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The Journal of Experimental Medicine Feb 2020Thymocyte egress is a critical determinant of T cell homeostasis and adaptive immunity. Despite the roles of G protein-coupled receptors in thymocyte emigration, the...
Thymocyte egress is a critical determinant of T cell homeostasis and adaptive immunity. Despite the roles of G protein-coupled receptors in thymocyte emigration, the downstream signaling mechanism remains poorly defined. Here, we report the discrete roles for the two branches of mevalonate metabolism-fueled protein prenylation pathway in thymocyte egress and immune homeostasis. The protein geranylgeranyltransferase Pggt1b is up-regulated in single-positive thymocytes, and loss of Pggt1b leads to marked defects in thymocyte egress and T cell lymphopenia in peripheral lymphoid organs in vivo. Mechanistically, Pggt1b bridges sphingosine-1-phosphate and chemokine-induced migratory signals with the activation of Cdc42 and Pak signaling and mevalonate-dependent thymocyte trafficking. In contrast, the farnesyltransferase Fntb, which mediates a biochemically similar process of protein farnesylation, is dispensable for thymocyte egress but contributes to peripheral T cell homeostasis. Collectively, our studies establish context-dependent effects of protein prenylation and unique roles of geranylgeranylation in thymic egress and highlight that the interplay between cellular metabolism and posttranslational modification underlies immune homeostasis.
Topics: Alkyl and Aryl Transferases; Animals; Cell Movement; Cells, Cultured; Farnesyltranstransferase; Homeostasis; Lymphopenia; Lysophospholipids; Mevalonic Acid; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Prenylation; Signal Transduction; Sphingosine; T-Lymphocytes; Thymocytes; Thymus Gland; cdc42 GTP-Binding Protein; p21-Activated Kinases
PubMed: 31722972
DOI: 10.1084/jem.20190969 -
Phytochemistry Jun 2021Ten undescribed anthranoids, including three anthraquinone acetals as racemic mixtures, (±)-kenganthranol G-I, and seven prenylated anthranols, (±)-kenganthranol J-M...
Ten undescribed anthranoids, including three anthraquinone acetals as racemic mixtures, (±)-kenganthranol G-I, and seven prenylated anthranols, (±)-kenganthranol J-M and harunganol G-I, together with thirteen known compounds, were isolated from the stem bark of Harungana madagascariensis. The structures of (±)-kenganthranol G and (±)-kenganthranol J were confirmed by X-ray crystallography. (±)-Kenganthranol G was separated into (+)-kenganthranol G and (-)-kenganthranol G by chiral HPLC and their absolute configurations were established by electronic circular dichroism. (±)-Kenganthranol L displayed α-glucosidase inhibitory activity with an IC of 4.4 μM.
Topics: Anthraquinones; Clusiaceae; Molecular Structure
PubMed: 33711738
DOI: 10.1016/j.phytochem.2021.112711 -
Natural Product Research Jul 2021Two new lanostane-type triterpenoids characterized with farnesyl hydroquinone moieties, ganocalidoins A () and B (), were isolated from the fruiting body of , together...
Two new lanostane-type triterpenoids characterized with farnesyl hydroquinone moieties, ganocalidoins A () and B (), were isolated from the fruiting body of , together with two known tripterpenes (-). The structures of compounds and were determined by extensive spectroscopic data including HRESIMS, 1D and 2D NMR. Ganocalidoins A and B showed anti-oxidant capacity with IC values of 38.7 ± 2.8 and 34.2 ± 1.8 μM, respectively. The compounds did not show tyrosinase inhibition activity.
Topics: Carbon-13 Magnetic Resonance Spectroscopy; Ganoderma; Hydroquinones; Prenylation; Proton Magnetic Resonance Spectroscopy; Triterpenes
PubMed: 31542946
DOI: 10.1080/14786419.2019.1667346 -
Frontiers in Chemistry 2022Clusiaceae plants contain a wide range of biologically active metabolites that have gotten a lot of interest in recent decades. The chemical compositions of these plants... (Review)
Review
Clusiaceae plants contain a wide range of biologically active metabolites that have gotten a lot of interest in recent decades. The chemical compositions of these plants have been demonstrated to have positive effects on a variety of ailments. The species has been studied for over 70 years, and many bioactive compounds with antioxidant, anti-proliferative, and anti-inflammatory properties have been identified, including xanthones, polycyclic polyprenylated acylphloroglucinols (PPAPs), benzophenones, and biphenyls. Prenylated side chains have been discovered in many of these bioactive substances. To date, there have been numerous studies on PPAPs and xanthones, while no comprehensive review article on biphenyls from Clusiaceae has been published. The unique chemical architectures and growing biological importance of biphenyl compounds have triggered a flurry of research and interest in their isolation, biological evaluation, and mechanistic studies. In particular, the FDA-approved drugs such as sonidegib, tazemetostat, daclatasvir, sacubitril and trifarotene are closely related to their biphenyl-containing moiety. In this review, we summarize the progress and development in the chemistry and biological activity of biphenyls in Clusiaceae, providing an in-depth discussion of their structural diversity and medicinal potential. We also present a preliminary discussion of the biological effects with or without prenyl groups on the biphenyls.
PubMed: 36531325
DOI: 10.3389/fchem.2022.987009 -
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 -
Journal of Cardiovascular Pharmacology Feb 2021Isoprenylation is an important post-transcriptional modification of small GTPases required for their activation and function. Isoprenoids, including farnesyl... (Review)
Review
Isoprenylation is an important post-transcriptional modification of small GTPases required for their activation and function. Isoprenoids, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate, are indispensable for isoprenylation by serving as donors of a prenyl moiety to small G proteins. In the human body, isoprenoids are mainly generated by the mevalonate pathway (also known as the cholesterol-synthesis pathway). The hydroxymethylglutaryl coenzyme A reductase catalyzes the first rate-limiting steps of the mevalonate pathway, and its inhibitor (statins) are widely used as lipid-lowering agents. In addition, the FPP synthase is also of critical importance for the regulation of the isoprenoids production, for which the inhibitor is mainly used in the treatment of osteoporosis. Synthetic FPP can be further used to generate geranylgeranyl pyrophosphate and cholesterol. Recent studies suggest a role for isoprenoids in the genesis and development of cardiovascular disorders, such as pathological cardiac hypertrophy, fibrosis, endothelial dysfunction, and fibrotic responses of smooth-muscle cells. Furthermore, statins and FPP synthase inhibitors have also been applied for the management of heart failure and other cardiovascular diseases rather than their clinical use for hyperlipidemia or bone diseases. In this review, we focus on the function of several critical enzymes, including hydroxymethylglutaryl coenzyme A reductase, FPP synthase, farnesyltransferase, and geranylgeranyltransferase in the mevalonate pathway which are involved in regulating the generation of isoprenoids and isoprenylation of small GTPases, and their pathophysiological role in the cardiovascular system. Moreover, we summarize recent research into applications of statins and the FPP synthase inhibitors to treat cardiovascular diseases, rather than for their traditional indications respectively.
Topics: Cardiovascular System; Cholesterol; Farnesyltranstransferase; Geranyltranstransferase; Humans; Hydroxymethylglutaryl CoA Reductases; Mevalonic Acid; Monomeric GTP-Binding Proteins; Polyisoprenyl Phosphates; Protein Prenylation; Sesquiterpenes
PubMed: 33538531
DOI: 10.1097/FJC.0000000000000952 -
Plants (Basel, Switzerland) Jun 2021Phytocannabinoids are a structurally diverse class of bioactive naturally occurring compounds found in angiosperms, fungi, and liverworts and produced in several plant... (Review)
Review
Phytocannabinoids are a structurally diverse class of bioactive naturally occurring compounds found in angiosperms, fungi, and liverworts and produced in several plant organs such as the flower and glandular trichrome of , the scales in , and oil bodies of liverworts such as species; they show a diverse role in humans and plants. Moreover, phytocannabinoids are prenylated polyketides, i.e., terpenophenolics, which are derived from isoprenoid and fatty acid precursors. Additionally, targeted productions of active phytocannabinoids have beneficial properties via the genes involved and their expression in a heterologous host. Bioactive compounds show a remarkable non-hallucinogenic biological property that is determined by the variable nature of the side chain and prenyl group defined by the enzymes involved in their biosynthesis. Phytocannabinoids possess therapeutic, antibacterial, and antimicrobial properties; thus, they are used in treating several human diseases. This review gives the latest knowledge on their role in the amelioration of abiotic (heat, cold, and radiation) stress in plants. It also aims to provide synthetic and biotechnological approaches based on combinatorial biochemical and protein engineering to synthesize phytocannabinoids with enhanced properties.
PubMed: 34203173
DOI: 10.3390/plants10071307 -
The Journal of Biological Chemistry Apr 2020Protein prenylation is an essential posttranslational modification and includes protein farnesylation and geranylgeranylation using farnesyl diphosphate or... (Review)
Review
Protein prenylation is an essential posttranslational modification and includes protein farnesylation and geranylgeranylation using farnesyl diphosphate or geranylgeranyl diphosphate as substrates, respectively. Geranylgeranyl diphosphate synthase is a branch point enzyme in the mevalonate pathway that affects the ratio of farnesyl diphosphate to geranylgeranyl diphosphate. Abnormal geranylgeranyl diphosphate synthase expression and activity can therefore disrupt the balance of farnesylation and geranylgeranylation and alter the ratio between farnesylated and geranylgeranylated proteins. This change is associated with the progression of nonalcoholic fatty liver disease (NAFLD), a condition characterized by hepatic fat overload. Of note, differential accumulation of farnesylated and geranylgeranylated proteins has been associated with differential stages of NAFLD and NAFLD-associated liver fibrosis. In this review, we summarize key aspects of protein prenylation as well as advances that have uncovered the regulation of associated metabolic patterns and signaling pathways, such as Ras GTPase signaling, involved in NAFLD progression. Additionally, we discuss unique opportunities for targeting prenylation in NAFLD/hepatocellular carcinoma with agents such as statins and bisphosphonates to improve clinical outcomes.
Topics: Animals; Disease Progression; Farnesyltranstransferase; Humans; Non-alcoholic Fatty Liver Disease; Polyisoprenyl Phosphates; Protein Prenylation; Protein Processing, Post-Translational
PubMed: 32139507
DOI: 10.1074/jbc.REV119.008897 -
ACS Applied Bio Materials May 2022Despite broad interest in understanding the biological implications of protein farnesylation in regulating different facets of cell biology, the use of this... (Review)
Review
Despite broad interest in understanding the biological implications of protein farnesylation in regulating different facets of cell biology, the use of this post-translational modification to develop protein-based materials and therapies remains underexplored. The progress has been slow due to the lack of accessible methodologies to generate farnesylated proteins with broad physicochemical diversities rapidly. This limitation, in turn, has hindered the empirical elucidation of farnesylated proteins' sequence-structure-function rules. To address this gap, we genetically engineered prokaryotes to develop operationally simple, high-yield biosynthetic routes to produce farnesylated proteins and revealed determinants of their emergent material properties (nano-aggregation and phase-behavior) using scattering, calorimetry, and microscopy. These outcomes foster the development of farnesylated proteins as recombinant therapeutics or biomaterials with molecularly programmable assembly.
Topics: Biocompatible Materials; Genetic Engineering; Protein Prenylation; Proteins; Temperature
PubMed: 35044146
DOI: 10.1021/acsabm.1c01162 -
The Journal of Pathology Mar 2022Investigations of major mevalonate pathway enzymes have demonstrated the importance of local isoprenoid synthesis in cardiac homeostasis. Farnesyl diphosphate synthase...
Investigations of major mevalonate pathway enzymes have demonstrated the importance of local isoprenoid synthesis in cardiac homeostasis. Farnesyl diphosphate synthase (FPPS) synthesizes isoprenoid precursors needed for cholesterol biosynthesis and protein prenylation. Wang, Zhang, Chen et al, in a recently published article in The Journal of Pathology, elegantly elucidated the pathological outcomes of FPPS deficiency in cardiomyocytes, which paradoxically resulted in increased prenylation of the small GTPases Ras and Rheb. Cardiomyocyte FPPS depletion caused severe dilated cardiomyopathy that was associated with enhanced GTP-loading and abundance of Ras and Rheb in lipidated protein-enriched cardiac fractions and robust activation of downstream hypertrophic ERK1/2 and mTOR signaling pathways. Cardiomyopathy and activation of ERK1/2 and mTOR caused by loss of FPPS were ameliorated by inhibition of farnesyltransferase, suggesting that impairment of FPPS activity results in promiscuous activation of Ras and Rheb through non-canonical actions of farnesyltransferase. Here, we discuss the findings and adaptive signaling mechanisms in response to disruption of local cardiomyocyte mevalonate pathway activity, highlighting how alteration in a key branch point in the mevalonate pathway affects cardiac biology and function and perturbs protein prenylation, which might unveil novel strategies and intricacies of targeting the mevalonate pathway to treat cardiovascular diseases. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Topics: Heart Failure; Humans; Mevalonic Acid; Monomeric GTP-Binding Proteins; Myocytes, Cardiac; Prenylation; Protein Prenylation
PubMed: 34783037
DOI: 10.1002/path.5837