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Bioscience, Biotechnology, and... Feb 2018Flavonoids are distributed across the plant kingdom and have attracted substantial attention owing to their potential benefits for human health. Several studies have... (Review)
Review
Flavonoids are distributed across the plant kingdom and have attracted substantial attention owing to their potential benefits for human health. Several studies have demonstrated that flavonoids prenylation enhances various biological activities, suggesting an attractive tool for developing functional foods. This review provides an overview of the current knowledge on how prenylation influences the biological activity and bioavailability of flavonoids. The enhancement effect of prenylation on the biological activities of dietary flavonoids in mammals was demonstrated by comparing the effect of 8-prenyl naringenin (8PN) with that of parent naringenin in the prevention of disuse muscle atrophy in mice. This enhancement results from higher muscular accumulation of 8PN than naringenin. As to bioavailability, despite the lower absorption of 8-prenyl quercetin (8PQ) compared with quercetin, higher 8PQ accumulation was found in the liver and kidney. These data imply that prenylation interferes with the elimination of flavonoids from tissues.
Topics: Animals; Biological Availability; Diet; Flavonoids; Humans; Intestinal Absorption; Prenylation; Tissue Distribution
PubMed: 29307271
DOI: 10.1080/09168451.2017.1415750 -
The Journal of Pathology Mar 2019Non-alcoholic fatty liver disease (NAFLD) often develops in concert with related metabolic diseases, such as obesity, dyslipidemia and insulin resistance. Prolonged...
Non-alcoholic fatty liver disease (NAFLD) often develops in concert with related metabolic diseases, such as obesity, dyslipidemia and insulin resistance. Prolonged lipid accumulation and inflammation can progress to non-alcoholic steatohepatitis (NASH). Although factors associated with the development of NAFLD are known, triggers for the progression of NAFLD to NASH are poorly understood. Recent findings published in The Journal of Pathology reveal the possible regulation of NASH progression by metabolites of the mevalonate pathway. Mevalonate can be converted into the isoprenoids farnesyldiphosphate (FPP) and geranylgeranyl diphosphate (GGPP). GGPP synthase (GGPPS), the enzyme that converts FPP to GGPP, is dysregulated in humans and mice during NASH. Both FPP and GGPP can be conjugated to proteins through prenylation, modifying protein function and localization. Deletion or knockdown of GGPPS favors FPP prenylation (farnesylation) and augments the function of liver kinase B1, an upstream kinase of AMP-activated protein kinase (AMPK). Despite increased AMPK activation, livers in Ggpps-deficient mice on a high-fat diet poorly oxidize lipids due to mitochondrial dysfunction. Although work from Liu et al provides evidence as to the potential importance of the prenylation portion of the mevalonate pathway during NAFLD, future studies are necessary to fully grasp any therapeutic or diagnostic potential. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Topics: Animals; Diet, High-Fat; Farnesyltranstransferase; Fibrosis; Glucose; Humans; Liver; Mice; Non-alcoholic Fatty Liver Disease; Prenylation; United Kingdom
PubMed: 30374976
DOI: 10.1002/path.5190 -
Applied Microbiology and Biotechnology Sep 2015Attachment of isoprene units to various acceptors by prenylation plays an important role in primary and secondary metabolism of living organisms. Protein prenylation... (Review)
Review
Attachment of isoprene units to various acceptors by prenylation plays an important role in primary and secondary metabolism of living organisms. Protein prenylation belongs to posttranslational modification and is involved in cellular regulation process. Prenylated secondary metabolites usually demonstrate promising biological and pharmacological activities. Prenyl transfer reactions catalyzed by prenyltransferases represent the key steps in the biosynthesis and contribute significantly to the structural and biological diversity of these compounds. In the last decade, remarkable progress has been achieved in the biochemical, molecular, and structural biological investigations of prenyltransferases, especially on those of the members of the dimethylallyltryptophan synthase (DMATS) superfamily. Until now, more than 40 of such soluble enzymes are identified and characterized biochemically. They catalyze usually regioselective and stereoselective prenylations of a series of aromatic substances including tryptophan, tryptophan-containing peptides, and other indole derivatives as well as tyrosine or even nitrogen-free substrates. Crystal structures of a number of prenyltransferases have been solved in the past 10 years and provide a solid basis for understanding the mechanism of prenyl transfer reactions.
Topics: Butadienes; Dimethylallyltranstransferase; Hemiterpenes; Pentanes; Prenylation; Protein Conformation; Protein Processing, Post-Translational; Proteins; Secondary Metabolism; Tyrosine
PubMed: 26216239
DOI: 10.1007/s00253-015-6811-y -
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 -
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 -
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 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 -
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