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Transplant Immunology Dec 2021MicroRNA-155(miR-155) and protein prenylation have been reported to participate in acute graft-versus-host disease (aGVHD) through modulating T lymphocyte...
Inhibition of the miR-155 and protein prenylation feedback loop alleviated acute graft-versus-host disease through regulating the balance between T helper 17 and Treg cells.
MicroRNA-155(miR-155) and protein prenylation have been reported to participate in acute graft-versus-host disease (aGVHD) through modulating T lymphocyte differentiation, however the mechanism remains elusive. In this study, we found that the expression of miR-155 and protein prenyltransferases in peripheral blood T lymphocytes of aGVHD mice was significantly increased. Suppression of miR-155 by antagomir-155 could remarkably reduce prenyltransferases mRNA and protein expression in T lymphocytes of aGVHD mice. Conversely, prenyltransferase inhibitors significantly reduced the level of miR-155. Inhibition of this feedback loop of miR-155 and protein prenylation in aGVHD mice led to improved survival and lower aGVHD histopathology scores and significantly induced T cell deficient differentiation towards T helper 17 (Th17) cells and titled differentiation towards CD4CD25 regulatory T (Treg) cells. Furthermore, the immunoregulatory effects and protection from aGVHD of prenyltransferase inhibitors could be reversed by the addition of miR-155. The dual treatment of prenylation inhibitors and antagomir-155 showed synergistic effects on T polarization and protection from aGVHD. Consistent with the in vivo changes, inhibition of this feedback loop of miR-155 and protein prenylation affected Th17 and Treg cell polarization in vitro. Our data suggest that miR-155 and protein prenylation may constitute a feedback loop that amplifies immune and inflammatory responses in subjects with aGVHD, and they may serve as potential targets for aGVHD prophylaxis and treatment.
Topics: Acute Disease; Animals; Feedback; Graft vs Host Disease; Mice; Mice, Inbred C57BL; MicroRNAs; Protein Prenylation; T-Lymphocytes, Regulatory
PubMed: 34487810
DOI: 10.1016/j.trim.2021.101461 -
The Journal of Organic Chemistry Sep 2022Nocardioazines A and B are prenylated, bioactive pyrroloindoline natural products, isolated from , with a desymmetrized -d-Trp-d-Trp DKP core. Based on our deeper...
Nocardioazines A and B are prenylated, bioactive pyrroloindoline natural products, isolated from , with a desymmetrized -d-Trp-d-Trp DKP core. Based on our deeper biosynthetic understanding, a biomimetic total synthesis of (+)-nocardioazine B is accomplished in merely seven steps and 23.2% overall yield. This pathway accesses regio- and stereoselectively C3-isoprenylated analogs of (+)-nocardioazine B, using the same number of steps and in similar efficiency. The successful strategy mandated that the biomimetic C3-prenylation step be executed early. The use of an unprotected carboxylic acid of Trp led to high diastereoselectivity toward formation of key intermediates -, -, and - (>19:1). Evidence shows that 1-methylation causes the prenylation reaction to bifurcate away to result in a C2-normal-prenylated isomer. Nocardioazine A, possessing an isoprenoidal-epoxide bridge, inhibits P-glycoprotein (P-gp)-mediated membrane efflux, in multidrug-resistant mammalian colon cancer cells. As several P-gp inhibitors have failed due to their toxicity effects, endogenous amino-acid-derived noncytotoxic inhibitors (from the nocardioazine core) are worthy leads toward a rejuvenated strategy against resistant carcinomas. This total synthesis provides direct access to Trp-derived isoprenylated DKP natural products and their derivatives.
Topics: Biological Products; Biomimetics; Diketopiperazines; Prenylation
PubMed: 35960860
DOI: 10.1021/acs.joc.2c01120 -
Accounts of Chemical Research Jul 2017Ribosomally synthesized and Post-translationally modified Peptides (RiPPs) take advantage of the ribosomal translation machinery to generate linear peptides that are...
Ribosomally synthesized and Post-translationally modified Peptides (RiPPs) take advantage of the ribosomal translation machinery to generate linear peptides that are subsequently modified with heterocycles and/or macrocycles to impose three-dimensional structure and thwart degradation by proteases. Although RiPP precursors are limited to proteinogenic amino acids, post-translational modifications (PTMs) can alter the structure of individual amino acids and thereby improve the stability and biological activity of the molecule. These "tailoring modifications" often occur on amino acid side chains-for example, hydroxylation, methylation, halogenation, prenylation, and acylation-but can also take place within the backbone, as in epimerization, or can result in capping of the N- or C-terminus. At one extreme, these modifications can be essential to the activity of the RiPP, either as a compulsory step in reaching the final molecule or by imparting chemical functionality required for biological activity. At the other extreme, tailoring PTMs may have little effect on the activity in an in vitro setting-possibly because of test conditions that do not match the biological context in which the PTMs evolved. Establishing the molecular basis for the function of tailoring PTMs often requires a three-dimensional structure of the RiPP bound to its biological target. These structures have revealed roles for tailoring PTMs that include providing additional hydrogen bonds to targets, rigidifying the RiPP structure to reduce the entropic cost of binding, or altering the secondary structure of the peptide backbone. Bacterial RiPPs are particularly suited to structural characterization, as they are relatively easy to isolate from laboratory cultures or to produce in a heterologous host. The identification of new tailoring PTMs within bacteria is also facilitated by clustering of the genes encoding tailoring enzymes with those of the RiPP precursor and primary modification enzymes. In this Account, we describe the effects of tailoring PTMs on RiPP structure, their interactions with biological targets, and their influence on RiPP stability, with a focus on bacterial RiPP classes. We also discuss the enzymes that generate tailoring PTMs and highlight examples of and prospects for engineering of RiPPs.
Topics: Acylation; Biological Products; Halogens; Hydroxylation; Methylation; Peptides; Prenylation; Protein Conformation; Protein Stability; Ribosomes
PubMed: 28682627
DOI: 10.1021/acs.accounts.7b00175 -
Characteristic metabolites of Hypericum plants: their chemical structures and biological activities.Journal of Natural Medicines Jun 2021Plants belonging to the genus Hypericum (Hypericaceae) are recognized as an abundant source of natural products with interesting chemical structures and intriguing... (Review)
Review
Plants belonging to the genus Hypericum (Hypericaceae) are recognized as an abundant source of natural products with interesting chemical structures and intriguing biological activities. In the course of our continuing study on constituents of Hypericum plants, aiming at searching natural product-based lead compounds for therapeutic agents, we have isolated more than 100 new characteristic metabolites classified as prenylated acylphloroglucinols, meroterpenes, ketides, dibenzo-1,4-dioxane derivatives, and xanthones including prenylated xanthones, phenylxanthones, and xanthonolignoids from 11 Hypericum plants and one Triadenum plant collected in Japan, China, and Uzbekistan or cultivated in Japan. This review summarizes their chemical structures and biological activities.
Topics: Biological Products; China; Hypericum; Japan; Molecular Structure; Phytochemicals; Prenylation; Uzbekistan
PubMed: 33555487
DOI: 10.1007/s11418-021-01489-y -
Organic & Biomolecular Chemistry Jan 2023Prenol and isoprenoids are common structural motifs in biological systems and possess diverse applications. An unprecedented direct catalytic prenylation of ketones...
Prenol and isoprenoids are common structural motifs in biological systems and possess diverse applications. An unprecedented direct catalytic prenylation of ketones using prenol is attained. This C-C bond formation reaction requires only a ruthenium pincer catalyst and a base, and HO is the only byproduct.
Topics: Ruthenium; Ketones; Hemiterpenes; Prenylation; Catalysis
PubMed: 36374234
DOI: 10.1039/d2ob01882a -
Current Cancer Drug Targets 2016The process of protein prenylation involves the covalent linkage of either farnesyl (15-carbon) or geranylgeranyl (20-carbon) isoprenoid lipds to conserved cysteine... (Review)
Review
The process of protein prenylation involves the covalent linkage of either farnesyl (15-carbon) or geranylgeranyl (20-carbon) isoprenoid lipds to conserved cysteine residues in the carboxyl-terminus of proteins. Protein geranylgeranyltransferase I (GGTase-I) is the enzyme that catalyzes the addition of the geranylgeranyl moiety from geranylgeranyl pyrophosphate to the target protein, which contains a Cterminal consensus sequence termed a CaaX motif. Geranylgeranylation is important to the function of a number of proteins, including the majority of Rho GTPases, G protein gamma subunits, and several other regulatory proteins. Studies over the past two decades have revealed that many of these proteins contribute to tumor development and metastasis. Blocking Rho GTPase activity through inhibition of GGTase-I in particular has been advanced as a potential strategy for disease therapy. This review will provide an overview of the CaaX prenyltransferases, the rationale for targeting GGTase-I in cancer in particular, and the current status of GGTase-I inhibitor (GGTI) development.
Topics: Alkyl and Aryl Transferases; Animals; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Neoplasms; Protein Prenylation
PubMed: 26648485
DOI: 10.2174/1568009616666151203224603 -
Applied Microbiology and Biotechnology Sep 2015Prenylated compounds are ubiquitously found in nature and demonstrate interesting biological and pharmacological activities. Prenyltransferases catalyze the attachment... (Review)
Review
Prenylated compounds are ubiquitously found in nature and demonstrate interesting biological and pharmacological activities. Prenyltransferases catalyze the attachment of prenyl moieties from different prenyl donors to various acceptors and contribute significantly to the structural and biological diversity of natural products. In the last decade, significant progress has been achieved for the prenyltransferases of the dimethylallyltryptophan synthase (DMATS) superfamily. More than 40 members of these soluble enzymes are identified in microorganisms and characterized biochemically. These enzymes were also successfully used for production of a large number of prenylated derivatives. N1-, C4-, C5-, C6-, and C7-prenylated tryptophan and N1-, C2-, C3-, C4-, and C7-prenylated tryptophan-containing peptides were obtained by using DMATS enzymes as biocatalysts. Tyrosine and xanthone prenyltransferases were used for production of prenylated derivatives of their analogs. More interestingly, the members of the DMATS superfamily demonstrated intriguing substrate and catalytic promiscuity and also used structurally quite different compounds as prenyl acceptors. Prenylated hydroxynaphthalenes, flavonoids, indolocarbazoles, and acylphloroglucinols, which are typical bacterial or plant metabolites, were produced by using several fungal DMATS enzymes. Furthermore, the potential usage of these enzymes was further expanded by using natural or unnatural DMAPP analogs as well as by coexpression with other genes like NRPS and by development of whole cell biocatalyst.
Topics: Biotechnology; Dimethylallyltranstransferase; Prenylation; Proteins; Tryptophan; Xanthones
PubMed: 26227408
DOI: 10.1007/s00253-015-6813-9 -
Pharmaceutical Patent Analyst Jan 2021There is expanding proof that specific natural compounds found in plants have additional conventional medicinal properties. One such compound is xanthohumol (XN), which... (Review)
Review
There is expanding proof that specific natural compounds found in plants have additional conventional medicinal properties. One such compound is xanthohumol (XN), which is being explored as an antimicrobial, anticarcinogenic, antidiabetic and anti-inflammatory agent - aside from its utilization in dealing with conditions like autism, bone and skin improvement and microbial infections, lipid-related illnesses, and so on. XN is reported to suppress the uncontrolled production of inflammatory mediators responsible for diseases including cardiovascular disease, neurodegeneration and tumors. Further, it is accounted to limit adipogenesis and control obesity by focusing on principal adipocyte marker proteins. It is most generally utilized in the brewing industry as an additive and flavoring agent to add bitterness and aroma to beer. Present investigation sum up the patents filed in most recent 2 years on development of different pharmaceutical mixes and strategies dependent on various therapeutic potentials of XN.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Products; Bone Diseases; Chalcones; Flavonoids; Humans; Humulus; Hypoglycemic Agents; Prenylation; Propiophenones
PubMed: 33445965
DOI: 10.4155/ppa-2020-0026 -
Journal of Molecular Biology Jan 2021Prenylation is a process widely prevalent in primary and secondary metabolism, contributing to functionality and chemical diversity in natural systems. Due to their high...
Prenylation is a process widely prevalent in primary and secondary metabolism, contributing to functionality and chemical diversity in natural systems. Due to their high regio- and chemoselectivities, prenyltransferases are also valuable tools for creation of new compounds by chemoenzymatic synthesis and synthetic biology. Over the last ten years, biochemical and structural investigations shed light on the mechanism and key residues that control the catalytic process, but to date crucial information on how certain prenyltransferases control regioselectivity and chemoselectivity is still lacking. Here, we advance a general understanding of the enzyme family by contributing the first structure of a tryptophan C5-prenyltransferase 5-DMATS. Additinally, the structure of a bacterial tryptophan C6-prenyltransferase 6-DMATS was solved. Analysis and comparison of both substrate-bound complexes led to the identification of key residues for catalysis. Next, site-directed mutagenesis was successfully implemented to not only modify the prenyl donor specificity but also to redirect the prenylation, thereby switching the regioselectivity of 6-DMATS to that of 5-DMATS. The general strategy of structure-guided protein engineering should be applicable to other related prenyltransferases, thus enabling the production of novel prenylated compounds.
Topics: Binding Sites; Catalysis; Dimethylallyltranstransferase; Hydrogen Bonding; Ligands; Models, Molecular; Molecular Conformation; Molecular Structure; Mutation; Prenylation; Protein Binding; Protein Engineering; Recombinant Proteins; Substrate Specificity; Tryptophan
PubMed: 33249189
DOI: 10.1016/j.jmb.2020.11.025 -
Fitoterapia Jun 2018A phytochemical investigation of the aerial parts of Hypericum annulatum Moris led to the isolation of five new prenylated acylphloroglucinol derivatives hyperannulatins...
A phytochemical investigation of the aerial parts of Hypericum annulatum Moris led to the isolation of five new prenylated acylphloroglucinol derivatives hyperannulatins A-E (1-3, 5 and 7) in addition to the known hypercalyxone A (4) and 3-geranyl-1-(2'-methylpropanoyl)phloroglucinol (6). The structures were determined by 1D and 2D NMR and MS spectroscopic techniques. Compounds 1 and 2 have in their structure evgenyl group, a rare hydrocarbon side chain. The cytotoxicity of isolated compounds was established on a panel of tumor cell lines (HL-60, HL-60/DOX, MDA-MB, SKW-3 and K-562) and was determined using MTT based assays. The compounds 1 and 2 showed to be the most potent cytotoxic agents, whose IC values against the chemosensitive cell lines ranged 3.42-5.87 μM and 1.48-8.21 μM, respectively. Noteworthy, albeit all tested compounds were less potent than podophyllotoxin their IC values were comparable to that of the other reference drug etoposide. In some of the cell lines compounds 1 and 2 even outclassed the cytotoxicity of etoposide.
Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Humans; Hypericum; Molecular Structure; Phloroglucinol; Prenylation
PubMed: 29627475
DOI: 10.1016/j.fitote.2018.03.011