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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 -
Annual Review of Genetics 1992
Review
Topics: Amino Acid Sequence; Animals; GTP-Binding Proteins; Genes, ras; Lamins; Molecular Sequence Data; Nuclear Proteins; Pheromones; Protein Prenylation; Protein Processing, Post-Translational
PubMed: 1482112
DOI: 10.1146/annurev.ge.26.120192.001233 -
Topics in Current Chemistry 2012Important biologically active indole alkaloids are decorated with prenyl (3,3-dimethylallyl) and tert-prenyl (1,1-dimethylallyl) groups. Covering the literature until... (Review)
Review
Important biologically active indole alkaloids are decorated with prenyl (3,3-dimethylallyl) and tert-prenyl (1,1-dimethylallyl) groups. Covering the literature until the end of 2010, this review article comprehensively summarises and discusses the currently available technologies of prenylation and tert-prenylation of indoles, which have been applied in natural products total syntheses or could be applied there in the near future. We focus on those procedures which introduce the C(5) units in one step, organised according to the indole position to be functionalised. Key strategies include electrophilic and nucleophilic prenylation and tert-prenylation, prenyl and tert-prenyl rearrangements, transition metal-mediated reactions and enzymatic methods.
Topics: Biological Products; Heterocyclic Compounds, 4 or More Rings; Indole Alkaloids; Indoles; Models, Chemical; Molecular Structure; Prenylation
PubMed: 21915778
DOI: 10.1007/128_2011_204 -
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 -
Recent Progress in Hormone Research 1994
Review
Topics: Alkyl and Aryl Transferases; Animals; GTP-Binding Proteins; Macromolecular Substances; Protein Prenylation; Signal Transduction; Transferases
PubMed: 8146425
DOI: 10.1016/b978-0-12-571149-4.50015-5 -
Accounts of Chemical Research Feb 2015CONSPECTUS: The role dynamics plays in proteins is of intense contemporary interest. Fundamental insights into how dynamics affects reactivity and product distributions... (Review)
Review
CONSPECTUS: The role dynamics plays in proteins is of intense contemporary interest. Fundamental insights into how dynamics affects reactivity and product distributions will facilitate the design of novel catalysts that can produce high quality compounds that can be employed, for example, as fuels and life saving drugs. We have used molecular dynamics (MD) methods and combined quantum mechanical/molecular mechanical (QM/MM) methods to study a series of proteins either whose substrates are too far away from the catalytic center or whose experimentally resolved substrate binding modes cannot explain the observed product distribution. In particular, we describe studies of farnesyl transferase (FTase) where the farnesyl pyrophosphate (FPP) substrate is ∼8 Å from the zinc-bound peptide in the active site of FTase. Using MD and QM/MM studies, we explain how the FPP substrate spans the gulf between it and the active site, and we have elucidated the nature of the transition state (TS) and offered an alternate explanation of experimentally observed kinetic isotope effects (KIEs). Our second story focuses on the nature of substrate dynamics in the aromatic prenyltransferase (APTase) protein NphB and how substrate dynamics affects the observed product distribution. Through the examples chosen we show the power of MD and QM/MM methods to provide unique insights into how protein substrate dynamics affects catalytic efficiency. We also illustrate how complex these reactions are and highlight the challenges faced when attempting to design de novo catalysts. While the methods used in our previous studies provided useful insights, several clear challenges still remain. In particular, we have utilized a semiempirical QM model (self-consistent charge density functional tight binding, SCC-DFTB) in our QM/MM studies since the problems we were addressing required extensive sampling. For the problems illustrated, this approach performed admirably (we estimate for these systems an uncertainty of ∼2 kcal/mol), but it is still a semiempirical model, and studies of this type would benefit greatly from more accurate ab initio or DFT models. However, the challenge with these methods is to reach the level of sampling needed to study systems where large conformational changes happen in the many nanoseconds to microsecond time regimes. Hence, how to couple expensive and accurate QM methods with sophisticated sampling algorithms is an important future challenge especially when large-scale studies of catalyst design become of interest. The use of MD and QM/MM models to elucidate enzyme catalytic pathways and to design novel catalytic agents is in its infancy but shows tremendous promise. While this Account summarizes where we have been, we also discuss briefly future directions that improve our fundamental ability to understand enzyme catalysis.
Topics: Farnesyltranstransferase; Molecular Dynamics Simulation; Protein Prenylation; Quantum Theory
PubMed: 25539152
DOI: 10.1021/ar500321u -
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 -
Nature Communications Jun 2023Prenylated and reverse-prenylated indolines are privileged scaffolds in numerous naturally occurring indole alkaloids with a broad spectrum of important biological...
Prenylated and reverse-prenylated indolines are privileged scaffolds in numerous naturally occurring indole alkaloids with a broad spectrum of important biological properties. Development of straightforward and stereoselective methods to enable the synthesis of structurally diverse prenylated and reverse-prenylated indoline derivatives is highly desirable and challenging. In this context, the most direct approaches to achieve this goal generally rely on transition-metal-catalyzed dearomative allylic alkylation of electron-rich indoles. However, the electron-deficient indoles are much less explored, probably due to their diminished nucleophilicity. Herein, a photoredox-catalyzed tandem Giese radical addition/Ireland-Claisen rearrangement is disclosed. Diastereoselective dearomative prenylation and reverse-prenylation of electron-deficient indoles proceed smoothly under mild conditions. An array of tertiary α-silylamines as radical precursors is readily incorporated in 2,3-disubstituted indolines with high functional compatibility and excellent diastereoselectivity (>20:1 d.r.). The corresponding transformations of the secondary α-silylamines provide the biologically important lactam-fused indolines in one-pot synthesis. Subsequently, a plausible photoredox pathway is proposed based on control experiments. The preliminary bioactivity study reveals a potential anticancer property of these structurally appealing indolines.
Topics: Electrons; Prenylation; Alkylation; Antipsychotic Agents; Indoles; Catalysis
PubMed: 37391418
DOI: 10.1038/s41467-023-39633-9 -
Molecular Microbiology Jan 1994Modification of proteins at C-terminal cysteine residue(s) by the isoprenoids farnesyl (C15) and geranylgeranyl (C20) is essential for the biological function of a... (Review)
Review
Modification of proteins at C-terminal cysteine residue(s) by the isoprenoids farnesyl (C15) and geranylgeranyl (C20) is essential for the biological function of a number of eukaryotic proteins including fungal mating factors and the small, GTP-binding proteins of the Ras superfamily. Three distinct enzymes, conserved between yeast and mammals, have been identified that prenylate proteins: farnesyl protein transferase, geranylgeranyl protein transferase type I and geranylgeranyl protein transferase type II. Each prenyl protein transferase has its own protein substrate specificity. Much has been learned about the biology, genetics and biochemistry of protein prenylation and prenyl protein transferases through studies of eukaryotic microorganisms, particularly Saccharomyces cerevisiae. The functional importance of protein prenylation was first demonstrated with fungal mating factors. The initial genetic analysis of prenyl protein transferases was in S. cerevisiae with the isolation and subsequent characterization of mutations in the RAM1, RAM2, CDC43 and BET2 genes, each of which encodes a prenyl protein transferase subunit. We review here these and other studies on protein prenylation in eukaryotic microbes and how they relate to and have contributed to our knowledge about protein prenylation in all eukaryotic cells.
Topics: Amino Acid Sequence; Animals; Dimethylallyltranstransferase; Genes, Fungal; Mammals; Molecular Sequence Data; Protein Prenylation; Saccharomyces cerevisiae; Substrate Specificity
PubMed: 8170384
DOI: 10.1111/j.1365-2958.1994.tb00302.x -
Current Opinion in Chemical Biology Feb 1998A specific set of proteins in eukaryotic cells contain covalently attached carboxy-terminal prenyl groups (15-carbon farnesyl and 20-carbon geranylgeranyl). Many of them... (Review)
Review
A specific set of proteins in eukaryotic cells contain covalently attached carboxy-terminal prenyl groups (15-carbon farnesyl and 20-carbon geranylgeranyl). Many of them are signaling proteins including Ras, heterotrimeric G proteins and Rab proteins. The protein prenyltransferases which attach prenyl groups to proteins have been well characterized, and an X-ray structure is available for protein farnesyltransferase. Inhibitors of protein farnesyltransferase are showing sufficient promise in preclinical trials as anti-cancer drugs to warrant widespread interest in the pharmaceutical industry.
Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Humans; Protein Prenylation
PubMed: 9667914
DOI: 10.1016/s1367-5931(98)80034-3