RSC Advances
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2022
·Vol. 12
·期 42
·27550-27554
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IF 4.036
Yuanyuan Xu,Dan Li,Wenxuan Wang,Kangping Xu,Guishan Tan,Jing Li,Shu-Ming Li,Xia Yu
Prenylation usually improves structural diversity and bioactivity in natural products. Unlike the discovered enzymatic gem-diprenylation of mono- and tri-cyclic aromatic systems, the enzymatic approach for gem-diprenylation of bi-cyclic hydroxynaphthalenes is new to science. Here we report an enzymatic example for dearomative C4 gem-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.
研究领域:
生物化学
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酶学
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有机化学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2020
·
IF 5.162
Jiali Yang,Ting Zhou,Yueming Jiang,Bao Yang
Prenylated flavonoids are good drug candidates due to multiple biological activities and health benefits. Prenyltransferase is an important enzyme involved in the biosynthesis of prenylated flavonoids. In this work, a flavonoid prenyltransferase (AhPT1) from Artocarpus heterophyllus showed an unexpectedly metal ion-induced specificity to flavonoid substrates. AhPT1 could catalyse 6- C -prenylation of genistein when Mg 2+ serving as cofactor. Its catalytic activity to 6-hydroxyflavone was undetectable. However, when Mn 2+ was used instead of Mg 2+ , 5- C -prenylated 6-hydroxyflavone was generated with a high conversion rate. Mn 2+ altered the regiospecificity of AhPT1 and turned it into a 5- C -prenyltransferase. 2′-Hydroxyl could improve the conversion rate of 6-hydroxyflavone, whereas 3′- or 4′-hydroxyl impaired the catalysis efficiency of AhPT1. NQIFDADID174 and DLTDVEGD305 were active motifs involved in substrate binding and catalysis. Asn166, Asp170, Asp174, Asp298, Asp301 and Asp305 in the active center were critical to the prenylation reaction.
研究领域:
生物化学
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酶学
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药理学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2022
·
IF 3.322
Ting Zhou,Bao Yang
Prenylated resveratrols are drug candidates presented in many natural sources. They possess multiple pharmacological activities. Due to the limited abundance in nature and disadvantage of chemical synthesis, it is required to produce prenylated resveratrols by biological strategy. In this work, a prenyltransferase iacE from Pestalotiopsis fici was prepared by heterologous overexpression. It could catalyze 2- C -prenylation of resveratrol efficiently. Dimethylallyl diphosphate (DMAPP) and geranyl diphosphate (GPP) could serve as prenyl donor. Glu97, Thr114 and Tyr413 were proved to be important residues in the active site by site-directed mutagenesis. The product was purified and identified to be 2- C -prenyl resveratrol by NMR . 2- C -prenyl resveratrol exerted neuroprotective activity through inhibiting ROS overproduction and improving the activities of antioxidant enzymes in HT22 cell. The genes involved in antioxidant defense were regulated, including upregulated CAT , SOD2 , NFE2L2 , GPx4 , and downregulated PTGS2 and ACSL4 . These results supplied a novel technique for prenylated resveratrols production.
研究领域:
生物技术
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药理学
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神经科学
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PubMed
高影响因子
JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE
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2025
·
IF 3.5
Zhengjiao Gao,Dingtao Tang,Bingfeng He,Jiajie Quan,Zhengke Zhang,Yueming Jiang,Bao Yang,Jiali Yang
BACKGROUND Prenylated flavonoids are widely distributed in plants, including fruits and vegetables in the Moraceae and Fabaceae families. These chemicals are potential functional food ingredients owing to their attractive biological activities. However, natural prenylated flavonoids are rare, which limits their application. RESULTS Here, we reported the prenylation of apigenin and genistein catalyzed by DMATS1, a dimethylallyl- l -tryptophan synthase from Fusarium fujikuroi . High-performance liquid chromatography–tandem mass spectrometry and nuclear magnetic resonance identified their structure as 6- C -prenylapigenin (6-PA) and 6- C -prenylgenistein (6-PG), respectively. Cell-based assay suggested that both 6-PA and 6-PG induced the proliferation of THP-1 cells under low concentrations and were safe in doses less than 50 μmol L −1 . 6-PA and 6-PG exhibited significant anti-inflammatory activity in lipopolysaccharide-stimulated THP-1 cells, and inhibited the production of nitric oxide as well as downregulating the transcriptional levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-8, and interleukin-1β. CONCLUSION The findings suggested that DMATS1 could catalyze the 6- C prenylation of apigenin and genistein, and the generated 6-PA and 6-PG exhibited anti-inflammatory activity, aiding in the recognition of 6-PA and 6-PG as nutraceuticals. © 2025 Society of Chemical Industry.
CAS / MDL:
研究领域:
植物化学
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药理学
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生物合成
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DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
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2021
·Vol. 36
·期 1
·e5239
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IF 1.902
Xiao-fang Ma,Qi Zhao,Yan Cheng,Dong-Mei Yan,Wei-Feng Zhu,Fei Li
Coumarins are a group of natural compounds commonly found in the families of Rutaceae and Umbelliferae. 7-Isopentenyloxycoumarin (ISC), auraptene (AUR), and umbelliprenin (UM) belong to prenyloxycoumarins (PYCs), which link isopentenyl, geranyl, and farnesyl group at C7 position, respectively. The substituent of 7-ethoxycoumarin (ETC) is the ethyl group. In this study, UPLC–ESI–QTOF–MS (ultra-performance liquid chromatography–electrospray ionization–quadrupole time of flight–MS)-based metabolomics was used to evaluate the in vivo and in vitro metabolism of PYCs. Results showed that ETC produced 10 known metabolites, and ISC was transformed into 17 metabolites in vivo and in vitro , which were undescribed compounds. A total of 35 AUR metabolites, including 34 undescribed metabolites were identified, and 21 metabolites were reported for the first time in UM. The results indicated that hydroxylation and N -acetylcysteine conjugation were the common metabolic reactions for PYCs. The metabolic rates of ETC, ISC, AUR and UM were 26%, 36%, 81%, and 38%, respectively, in human liver microsome, while they were 24%, 40%, 80%, and 37%, respectively, in mouse liver microsomes. In addition, recombinant cytochrome P450s (CYPs) screening showed that CYP1A1, 2C19, 3A4, and 3A5 were the major metabolic enzymes involved in the formation of hydroxylation metabolites. Together, these results suggest that the isopentenyl group plays an important role in the metabolism of PYCs.
研究领域:
药理学
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植物化学
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代谢研究
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2021
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IF 5.279
Cong Qiu,Yang Liu,Yangbao Wu,Linguo Zhao,Jianjun Pei
Prenyl groups increase the lipophilicity of flavonoids, endowing them with a special activity, selectivity, and pharmacological properties by prenylation. Herein, a novel prenyltransferase (ShFPT) gene from Streptomyces sp. NT11 was expressed in Escherichia coli, and its biochemical characteristics were determined. ShFPT exhibited high selectivity to prenylate naringenin at C-6 to generate 6-prenylnaringenin. The optimal activity was observed at pH 6.0 and 55 °C. The Kcat and Km for naringenin were 0.0095 s–1 and 0.20 mM, respectively. Several promiscuous kinase and isopentenyl phosphate kinase genes were screened to develop the most efficient dimethylallyl diphosphate (DMAPP) synthesis pathway for 6-prenylnaringenin synthesis in E. coli. The 6-prenylnaringenin production was improved by changing the induction strategies and optimizing the bioconversion conditions. Finally, 6-prenylnaringenin production reached the highest yield of 69.9 mg/L with average productivity of 4.0 mg/L/h after 16 h incubation, which is the highest yield for any prenylated flavonoid reported to date in E. coli. Therefore, this study provides an efficient method for 6-prenylnaringenin production and reveals the DMAPP synthesis pathway.
研究领域:
生物化学
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微生物学
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药理学
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DOI
PubMed
高影响因子
FOOD CHEMISTRY
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2022
·
IF 9.231
Shengtao Bo,Sui Kiat Chang,Ting Zhou,Hong Zhu,Yueming Jiang,Bao Yang
Prenylated stilbenoids are good candidates of nutraceuticals presented in food resources. The levels of natural prenylated stilbenoids are usually low. Biotransformation is a promising synthesis strategy to produce novel bioactive compounds. However, information regarding biosynthesis of prenylated stilbenoids is rare. In this work, prenyltransferase and geranyl diphosphate biosynthesis pathway were overexpressed in E. coli . Multiple prenyltransferase genes were tested and Ambp1 was found to be effective on resveratrol geranylation. The products were identified by mass spectrometry and nuclear magnetic resonance spectroscopy as 4- C -geranyl resveratrol ( 1 ) and 3- O -geranyl resveratrol ( 2, novel chemical). By optimization of culture conditions, a yield of 36.9% was achieved for the conversion to geranylated resveratrol from resveratrol. These two compounds demonstrated good antioxidant activities with IC 50 values of 28.09 μM for 4- C -geranyl resveratrol and 403.88 μM for 3- O -geranyl resveratrol. The results were helpful for developing novel technique to produce prenylated phenolics.
研究领域:
生物技术
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药物化学
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营养保健品
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DOI
PubMed
高影响因子
MOLECULES
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2022
·Vol. 27
·期 20
·6952
·
IF 4.927
Liqiong Sun,Zhijuan Tang,Minxin Wang,Jun Shi,Yajuan Lin,Tiefeng Sun,Zhilu Zou,Zebin Weng
With the abuse of antibiotics, bacterial antibiotic resistance is becoming a major public healthcare issue. Natural plants, especially traditional Chinese herbal medicines, which have antibacterial activity, are important sources for discovering potential bacteriostatic agents. This study aimed to develop a fast and reliable method for screening out antimicrobial compounds targeting the MRSA membrane fromPsoralea corylifoliaLinn. seed. A UPLC-MS/MS method was applied to identify the prenylated flavonoids in major fractions from the extracts ofPsoralea corylifoliaLinn. seed. The broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) of different fractions and compounds. The morphological and ultrastructural changes of MRSA were determined by scanning electron microscopy (SEM). The membrane-targeting mechanism of the active ingredients was explored by membrane integrity assays, membrane fluidity assays, membrane potential assays, ATP, and ROS determination. We identified eight prenylated flavonoids inPsoralea corylifoliaLinn. seed. The antibacterial activity and mechanism studies showed that this type of compound has a unique destructive effect on MRSA cell membranes and does not result in drug resistance. The results revealed that prenylated flavonoids inPsoralea corylifoliaLinn. seeds are promising candidates for the development of novel antibiotic agents to combat MRSA-associated infections.Keywords:methicillin-resistantStaphylococcus aureus;Psoralea corylifoliaLinn. seed;prenylated flavonoids;UPLC-MS/MS;bacterial membrane
研究领域:
微生物学
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药理学
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中药学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2022
·Vol. 23
·期 21
·12904
·
IF 6.208
Cong Qiu,Yang Liu,Yangbao Wu,Linguo Zhao,Jianjun Pei
Dimethylallyl diphosphate (DMAPP) is a key intermediate metabolite in the synthesis of isoprenoids and is also the prenyl donor for biosynthesizing prenylated flavonoids. However, it is difficult to prepare DMAPP via chemical and enzymatic methods. In this study, three promiscuous kinases fromShigella flexneri(SfPK),Escherichia coli(EcPK), andSaccharomyces cerevisiae(ScPK) and three isopentenyl phosphate kinases fromMethanolobus tindarius(MtIPK),Methanothermobacter thermautotrophicusstr. Delta H (MthIPK), andArabidopsis thaliana(AtIPK) were cloned and expressed inEscherichia coli. The enzymatic properties of recombinant enzymes were determined. TheKcat/Kmvalue of SfPK for DMA was 6875 s−1M−1, which was significantly higher than those of EcPK and ScPK. TheKcat/Kmvalue of MtIPK for DMAP was 402.9 s−1M−1, which was ~400% of that of MthIPK. SfPK was stable at pH 7.0–9.5 and had a 1 h half-life at 65 °C. MtIPK was stable at pH 6.0–8.5 and had a 1 h half-life at 50 °C. The stability of SfPK and MtIPK was better than that of the other enzymes. Thus, SfPK and MtIPK were chosen to develop a one-pot enzymatic cascade for producing DMAPP from DMA because of their catalytic efficiency and stability. The optimal ratio between SfPK and MtIPK was 1:8. The optimal pH and temperature for the one-pot enzymatic cascade were 7.0 and 35 °C, respectively. The optimal concentrations of ATP and DMA were 10 and 80 mM, respectively. Finally, maximum DMAPP production reached 1.23 mM at 1 h under optimal conditions. Therefore, the enzymatic method described herein for the biosynthesis of DMAPP from DMA can be widely used for the synthesis of isoprenoids and prenylated flavonoids.Keywords:dimethylallyl diphosphate;promiscuous kinase;isopentenyl phosphate kinase;one-pot enzymatic cascade
研究领域:
生物化学
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合成生物学
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DOI
PubMed
高影响因子
Food & Function
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2020
·Vol. 11
·期 12
·10568-10579
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IF 4.171
Jing Xu,Shan Jin,Fei Gan,Hui Xiong,Zhinan Mei,Yu Chen,Guangzhong Yang
The fruits of Garcinia xanthochymus can be eaten raw or processed into jams, preserves and vinegar. They provide not only vitamin and protein nutrients, but also pharmacologically active compounds, among which polycyclic polyprenylated acylphloroglucinols (PPAPs) are a major class. According to the literature, PPAPs exhibited good anti-cancer effects. This study investigated the antitumor effects and the underlying mechanism of S1 (the regioisomeric mixture of xanthochymol and guttiferone E) and S2 (the regioisomeric mixture of isoxanthochymol and cycloxanthochymol) isolated from the fruits of G. xanthochymus. In an H22 allograft mouse model, S1 and S2 could suppress the liver tumor growth and phosphorylation of STAT3. Computational modeling showed that S1 and S2 could form hydrogen bonds with the SH2 domain of STAT3. In HepG2 and MCF-7 cell lines, S1 and S2 downregulated the expression of p-STAT3Tyr705. Moreover, S1 and S2 inhibited the phosphorylation of JAK2 and Src, which are the upstream kinases of STAT3, and the expression of various STAT3-regulated genes, including anti-apoptotic (Bcl-XL, Mcl-1 and survivin), proliferative (cyclin D1) and angiogenic (VEGF) genes. As a result, S1 and S2 arrested the cell cycle and induced cell apoptosis, which were proved by the activation of cleaved caspase-3 and caspase-8. These results demonstrated that S1 and S2 from G. xanthochymus exhibited antitumor effects through the inactivation of STAT3, and could be promising candidates for cancer treatment.
研究领域:
药理学
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肿瘤学
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分子生物学
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生物化学
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DOI
PubMed
高影响因子
AAPS Journal
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2013
·Vol. 16
·期 1
·101-113
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IF 4.386
Qiao Xue,Ji Shuai,Yu Si-wang,Lin Xiong-hao,Jin Hong-wei,Duan Yao-kai,Zhang Liang-ren,Guo De-an,Ye Min
Licorice has been shown to affect the activities of several cytochrome P450 enzymes. This study aims to identify the key constituents in licorice which may affect these activities. Bioactivity assay was combined with metabolic profiling to identify these compounds in several complex licorice extracts. Firstly, the inhibition potencies of 40 pure licorice compounds were tested using an liquid chromatography/tandem mass spectrometry cocktail method. Significant inhibitors of human P450 isozymes 1A2, 2C9, 2C19, 2D6, and 3A4 were then selected for examination of their structural features by molecular docking to determine their molecular interaction with several P450 isozymes. Based on the present in vitro inhibition findings, along with our previous in vivo metabolic studies and the prevalence of individual compounds in licorice extract, we identified several licorice constituents, viz ., liquiritigenin, isoliquiritigenin, together with seven isoprenylated flavonoids and arylcoumarins, which could be key components responsible for the herb–drug interaction between cytochrome P450 and licorice. In addition, hydrophilic flavonoid glycosides and saponins may be converted into these P450 inhibitors in vivo . These studies represent a comprehensive examination of the potential effects of licorice components on the metabolic activities of P450 enzymes.
研究领域:
药理学
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分析化学
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生物化学
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药学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）