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Critical Reviews in Food Science and... 2022Functional foods play an important role in health care and chronic diseases prevention, particularly cancer. Prenylated flavonoids are presented in many food resources.... (Review)
Review
Functional foods play an important role in health care and chronic diseases prevention, particularly cancer. Prenylated flavonoids are presented in many food resources. They are recognized as neutraceuticals due to their diverse health benefits. Up to now, more than 1000 prenylated flavonoids have been identified in plants. Their food resources are reviewed in this paper. Due to the good safety and cancer prevention effect of prenylated flavonoids, this paper reviews the cancer prevention activities and mechanisms reported in last decade. The structure-activity relationship is discussed. Due to the limited availability in nature, the heterologously biosynthetic technique of prenylated flavonoids is discussed in this review. Inclusion of dietary prenylated flavonoids into human diet is highly desirable. This paper combines the up-to-date information and give a clear image regarding prenylated flavonoids as neutraceuticals.
Topics: Delivery of Health Care; Flavonoids; Humans; Neoplasms; Prenylation; Structure-Activity Relationship
PubMed: 33543993
DOI: 10.1080/10408398.2021.1881437 -
Journal of Internal Medicine Aug 2020The RAS genes, which include H, N, and KRAS, comprise the most frequently mutated family of oncogenes in cancer. Mutations in KRAS - such as the G12C mutation - are... (Review)
Review
The RAS genes, which include H, N, and KRAS, comprise the most frequently mutated family of oncogenes in cancer. Mutations in KRAS - such as the G12C mutation - are found in most pancreatic, half of colorectal and a third of lung cancer cases and is thus responsible for a substantial proportion of cancer deaths. Consequently, KRAS has been the subject of exhaustive drug-targeting efforts over the past 3-4 decades. These efforts have included targeting the KRAS protein itself but also its posttranslational modifications, membrane localization, protein-protein interactions and downstream signalling pathways. Most of these strategies have failed and no KRAS-specific drugs have yet been approved. However, for one specific mutation, KRAS , there is light on the horizon. MRTX849 was recently identified as a potent, selective and covalent KRAS inhibitor that possesses favourable drug-like properties. MRTX849 selectively modifies the mutant cysteine residue in GDP-bound KRAS and inhibits GTP-loading and downstream KRAS-dependent signalling. The drug inhibits the in vivo growth of multiple KRAS -mutant cell line xenografts, causes tumour regression in patient-derived xenograft models and shows striking responses in combination with other agents. It has also produced objective responses in patients with mutant-specific lung and colorectal cancer. In this review, we discuss the history of RAS drug-targeting efforts, the discovery of MRTX849, and how this drug provides an exciting and long-awaited opportunity to selectively target mutant KRAS in patients.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Mutation; Neoplasms; Protein Prenylation; Proto-Oncogene Proteins p21(ras)
PubMed: 32176377
DOI: 10.1111/joim.13057 -
Accounts of Chemical Research Apr 2020From structure elucidation and biogenesis to synthetic methodology and total synthesis, terpene natural products have profoundly influenced the development of organic... (Review)
Review
From structure elucidation and biogenesis to synthetic methodology and total synthesis, terpene natural products have profoundly influenced the development of organic chemistry. Moreover, their myriad functional attributes range from fragrance to pharmaceuticals and have had great societal impact. Ruzicka's formulation of the "biogenetic isoprene rule," a Nobel Prize winning discovery now over 80 years old, allowed for identification of higher order terpene (aka "isoprenoid") structures from simple five-carbon isoprene fragments. Notably, the isoprene rule still holds pedagogical value to students of organic chemistry today. Our laboratory has completed syntheses of over two dozen terpene and meroterpene structures to date, and the isoprene rule has served as a key pattern recognition tool for our synthetic planning purposes. At the strategic level, great opportunity exists in finding unique and synthetically simplifying ways to connect the formal C isoprene fragments embedded in terpenes. Biomimetic cationic polyene cyclizations represent the earliest incarnation of this idea, which has facilitated expedient routes to certain terpene polycycle classes. Nonetheless, a large swath of terpene chemical space remains inaccessible using this approach.In this Account, we describe strategic insight into our endeavors in terpene synthesis published over the last five years. We show how biosynthetic understanding, combined with a desire to utilize abundant and inexpensive [C] building blocks, has led to efficient, abiotic syntheses of multiple complex terpenes with disparate ring systems. Informed by nature, but unconstrained by its processes, our synthetic assembly exploits chemical reactivity across diverse reaction types-including radical, anionic, pericyclic, and metal-mediated transformations.First, we detail an eight-step synthesis of the cembrane diterpene chatancin from dihydrofarnesal using a bioinspired-but not -mimetic-cycloaddition. Next, we describe the assembly of the antimalarial cardamom peroxide using a polyoxygenation cascade to fuse multiple units of molecular oxygen onto a dimeric skeleton. This three-to-four-step synthesis arises from (-)-myrtenal, an inexpensive pinene oxidation product. We then show how a radical cyclization cascade can forge the hallmark cyclooctane ring system of the complex sesterterpene 6--ophiobolin N from two simple polyprenyl precursors, (-)-linalool and farnesol. To access the related, more complex metabolite 6-ophiobolin A, we exploited the plasticity of our synthetic route and found that use of geraniol (C) rather than farnesol (C) gave us the flexibility needed to address the additional oxidation found in this congener. Following this work, we describe two strategies to access several guaianolide sesquiterpenes. Retrosynthetic disconnection to monoterpenes, carvone or (-)-linalool, coupled with a powerful allylation strategy allowed us to address guaianolides with disparate stereochemical motifs. Finally, we examine a semisynthetic approach to the sesquiterpenes from the abundant 15-carbon feedstock terpene (+)-cedrol using an abiotic ring shift and multiple C-H oxidation reactions inspired by a postulated biosynthesis of this natural product class.
Topics: Chemistry Techniques, Synthetic; Neoprene; Terpenes
PubMed: 32202757
DOI: 10.1021/acs.accounts.0c00055 -
Trends in Biotechnology Aug 2020In plants, prenylation of aromatic compounds, such as (iso)flavonoids and stilbenoids, by membrane-bound prenyltransferases (PTs), is an essential step in the... (Review)
Review
In plants, prenylation of aromatic compounds, such as (iso)flavonoids and stilbenoids, by membrane-bound prenyltransferases (PTs), is an essential step in the biosynthesis of many bioactive compounds. Prenylated aromatic compounds have various health-beneficial properties that are interesting for industrial applications, but their exploitation is limited due to their low abundance in nature. Harnessing plant aromatic PTs for prenylation in microbial cell factories may be a sustainable and economically viable alternative. Limitations in prenylated aromatic compound production have been identified, including availability of prenyl donor substrate. In this review, we summarize the current knowledge about plant aromatic PTs and discuss promising strategies towards the optimized production of prenylated aromatic compounds by microbial cell factories.
Topics: Dimethylallyltranstransferase; Humans; Metabolic Engineering; Plants; Prenylation; Substrate Specificity
PubMed: 32299631
DOI: 10.1016/j.tibtech.2020.02.006 -
Frontiers in Immunology 2021Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder characterized by life-long recurring episodes of fever and inflammation, often without clear... (Review)
Review
Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder characterized by life-long recurring episodes of fever and inflammation, often without clear cause. MKD is caused by bi-allelic pathogenic variants in the gene, resulting in a decreased activity of the encoded enzyme mevalonate kinase (MK). MK is an essential enzyme in the isoprenoid biosynthesis pathway, which generates both non-sterol and sterol isoprenoids. The inflammatory symptoms of patients with MKD point to a major role for isoprenoids in the regulation of the innate immune system. In particular a temporary shortage of the non-sterol isoprenoid geranylgeranyl pyrophosphate (GGPP) is increasingly linked with inflammation in MKD. The shortage of GGPP compromises protein prenylation, which is thought to be one of the main causes leading to the inflammatory episodes in MKD. In this review, we discuss current views and the state of knowledge of the pathogenetic mechanisms in MKD, with particular focus on the role of compromised protein prenylation.
Topics: Biosynthetic Pathways; Genetic Association Studies; Humans; Immunotherapy; Inflammation; Mevalonate Kinase Deficiency; Protein Prenylation; Terpenes
PubMed: 34539662
DOI: 10.3389/fimmu.2021.724991 -
Phytotherapy Research : PTR Jan 2021Propolis, a resinous substance, is collected from plants and processed by honeybees to seal holes and cracks in beehives, protecting them from microbial infection. Based... (Review)
Review
Propolis, a resinous substance, is collected from plants and processed by honeybees to seal holes and cracks in beehives, protecting them from microbial infection. Based on the plant source and geographical location, propolis is categorized into seven groups. Of these, Pacific propolis, found in the Pacific islands, originates from Macaranga spp. and is, therefore, known as Macaranga-type Pacific propolis. Okinawa propolis and Taiwanese propolis, which are both Macaranga-type propolis, are rich in prenylated flavonoids from the same botanical source, Macaranga tanarius, and are used locally as traditional remedies. They are reported to have a wide range of pharmacological benefits, including antioxidant, anti-inflammation, antimicrobial, anticancer, antidiabetic, anti-Alzheimer's, anti-melanogenic, and longevity-extending effects. However, not much is known about their mode of action, and recently, the extract of Okinawa propolis and its major prenylated flavonoids were found to selectively inhibit the oncogenic kinase, p21-activated kinase 1 (PAK1). PAK1 enables cross-talking among several signaling pathways, causing many diseases/disorders. The existing results reviewed here support the use of Macaranga-type Pacific propolis for the effective development of safe herbal drugs and functional foods. Furthermore, its mode of action by modulating PAK1 can be explored, and the geographical and seasonal effects on its chemistry and biology, and its pharmacokinetics and toxicology should be studied as well.
Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Bees; Euphorbiaceae; Flavonoids; Humans; Hypoglycemic Agents; Longevity; Molecular Structure; Pacific Islands; Prenylation; Propolis; p21-Activated Kinases
PubMed: 32776610
DOI: 10.1002/ptr.6819 -
Current Medicinal Chemistry 2022Cancer is an uncontrolled cell growth that can generate diverse types of cancer, in which these will also present a different behavior in the face of pharmacological... (Review)
Review
Cancer is an uncontrolled cell growth that can generate diverse types of cancer, in which these will also present a different behavior in the face of pharmacological treatment. These cancers' types are found in one of the three categories, leukemias (also named lymphomas), carcinomas, and sarcomas. In general, cancer's pathogenesis is associated with three genetic mutations, where could emerge from oncogenes, tumor suppressor genes, and/or genes responsible for regulating DNA replication. The term "undruggable" is frequently related to the difficulty to design drugs to specific targets, such as MYC, MYB, NF-κB, and RAS family of proteins. This last comprises more than 140 proteins, and these are responsible for 30% of mutations in human cancers. Also, there are three ras genes transcribed in human cells, called H-, K-, and N-ras oncogenes. Still, the RAS proteins (farnesyltransferase (FTase) and geranylgeranyltransferase (GGTase) enzymes) perform essential steps in post-translational modification of eukaryotes cells, such as (1) the farnesylation of the cysteine residue at the C-terminal tetrapeptide CAAX; (2) proteolytic cleavage of the three C-terminal AAX oligopeptide; and (3) carboxymethylation of the new C-terminal prenylated cysteine. Thus, the inhibition of this undruggable RAS family of proteins has been considered a promising alternative to design new anticancer agents since they are responsible for many types of human cancers. Then, the manumycin A (obtained from the Streptomyces parvulus Tü64) and its analogs (epoxyquinol core with or without their southern and eastern side chains; and dihydroxycyclohexenones core) have been described as promising FTase inhibitors, which have demonstrated their benefits against several types of cancer. In this review, a complete introduction about cancer and its relation with RAS proteins is provided, as well as, the prenylation mechanism of the cysteine residue is discussed in detail. Posteriorly, studies involving manumycin-related compounds are described, showing some synthetic routes for obtaining them and utilizing these natural products in monotherapies or combined therapies with other anticancer drugs.
Topics: Alkyl and Aryl Transferases; Biological Products; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Neoplasms; Polyenes; Polyunsaturated Alkamides
PubMed: 33719954
DOI: 10.2174/0929867328666210315123848 -
CaaX-motif-adjacent residues influence G protein gamma (Gγ) prenylation under suboptimal conditions.The Journal of Biological Chemistry Nov 2023Prenylation is an irreversible post-translational modification that supports membrane interactions of proteins involved in various cellular processes, including...
Prenylation is an irreversible post-translational modification that supports membrane interactions of proteins involved in various cellular processes, including migration, proliferation, and survival. Dysregulation of prenylation contributes to multiple disorders, including cancers and vascular and neurodegenerative diseases. Prenyltransferases tether isoprenoid lipids to proteins via a thioether linkage during prenylation. Pharmacological inhibition of the lipid synthesis pathway by statins is 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 inhibition. We examined the prenylation 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 prenylation and membrane interactions of the prenylated proteins. Our findings suggest that specific Ct residues regulate membrane interactions of the Gγ polypeptide, statin sensitivity, and extent of prenylation. Our results also show 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 indicate a plausible mechanism allowing for statins to differentially perturb heterotrimeric G protein signaling in cells depending on their Gγ-subtype composition. Our results may also provide molecular reasoning for repurposing statins as Ras oncogene inhibitors and the failure of using prenyltransferase inhibitors in cancer treatment.
Topics: Humans; Amino Acid Motifs; Drug Resistance; HeLa Cells; Heterotrimeric GTP-Binding Proteins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Models, Molecular; Mutation; Protein Prenylation; Protein Structure, Tertiary; Protein Transport; Signal Transduction
PubMed: 37739036
DOI: 10.1016/j.jbc.2023.105269 -
Molecules (Basel, Switzerland) Dec 20207-Isopentenyloxycoumarin is among the most widespread naturally occurring prenyloxy umbelliferone derivatives. This secondary metabolite of mixed biosynthetic origin has... (Review)
Review
7-Isopentenyloxycoumarin is among the most widespread naturally occurring prenyloxy umbelliferone derivatives. This secondary metabolite of mixed biosynthetic origin has been typically isolated from plants belonging to several genera of the Rutaceae and Apiaceae families, comprising widely used medicinal plants and in general plants with beneficial effects on human welfare, as well as edible fruits and vegetables. Although known for quite a long time (more than 50 years), only in the last two decades has this natural compound been revealed to exert powerful and promising pharmacological properties, such as active cancer chemopreventive, antibacterial, antiprotozoal, antifungal, anti-inflammatory, neuroprotective, and antioxidant properties, among the activities best outlined in the recent literature. The aim of this comprehensive miniature review article is to detail the novel natural sources and the effects described during the last decade for 7-isopentenyloxycoumarin and what has been reported on the mechanisms of action underlying the observed biological activities of this oxyprenylated secondary metabolite. In view of the herein described data, suggestions on how to address future research on the abovementioned natural product and structurally related derivatives in the best ways according to the authors will be also provided.
Topics: Anti-Infective Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Apiaceae; Coumarins; Humans; Neuroprotective Agents; Oxidation-Reduction; Plant Extracts; Plants, Medicinal; Prenylation; Rutaceae; Secondary Metabolism
PubMed: 33327602
DOI: 10.3390/molecules25245923 -
ELife Mar 2022Isopentenyl pyrophosphate (IPP) is an essential metabolic output of the apicoplast organelle in malaria parasites and is required for prenylation-dependent vesicular...
Isopentenyl pyrophosphate (IPP) is an essential metabolic output of the apicoplast organelle in malaria parasites and is required for prenylation-dependent vesicular trafficking and other cellular processes. We have elucidated a critical and previously uncharacterized role for IPP in apicoplast biogenesis. Inhibiting IPP synthesis blocks apicoplast elongation and inheritance by daughter merozoites, and apicoplast biogenesis is rescued by exogenous IPP and polyprenols. Knockout of the only known isoprenoid-dependent apicoplast pathway, tRNA prenylation by MiaA, has no effect on blood-stage parasites and thus cannot explain apicoplast reliance on IPP. However, we have localized an annotated polyprenyl synthase (PPS) to the apicoplast. PPS knockdown is lethal to parasites, rescued by IPP and long- (C) but not short-chain (≤C) prenyl alcohols, and blocks apicoplast biogenesis, thus explaining apicoplast dependence on isoprenoid synthesis. We hypothesize that PPS synthesizes long-chain polyprenols critical for apicoplast membrane fluidity and biogenesis. This work critically expands the paradigm for isoprenoid utilization in malaria parasites and identifies a novel essential branch of apicoplast metabolism suitable for therapeutic targeting.
Topics: Animals; Apicoplasts; Malaria, Falciparum; Parasites; Plasmodium falciparum; Polyprenols; Protozoan Proteins; Terpenes
PubMed: 35257658
DOI: 10.7554/eLife.73208