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Frontiers in Oncology 2019Tumor metastasis is a sequential event accounting for numerous cancer-related fatalities worldwide. The process of metastasis serially involves invasion, intravasation,... (Review)
Review
Tumor metastasis is a sequential event accounting for numerous cancer-related fatalities worldwide. The process of metastasis serially involves invasion, intravasation, extravasation, and tumor growth at the secondary site. Migration and invasion enhancer 1 (MIEN1) is a membrane associated protein overexpressed in various human cancers. Biological activity of MIEN1 is driven by geranylgeranyltransferase-I mediated prenylation at CAAX motif and methylation of the prenylated protein that anchors MIEN1 into the cellular membrane. Post-translationally modified MIEN1 interacts with Syk kinase and Annexin A2 protein; polymerizes G-actin and stabilizes F-actin filament; induces focal adhesion kinase phosphorylation and decrease cofilin phosphorylation implicated in both invasion and metastasis of different cancer types. In the present review, we discuss the structure, function, and involvement of MIEN1 in cancer progression. We also highlight the future prospects of MIEN1 as an emerging molecule and novel target in cancer cell invasion and metastasis.
PubMed: 31552186
DOI: 10.3389/fonc.2019.00868 -
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 -
Lipidation of small GTPase Cdc42 as regulator of its physiological and pathophysiological functions.Frontiers in Physiology 2022The protein cell division cycle 42 (Cdc42) is a small GTPase of the Rho family regulating a plethora of physiological functions in a tissue, cell and... (Review)
Review
The protein cell division cycle 42 (Cdc42) is a small GTPase of the Rho family regulating a plethora of physiological functions in a tissue, cell and subcellular-specific manner participating in multiple signaling pathways. Since the corresponding signaling hubs are mainly organized along the cellular membranes, cytosolic proteins like Cdc42 need to be properly targeted and held at the membrane. Here, lipid modifications come into play: Cdc42 can be associated with membranes by different lipid anchors including prenylation (Cdc42-prenyl) and palmitoylation (Cdc42-palm). While Cdc42-prenyl is ubiquitously expressed, Cdc42-palm splicing variant in mainly expressed in the brain. Mechanisms underlying Cdc42 lipidation as well as its regulation are the main topic of this review. Furthermore, we will discuss the functional importance of Cdc42 lipid modifications with the focus on the role of different lipids in regulating defined Cdc42 functions. Finally, we will provide an overview of the possible implementation of Cdc42 lipidation in pathological conditions and different diseases.
PubMed: 36699687
DOI: 10.3389/fphys.2022.1088840 -
Synthetic and Systems Biotechnology Jun 2021Prenyltransferase (PTase) enzymes play crucial roles in natural product biosynthesis by transferring isoprene unit(s) to target substrates, thereby generating prenylated...
Prenyltransferase (PTase) enzymes play crucial roles in natural product biosynthesis by transferring isoprene unit(s) to target substrates, thereby generating prenylated compounds. The prenylation step leads to a diverse group of natural products with improved membrane affinity and enhanced bioactivity, as compared to the non-prenylated forms. The last two decades have witnessed increasing studies on the identification, characterization, enzyme engineering, and synthetic biology of microbial PTase family enzymes. We herein summarize several examples of microbial soluble aromatic PTases for chemoenzymatic syntheses of unnatural novel prenylated compounds.
PubMed: 33778178
DOI: 10.1016/j.synbio.2021.02.001 -
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 -
Biotechnology For Biofuels and... Apr 2023Advanced spark ignition engines require high performance fuels with improved resistance to autoignition. Biologically derived olefinic alcohols have arisen as promising...
BACKGROUND
Advanced spark ignition engines require high performance fuels with improved resistance to autoignition. Biologically derived olefinic alcohols have arisen as promising blendstock candidates due to favorable octane numbers and synergistic blending characteristics. However, production and downstream separation of these alcohols are limited by their intrinsic toxicity and high aqueous solubility, respectively. Bioproduction of carboxylate esters of alcohols can improve partitioning and reduce toxicity, but in practice has been limited to saturated esters with characteristically low octane sensitivity. If olefinic esters retain the synergistic blending characteristics of their alcohol counterparts, they could improve the bioblendstock combustion performance while also retaining the production advantages of the ester moiety.
RESULTS
Optimization of Escherichia coli isoprenoid pathways has led to high titers of isoprenol and prenol, which are not only excellent standalone biofuel and blend candidates, but also novel targets for esterification. Here, a selection of olefinic esters enhanced blendstock performance according to their degree of unsaturation and branching. E. coli strains harboring optimized mevalonate pathways, thioester pathways, and heterologous alcohol acyltransferases (ATF1, ATF2, and SAAT) were engineered for the bioproduction of four novel olefinic esters. Although prenyl and isoprenyl lactate titers were limited to 1.48 ± 0.41 mg/L and 5.57 ± 1.36 mg/L, strains engineered for prenyl and isoprenyl acetate attained titers of 176.3 ± 16.0 mg/L and 3.08 ± 0.27 g/L, respectively. Furthermore, prenyl acetate (20% bRON = 125.8) and isoprenyl acetate (20% bRON = 108.4) exhibited blend properties comparable to ethanol and significantly better than any saturated ester. By further scaling cultures to a 2-L bioreactor under fed-batch conditions, 15.0 ± 0.9 g/L isoprenyl acetate was achieved on minimal medium. Metabolic engineering of acetate pathway flux further improved titer to attain an unprecedented 28.0 ± 1.0 g/L isoprenyl acetate, accounting for 75.7% theoretical yield from glucose.
CONCLUSION
Our study demonstrated novel bioproduction of four isoprenoid oxygenates for fuel blending. Our optimized E. coli production strain generated an unprecedented titer of isoprenyl acetate and when paired with its favorable blend properties, may enable rapid scale-up of olefinic alcohol esters for use as a fuel blend additive or as a precursor for longer-chain biofuels and biochemicals.
PubMed: 37016410
DOI: 10.1186/s13068-023-02301-7 -
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 -
RSC Advances Sep 2022Prenylation usually improves structural diversity and bioactivity in natural products. Unlike the discovered enzymatic -diprenylation of mono- and tri-cyclic aromatic...
Prenylation usually improves structural diversity and bioactivity in natural products. Unlike the discovered enzymatic -diprenylation of mono- and tri-cyclic aromatic systems, the enzymatic approach for -diprenylation of bi-cyclic hydroxynaphthalenes is new to science. Here we report an enzymatic example for dearomative C4 -diprenylation of α-hydroxynaphthalenes, by the F253G mutant of a fungal prenyltransferase CdpC3PT. Experimental evidence suggests a sequential electrophilic substitution mechanism. We also explained the alteration of catalytic properties on CdpC3PT after mutation on F253 by modeling. This study provides a valuable addition to the synthetic toolkit for compound prenylation and it also contributes to the mechanistic study of prenylating enzymes.
PubMed: 36276050
DOI: 10.1039/d2ra04837j