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Critical Reviews in Food Science and... 2023Prenylated stilbenoids are a unique class of natural phenolic compounds consisting of C6-C2-C6 skeleton with prenyl substitution. They are potential nutraceuticals and... (Review)
Review
Prenylated stilbenoids are a unique class of natural phenolic compounds consisting of C6-C2-C6 skeleton with prenyl substitution. They are potential nutraceuticals and dietary supplements presented in some edible plants. Prenylated stilbenoids demonstrate promising health benefits, including antioxidant, anti-cancer, anti-inflammatory, anti-microbial activities. This review reports the structure, bioactivity and potential application of prenylated stilbeniods in food industry. Edible sources of these compounds are compiled and summarized. Structure-activity relationship of prenylated stilbenoids are also highlighted. The biosynthesis strategies of prenylated stilbenoids are reviewed. The findings of these compounds as food preservative, nutraceuticals and food additive are discussed. This paper combines the up-to-date information and gives a full image of prenylated stilbenoids.
Topics: Stilbenes; Prenylation; Anti-Inflammatory Agents; Structure-Activity Relationship; Phenols
PubMed: 35373665
DOI: 10.1080/10408398.2022.2056131 -
Journal of the American Chemical Society Nov 2023Prenyltransferases in cyanobactin biosynthesis are of growing interest as peptide alkylation biocatalysts, but their prenylation modes characterized so far have been...
Prenyltransferases in cyanobactin biosynthesis are of growing interest as peptide alkylation biocatalysts, but their prenylation modes characterized so far have been limited to dimethylallylation (C5) or geranylation (C10). Here we engaged in structure-guided engineering of the prenyl-binding pocket of a His--geranyltransferase LimF to modulate its prenylation mode. Contraction of the pocket by a single mutation led to a His--dimethylallyltransferase. More importantly, pocket expansion by a double mutation successfully repurposed LimF for farnesylation (C15), which is an unprecedented mode in this family. Furthermore, the obtained knowledge of the essential residues to construct the farnesyl-binding pocket has allowed for rational design of a Tyr--farnesyltransferase by a triple mutation of a Tyr--dimethylallyltransferase PagF. These results provide an approach to manipulate the prenyl specificity of cyanobactin prenyltransferases, broadening the chemical space covered by this class of enzymes and expanding the toolbox of peptide alkylation biocatalysts.
Topics: Dimethylallyltranstransferase; Peptides, Cyclic; Prenylation; Peptides; Substrate Specificity
PubMed: 37877712
DOI: 10.1021/jacs.3c07373 -
Bone Oct 2020Bisphosphonates (BP) are a class of calcium-binding drug used to prevent bone resorption in skeletal disorders such as osteoporosis and metastatic bone disease. They act... (Review)
Review
Bisphosphonates (BP) are a class of calcium-binding drug used to prevent bone resorption in skeletal disorders such as osteoporosis and metastatic bone disease. They act by selectively targeting bone-resorbing osteoclasts and can be grouped into two classes depending on their intracellular mechanisms of action. Simple BPs cause osteoclast apoptosis after cytoplasmic conversion into toxic ATP analogues. In contrast, nitrogen-containing BPs potently inhibit FPP synthase, an enzyme of the mevalonate (cholesterol biosynthesis) pathway. This results in production of a toxic metabolite (ApppI) and the loss of long-chain isoprenoid lipids required for protein prenylation, a process necessary for the function of small GTPase proteins essential for the survival and activity of osteoclasts. In this review we provide a state-of-the-art overview of these mechanisms of action and a historical perspective of how they were discovered. Finally, we challenge the long-held dogma that BPs act only in the skeleton and highlight recent studies that reveal insights into hitherto unknown effects on tumour-associated and tissue-resident macrophages.
Topics: Bone Resorption; Bone and Bones; Diphosphonates; Humans; Osteoclasts; Protein Prenylation
PubMed: 32569873
DOI: 10.1016/j.bone.2020.115493 -
Biochemistry Sep 2022The regiospecific prenylation of an aromatic amino acid catalyzed by a dimethylallyl-l-tryptophan synthase (DMATS) is a key step in the biosynthesis of many fungal and...
The regiospecific prenylation of an aromatic amino acid catalyzed by a dimethylallyl-l-tryptophan synthase (DMATS) is a key step in the biosynthesis of many fungal and bacterial natural products. DMATS enzymes share a common "ABBA" fold with divergent active site contours that direct alternative C-C, C-N, and C-O bond-forming trajectories. DMATS1 from catalyzes the reverse N-prenylation of l-Trp by generating an allylic carbocation from dimethylallyl diphosphate (DMAPP) that then alkylates the indole nitrogen of l-Trp. DMATS1 stands out among the greater DMATS family because it exhibits unusually broad substrate specificity: it can utilize geranyl diphosphate (GPP) or l-Tyr as an alternative prenyl donor or acceptor, respectively; it can catalyze both forward and reverse prenylation, i.e., at C1 or C3 of DMAPP; and it can catalyze C-N and C-O bond-forming reactions. Here, we report the crystal structures of DMATS1 and its complexes with l-Trp or l-Tyr and unreactive thiolodiphosphate analogues of the prenyl donors DMAPP and GPP. Structures of ternary complexes mimic Michaelis complexes with actual substrates and illuminate active site features that govern prenylation regiochemistry. Comparison with CymD, a bacterial enzyme that catalyzes the reverse N-prenylation of l-Trp with DMAPP, indicates that bacterial and fungal DMATS enzymes share a conserved reaction mechanism. However, the narrower active site contour of CymD enforces narrower substrate specificity. Structure-function relationships established for DMATS enzymes will ultimately inform protein engineering experiments that will broaden the utility of these enzymes as useful tools for synthetic biology.
Topics: Biological Products; Catalysis; Dimethylallyltranstransferase; Fusarium; Hemiterpenes; Indoles; Neoprene; Nitrogen; Organophosphorus Compounds; Prenylation; Substrate Specificity; Tryptophan; Tryptophan Synthase
PubMed: 36084241
DOI: 10.1021/acs.biochem.2c00350 -
Journal of Natural Products Mar 2019Current treatment options for bacterial infections are dependent on antibiotics that inhibit microbial growth and viability. These approaches result in the evolution of...
Current treatment options for bacterial infections are dependent on antibiotics that inhibit microbial growth and viability. These approaches result in the evolution of drug-resistant strains of bacteria. An anti-infective strategy that is less likely to lead to the development of resistance is the disruption of quorum sensing mechanisms, which are involved in promoting virulence. The goal of this study was to identify fungal metabolites effective as quorum sensing inhibitors. Three new prenylated diresorcinols (1-3), along with two known compounds, (4 R) -regiolone and decarboxycitrinone, were isolated from a freshwater fungus (Helotiales sp.) from North Carolina. Their structures were assigned on the basis of HRESIMS and NMR experiments. The structure of compound 1 was confirmed via X-ray diffraction analysis, and its absolute configuration was established by TDDFT-ECD and optical rotation calculations. Compounds 1-3 suppressed quorum sensing in a clinical isolate of methicillin-resistant Staphylococcus aureus (MRSA), with IC values ranging from 0.3 to 12.5 μM. These compounds represent potential leads in the development of antivirulence therapeutics.
Topics: Bacteria; Fungi; Prenylation; Quorum Sensing; Resorcinols
PubMed: 30730742
DOI: 10.1021/acs.jnatprod.8b00925 -
Enzyme and Microbial Technology Feb 2023The prenylation of flavonoids is a main type of structural modification and can endow flavonoids with greater bioactivity and bioavailability. A soluble...
The prenylation of flavonoids is a main type of structural modification and can endow flavonoids with greater bioactivity and bioavailability. A soluble prenyltransferase (NgFPT) gene from Nocardiopsis gilva was cloned, expressed and characterized in Escherichia coli. The optimal activity of NgFPT was at pH 7.5 and 30 °C. The activity of NgFPT was significantly enhanced by Ca, Al, and DMSO. NgFPT showed high selectivity to prenylate flavanones at 3'-C to generate 3'-C-prenyl-flavanones. The Kcat and Km of recombinant NgFPT for naringenin were 0.001 s and 0.045 mM, respectively. Then, recombinant strains were reconstructed by introducing NgFPT gene and the isopentenol utilization pathway. Escherichia coli hosts and fusion tags were screened to improve the yield of 3'-C-prenyl-naringenin in vivo, resulting in maximal 3'-C-prenyl-naringenin production at 3.5 mg/L. By optimizing biotransformation conditions and adopting the resting cell bioconversion, maximum 3'-C-prenyl-naringenin production reached 10.3 mg/L with a specific productivity of 0.21 mg/L/h after 48 h incubation. Thus, the article provides a regiospecific soluble prenyltransferase and a method for the production of 3'-C-prenyl-naringenin by metabolic engineering.
Topics: Dimethylallyltranstransferase; Prenylation; Flavanones; Flavonoids; Escherichia coli
PubMed: 36395620
DOI: 10.1016/j.enzmictec.2022.110154 -
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 -
Nature Chemistry Jun 2019Post-translational farnesylation or geranylgeranylation at a C-terminal cysteine residue regulates the localization and function of over 100 proteins, including the Ras...
Post-translational farnesylation or geranylgeranylation at a C-terminal cysteine residue regulates the localization and function of over 100 proteins, including the Ras isoforms, and is a therapeutic target in diseases including cancer and infection. Here, we report global and selective profiling of prenylated proteins in living cells enabled by the development of isoprenoid analogues YnF and YnGG in combination with quantitative chemical proteomics. Eighty prenylated proteins were identified in a single human cell line, 64 for the first time at endogenous abundance without metabolic perturbation. We further demonstrate that YnF and YnGG enable direct identification of post-translationally processed prenylated peptides, proteome-wide quantitative analysis of prenylation dynamics and alternative prenylation in response to four different prenyltransferase inhibitors, and quantification of defective Rab prenylation in a model of the retinal degenerative disease choroideremia.
Topics: Adaptor Proteins, Signal Transducing; Alkynes; Animals; Cell Line; Gene Knockout Techniques; Humans; Mass Spectrometry; Mice, Knockout; Molecular Probes; Protein Prenylation; Proteins; Proteome; Proteomics
PubMed: 30936521
DOI: 10.1038/s41557-019-0237-6 -
Recent Patents on Endocrine, Metabolic... 2015Nuclear lamins, namely lamins A, B and C, surround the nucleoplasmic contents in a meshlike network called the nuclear lamina. These intermediate filaments provide a... (Review)
Review
Nuclear lamins, namely lamins A, B and C, surround the nucleoplasmic contents in a meshlike network called the nuclear lamina. These intermediate filaments provide a structural framework to the nuclear envelope (NE), play a role in arrangement of the chromatin within the nucleus, in DNA replication and also participate in DNA damage repair. In order for lamins to be involved in these important nuclear processes and to be functionally active, they undergo a series of post-translational modifications (farnesylation, endoproteolytic cleavage, carboxylmethylation etc.), of which farnesylation is the most studied. Improper farnesylation of lamin proteins, especially lamin A, leads to a number of diseases affecting the striated muscle (e.g. Emery- Dreifuss Muscular Dystrophy, Dilated Cardiomyopathy), adipose tissue (e.g. Dunnigan-type familial partial lipodystrophy) and could result in abnormal senescence and growth deformities (e.g. Progeria syndrome); these are referred to as laminopathies. Despite the existing literature and evidence regarding functions of lamins and diseases associated with abnormal lamin processing, a lot remains to be understood in regards to lamin biology and their role as potential therapeutic targets. In this brief review, we have attempted to summarize the roles of lamins in physiology and pathology of the cell and in type 2 diabetes mellitus [T2DM] and also enlisted patents on methods, systems and devices developed for improving pancreatic beta cell function in diabetes mellitus.
Topics: Animals; Chromatin; DNA Replication; Endoplasmic Reticulum Stress; Humans; Insulin-Secreting Cells; Lamins; Mutation; Nuclear Envelope; Prenylation
PubMed: 26453024
DOI: 10.2174/1872214809666151009120402 -
Phytochemistry Nov 2021Prenylated flavonoids, a unique class of flavonoids which combine a flavonoid skeleton and a lipophilic prenyl side-chain, possess great potential biological activities... (Review)
Review
Prenylated flavonoids, a unique class of flavonoids which combine a flavonoid skeleton and a lipophilic prenyl side-chain, possess great potential biological activities including cytotoxicity, anti-inflammation, anti-Alzheimer, anti-microbial, anti-oxidant, anti-diabetes, estrogenic, vasorelaxant and enzyme inhibition. Recently, prenylated flavonoids have become an indispensable anchor for the development of new therapeutic agents, and have received increasing from medicinal chemists. The prenylated flavonoids have been outstanding developed through isolation, semi or fully synthesis in a very short period of time, which proves the great value in medicinal chemistry researches. In this review, research progress of prenylated flavonoids including natural prenylated flavonoids, structural modification, synthetic methodologies and pharmacological activities was summarized comprehensively. Furthermore, the structure-activity relationships (SARs) of prenylated flavonoids were summarized which provided a basis for the selective design and optimization of multifunctional prenylated flavonoid derivatives for the treatment of multi-factorial diseases in clinic.
Topics: Anti-Inflammatory Agents; Antioxidants; Flavonoids; Prenylation; Structure-Activity Relationship
PubMed: 34403885
DOI: 10.1016/j.phytochem.2021.112895