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The Journal of Antimicrobial... Dec 2003Prenylation is a site-specific lipid modification of proteins. Although first described for a variety of cellular proteins, it has become apparent that viruses can also... (Review)
Review
Prenylation is a site-specific lipid modification of proteins. Although first described for a variety of cellular proteins, it has become apparent that viruses can also make use of this post-translational modification provided by their host cells. Depriving a virus access to prenylation can have dramatic effects on the targeted virus's life cycle. Selective pharmacological inhibitors of prenylating enzymes have been developed and shown to have potent antiviral effects in both in vitro and in vivo systems. Because prenylation inhibitors target a host cell function, are available in oral form and are surprisingly well tolerated in human trials, these compounds represent an attractive new class of antiviral agents with potential for broad-spectrum activity. After a brief outline of host cell prenylation pathways, we review below the development of prenylation inhibition as an antiviral strategy applied to a prototype target, hepatitis delta virus (HDV), and discuss the potential application of prenylation inhibitors to a broad range of other viruses.
Topics: Antiviral Agents; Hepatitis Delta Virus; Humans; Protein Prenylation; Virus Assembly
PubMed: 14613953
DOI: 10.1093/jac/dkg490 -
Phytochemistry 2009Prenylation plays a major role in the diversification of aromatic natural products, such as phenylpropanoids, flavonoids, and coumarins. This biosynthetic reaction... (Review)
Review
Prenylation plays a major role in the diversification of aromatic natural products, such as phenylpropanoids, flavonoids, and coumarins. This biosynthetic reaction represents the crucial coupling process of the shikimate or polyketide pathway providing an aromatic moiety and the isoprenoid pathway derived from the mevalonate or methyl erythritol phosphate (MEP) pathway, which provides the prenyl (isoprenoid) chain. In particular, prenylation contributes strongly to the diversification of flavonoids, due to differences in the prenylation position on the aromatic rings, various lengths of prenyl chain, and further modifications of the prenyl moiety, e.g., cyclization and hydroxylation, resulting in the occurrence of ca. 1000 prenylated flavonoids in plants. Many prenylated flavonoids have been identified as active components in medicinal plants with biological activities, such as anti-cancer, anti-androgen, anti-leishmania, and anti-nitric oxide production. Due to their beneficial effects on human health, prenylated flavonoids are of particular interest as lead compounds for producing drugs and functional foods. However, the gene coding for prenyltransferases that catalyze the key step of flavonoid prenylation have remained unidentified for more than three decades, because of the membrane-bound nature of these enzymes. Recently, we have succeeded in identifying the first prenyltransferase gene SfN8DT-1 from Sophora flavescens, which is responsible for the prenylation of the flavonoid naringenin at the 8-position, and is specific for flavanones and dimethylallyl diphosphate (DMAPP) as substrates. Phylogenetic analysis showed that SfN8DT-1 has the same evolutionary origin as prenyltransferases for vitamin E and plastoquinone. A prenyltransferase GmG4DT from soybean, which is involved in the formation of glyceollin, was also identified recently. This enzyme was specific for pterocarpan as its aromatic substrate, and (-)-glycinol was the native substrate yielding the direct precursor of glyceollin I. These enzymes are localized to plastids and the prenyl chain is derived from the MEP pathway. Further relevant genes involved in the prenylation of other types of polyphenol are expected to be cloned by utilizing the sequence information provided by the above studies.
Topics: Biological Products; Dimethylallyltranstransferase; Molecular Structure; Plants; Prenylation
PubMed: 19819506
DOI: 10.1016/j.phytochem.2009.08.023 -
Critical Reviews in Biochemistry and... Jun 2018The mevalonate-isoprenoid-cholesterol biosynthesis pathway plays a key role in human health and disease. The importance of this pathway is underscored by the discovery... (Review)
Review
The mevalonate-isoprenoid-cholesterol biosynthesis pathway plays a key role in human health and disease. The importance of this pathway is underscored by the discovery that two major isoprenoids, farnesyl and geranylgeranyl pyrophosphate, are required to modify an array of proteins through a process known as protein prenylation, catalyzed by prenyltransferases. The lipophilic prenyl group facilitates the anchoring of proteins in cell membranes, mediating protein-protein interactions and signal transduction. Numerous essential intracellular proteins undergo prenylation, including most members of the small GTPase superfamily as well as heterotrimeric G proteins and nuclear lamins, and are involved in regulating a plethora of cellular processes and functions. Dysregulation of isoprenoids and protein prenylation is implicated in various disorders, including cardiovascular and cerebrovascular diseases, cancers, bone diseases, infectious diseases, progeria, and neurodegenerative diseases including Alzheimer's disease (AD). Therefore, isoprenoids and/or prenyltransferases have emerged as attractive targets for developing therapeutic agents. Here, we provide a general overview of isoprenoid synthesis, the process of protein prenylation and the complexity of prenylated proteins, and pharmacological agents that regulate isoprenoids and protein prenylation. Recent findings that connect isoprenoids/protein prenylation with AD are summarized and potential applications of new prenylomic technologies for uncovering the role of prenylated proteins in the pathogenesis of AD are discussed.
Topics: Alzheimer Disease; Animals; Dimethylallyltranstransferase; Heterotrimeric GTP-Binding Proteins; Humans; Protein Prenylation; Terpenes
PubMed: 29718780
DOI: 10.1080/10409238.2018.1458070 -
Annual Review of Biochemistry 1996Prenylation is a class of lipid modification involving covalent addition of either farnesyl (15-carbon) or geranylgeranyl (20-carbon) isoprenoids to conserved cysteine... (Review)
Review
Prenylation is a class of lipid modification involving covalent addition of either farnesyl (15-carbon) or geranylgeranyl (20-carbon) isoprenoids to conserved cysteine residues at or near the C-terminus of proteins. Known prenylated proteins include fungal mating factors, nuclear lamins, Ras and Ras-related GTP-binding proteins (G proteins), the subunits of trimeric G proteins, protein kinases, and at least one viral protein. Prenylation promotes membrane interactions of most of these proteins, which is not surprising given the hydrophobicity of the lipids involved. In addition, however, prenylation appears to play a major role in several protein-protein interactions involving these species. The emphasis in this review is on the enzymology of prenyl protein processing and the functional significance of prenylation in cellular events. Several other recent reviews provide more detailed coverage of aspects of prenylation that receive limited attention here owing to length restrictions (1-4).
Topics: GTP-Binding Proteins; Protein Prenylation
PubMed: 8811180
DOI: 10.1146/annurev.bi.65.070196.001325 -
Biochemical and Biophysical Research... Dec 2011Post translational modifications are required for proteins to be fully functional. The three step process, prenylation, leads to farnesylation or geranylgeranylation,... (Review)
Review
Post translational modifications are required for proteins to be fully functional. The three step process, prenylation, leads to farnesylation or geranylgeranylation, which increase the hydrophobicity of the prenylated protein for efficient anchoring into plasma membranes and/or organellar membranes. Prenylated proteins function in a number of signaling and regulatory pathways that are responsible for basic cell operations. Well characterized prenylated proteins include Ras, Rac and Rho. Recently, pathogenic prokaryotic proteins, such as SifA and AnkB, have been shown to be prenylated by eukaryotic host cell machinery, but their functions remain elusive. The identification of other bacterial proteins undergoing this type of host-directed post-translational modification shows promise in elucidating host-pathogen interactions to develop new therapeutics. This review incorporates new advances in the study of protein prenylation into a broader aspect of biology with a focus on host-pathogen interaction.
Topics: Amino Acid Sequence; Ankyrins; Bacteria; Bacterial Proteins; Glycoproteins; Host-Pathogen Interactions; Humans; Molecular Sequence Data; Periplasmic Proteins; Protein Prenylation
PubMed: 22079293
DOI: 10.1016/j.bbrc.2011.10.142 -
Science China. Life Sciences Apr 2015The protein prenylation is one of the essential post-translational protein modifications, which extensively exists in the eukaryocyte. It includes protein farnesylation... (Review)
Review
The protein prenylation is one of the essential post-translational protein modifications, which extensively exists in the eukaryocyte. It includes protein farnesylation and geranylgeranylation, using farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP) as the substrate, respectively. The prenylation occurs by covalent addition of these two types of isoprenoids to cysteine residues at or near the carboxyl terminus of the proteins that possess CaaX motif, such as Ras small GTPase family. The attachment of hydrophobic prenyl groups can anchor the proteins to intracellular membranes and trigger downstream cell signaling pathway. Geranylgeranyl biphosphate synthase (GGPPS) catalyzes the synthesis of 20-carbon GGPP from 15-carbon FPP. The abnormal expression of this enzyme will affect the relative content of FPP and GGPP, and thus disrupts the balance between protein farnesylation and geranylgeranylation, which participates into various aspects of cellular physiology and pathology. In this paper, we mainly review the property of this important protein post-translational modification and research progress in its regulation of cigarette smoke induced pulmonary disease, adipocyte insulin sensitivity, the inflammation response of Sertoli cells, the hepatic lipogenesis and the cardiac hypertrophy.
Topics: Cardiomegaly; Diterpenes; Humans; Protein Prenylation
PubMed: 25862656
DOI: 10.1007/s11427-015-4836-1 -
Journal of Lipid Research Dec 1992
Review
Topics: Amino Acid Sequence; Animals; Binding Sites; Dimethylallyltranstransferase; Humans; Protein Prenylation; Proteins
PubMed: 1479283
DOI: No ID Found -
Archives of Biochemistry and Biophysics Oct 2014Prenylflavonoids are distributed widely in the plant kingdom and have attracted appreciable attention because of their potential benefits for human health. Prenylation... (Review)
Review
Prenylflavonoids are distributed widely in the plant kingdom and have attracted appreciable attention because of their potential benefits for human health. Prenylation may be a promising tool for applying the biological functions of flavonoids to clinical uses. The bioavailability and bioaccumulation of prenylflavonoids have not been clarified, but extensive studies have been accomplished on their biological functions. This review provides current knowledge on the bioavailability of prenylflavonoids, including their absorption and metabolism in the intestine, as well as their bioaccumulation in specific tissues. Despite higher uptake into epithelial cells of the digestive tract, the bioavailability of single-dose prenylflavonoids seems to be lower than that of the parent flavonoids. Efflux from epithelial cells to the blood circulation is likely to be restricted by prenyl groups, resulting in insufficient increase in the plasma concentration. Rodent studies have revealed that prenylation enhances accumulation of naringenin in muscle tissue after long-term feeding; and that prenylation accelerates accumulation of quercetin in liver tissue. Efflux from hepatocytes to blood and enterohepatic circulations may be restricted by prenyl groups, thereby promoting slow excretion of prenylflavonoids from the blood circulation and efficient uptake to tissues. The hepatotoxicity and other deleterious effects, taken together with beneficial effects, should be considered because unexpectedly high accumulation may occur in some tissues after long-term supplementation.
Topics: Animals; Biological Availability; Diet; Flavonoids; Humans; Intestinal Mucosa; Intestines; Microbiota; Prenylation
PubMed: 24736381
DOI: 10.1016/j.abb.2014.04.002 -
Chembiochem : a European Journal of... Sep 2022Regioselective carbon-carbon bond formation belongs to the challenging tasks in organic synthesis. In this context, C-C bond formation catalyzed by...
Regioselective carbon-carbon bond formation belongs to the challenging tasks in organic synthesis. In this context, C-C bond formation catalyzed by 4-dimethylallyltryptophan synthases (4-DMATSs) represents a possible tool to regioselectively synthesize C4-prenylated indole derivatives without site-specific preactivation and circumventing the need of protection groups as used in chemical synthetic approaches. In this study, a toolbox of 4-DMATSs to produce a set of 4-dimethylallyl tryptophan and indole derivatives was identified. Using three wild-type enzymes as well as variants, various C5-substituted tryptophan derivatives as well as N-methyl tryptophan were successfully prenylated with conversions up to 90 %. Even truncated tryptophan derivatives like tryptamine and 3-indole propanoic acid were regioselectively prenylated in position C4. The acceptance of C5-substituted tryptophan derivatives was improved up to 5-fold by generating variants (e. g. T108S). The feasibility of semi-preparative prenylation of selected tryptophan derivatives was successfully demonstrated on 100 mg scale at 15 mM substrate concentration, allowing to reduce the previously published multistep chemical synthetic sequence to just a single step.
Topics: Biocatalysis; Carbon; Dimethylallyltranstransferase; Indoles; Prenylation; Substrate Specificity; Tryptophan
PubMed: 35770709
DOI: 10.1002/cbic.202200311 -
Nature Methods Jun 2019
Topics: Protein Prenylation
PubMed: 31147650
DOI: 10.1038/s41592-019-0446-3