among the 8000 possible Cxxx sequence combinations. Further, this study aims to subdivide the prenylated sequences as either shunted (i.e., uncleaved) or cleaved (i.e., canonical). Predictions were determined for Saccharomyces cerevisiae FTase and compared to results derived using currently available prenylation prediction methods. In silico predictions were further evaluated using in vivo methods coupled to two yeast reporters, the yeast mating pheromone a-factor and Hsp40 Ydj1p, that represent proteins with canonical and shunted CaaX motifs, respectively. Our machine learning-based approach expands the repertoire of predicted FTase targets and provides a framework for functional classification.
Topics: Alkyl and Aryl Transferases; Farnesyltranstransferase; Machine Learning; Protein Prenylation; Saccharomyces cerevisiae; Substrate Specificity
PubMed: 35749383
DOI: 10.1371/journal.pone.0270128 -
Molecular & Cellular Proteomics : MCP Aug 2023Proteins containing a CAAX motif at the C-terminus undergo prenylation for localization and activity and include a series of key regulatory proteins, such as RAS...
Proteins containing a CAAX motif at the C-terminus undergo prenylation for localization and activity and include a series of key regulatory proteins, such as RAS superfamily members, heterotrimeric G proteins, nuclear lamina protein, and several protein kinases and phosphatases. However, studies of prenylated proteins in esophageal cancer are limited. Here, through research on large-scale proteomic data of esophageal cancer in our laboratory, we found that paralemmin-2 (PALM2), a potential prenylated protein, was upregulated and associated with poor prognosis in patients. Low-throughput verification showed that the expression of PALM2 in esophageal cancer tissues was higher than that in their paired normal esophageal epithelial tissues, and it was generally expressed in the membrane and cytoplasm of esophageal cancer cells. PALM2 interacted with the two subunits of farnesyl transferase (FTase), FNTA and FNTB. Either the addition of an FTase inhibitor or mutation in the CAAX motif of PALM2 (PALM2) impaired its membranous localization and reduced the membrane location of PALM2, indicating PALM2 was prenylated by FTase. Overexpression of PALM2 enhanced the migration of esophageal squamous cell carcinoma cells, whereas PALM2 lost this ability. Mechanistically, PALM2 interacted with the N-terminal FERM domain of ezrin of the ezrin/radixin/moesin (ERM) family. Mutagenesis indicated that lysine residues K253/K254/K262/K263 in ezrin's FERM domain and C408 in PALM2's CAAX motif were important for PALM2/ezrin interaction and ezrin activation. Knockout of ezrin prevented enhanced cancer cell migration by PALM2 overexpression. PALM2, depending on its prenylation, increased both ezrin membrane localization and phosphorylation of ezrin at Y146. In summary, prenylated PALM2 enhances the migration of cancer cells by activating ezrin.
Topics: Humans; Cell Movement; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Proteomics
PubMed: 37328063
DOI: 10.1016/j.mcpro.2023.100593 -
Science Translational Medicine Jul 2021Accumulation of the parkin-interacting substrate (PARIS; ), due to inactivation of parkin, contributes to Parkinson's disease (PD) through repression of peroxisome...
Accumulation of the parkin-interacting substrate (PARIS; ), due to inactivation of parkin, contributes to Parkinson's disease (PD) through repression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α; ) activity. Here, we identify farnesol as an inhibitor of PARIS. Farnesol promoted the farnesylation of PARIS, preventing its repression of PGC-1α via decreasing PARIS occupancy on the promoter. Farnesol prevented dopaminergic neuronal loss and behavioral deficits via farnesylation of PARIS in PARIS transgenic mice, ventral midbrain transduction of AAV-PARIS, adult conditional parkin KO mice, and the α-synuclein preformed fibril model of sporadic PD. PARIS farnesylation is decreased in the substantia nigra of patients with PD, suggesting that reduced farnesylation of PARIS may play a role in PD. Thus, farnesol may be beneficial in the treatment of PD by enhancing the farnesylation of PARIS and restoring PGC-1α activity.
Topics: Animals; Dopamine; Mice; Parkinson Disease; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Prenylation; Repressor Proteins; Substantia Nigra
PubMed: 34321320
DOI: 10.1126/scitranslmed.aax8891