PLANT JOURNAL
·
2025
·Vol. 121
·期 3
·e17248
·
IF 5.7
Xiaomeng Zhang,Xinquan Tian,Junyu Luo,Xiaoyang Wang,Shoupu He,Gaofei Sun,Ruidan Dong,Panhong Dai,Xiao Wang,Zhaoe Pan,Baojun Chen,Daowu Hu,Liru Wang,Baoyin Pang,Aishuang Xing,Guoyong Fu,Baoquan Wang,Jinjie Cui,Lei Ma,Xiongming Du
SUMMARY Phloridzin has various functions, including antioxidant properties and the treatment of diabetes, and has long been used in pharmaceutical and physiological research. The glycosylation of phloretin is a key step in the biosynthesis of phloridzin. In this study, a genome-wide association study (GWAS) based on phloridzin content was applied, and the key gene GhUGT88F3 for phloridzin-specific biosynthesis was identified in cotton. A single-base deletion in GhUGT88F3 in haplotype I caused a frameshift mutation, leading to premature translation termination and a significant reduction in phloridzin content. Molecular docking revealed important amino acid residues for GhUGT88F3's UDP-glucose transfer activity. Additionally, the transcription factor GhMYB330 was found to positively regulate GhUGT88F3 expression through population transcriptome analysis and LUC experiment. Moreover, phloridzin content was significantly elevated in both GhUGT88F3 and GhMYB330 overexpression transgenic plants. This study expands the diversity of UDP-glucosyltransferases in plants and offers a potential strategy for the sustainable production of bioactive compounds with therapeutic potential.
研究领域:
植物学
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遗传学
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生物化学
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Simin Liu,Jiamei Liu,Linguo Zhao,Jianjun Pei
Glycosylation, one of the most common and significant modifications in nature, has prompted the development of a cellobiose phosphorolysis route for glycosylation in vivo. However, the process of glycosylation is hampered by the notably low conversion rate of cellobiose. In this work, regulation of the carbon source supply by changing the ratio of glucose to cellobiose improved the conversion rate of cellobiose, resulting in enhancing the efficiency of glycosylation and the production of vitexin. Moreover, three genes (pgm, agp, and ushA) involved in the degradation of UDP-glucose were knocked out to relieve the degradation and diversion of the cellobiose phosphorolysis route. Finally, through the optimization of conversion conditions, we observed a continuous enhancement in cellobiose conversion rate and vitexin production in BL21ΔushAΔagp-TcCGT-CepA, corresponding to an increased concentration of added glucose. The maximum production of vitexin reached 2228 mg/L with the addition of 2 g/L cellobiose and 6 g/L glucose, which was 312% of that in BL21-TcCGT-CepA with the addition of 2 g/L cellobiose. The conversion rate of cellobiose in BL21ΔushAΔagp-TcCGT-CepA reached 88%, which was the highest conversion rate of cellobiose to date. Therefore, this study presents a cost-effective and efficient method to enhance the conversion rate of cellobiose during the glycosylation process.
研究领域:
生物化学
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代谢工程
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DOI
PubMed
高影响因子
BIORESOURCE TECHNOLOGY
·
2025
·
IF 9
Jishan Li,Muyang Li,Chenyu Yong,Zhemin Zhou,Laichuang Han,Zhongmei Liu
UDP-glucose (UDPG), a nucleoside diphosphate sugar, is an important sugar donor for the biosynthesis of various glycoside compounds. Sucrose synthase (SuSy) can catalyze the synthesis of high-value UDPG from the cost-effective sucrose. By redesigning the substrate-binding pocket of SuSy in Denitrovibrio acetiphilus DSM 12809, a variant with 8.1-fold increased activity was generated in this study. Structural analysis revealed that the synergistic effect of the newly introduced hydrogen bonds and salt bridges was crucial for the enhanced activity. The yield of UDPG reached 127.6 g/L/h using this variant for catalysis. Moreover, when cascaded with glycosyltransferase for salidroside production, the yield of salidroside increased 2.7-fold, and a UDP recycling number of 3.2 was achieved. These results provide technical support for the industrial application of SuSy in the biosynthesis of nucleotide sugars and glycosides.
研究领域:
生物化学
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工业微生物学
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PubMed
高影响因子
PLANT JOURNAL
·
2021
·Vol. 109
·期 6
·1489-1506
·
IF 6.486
Mingyue Zhao,Jieyang Jin,Jingming Wang,Ting Gao,Yu Luo,Tingting Jing,Yutong Hu,Yuting Pan,Mengqian Lu,Wilfried Schwab,Chuankui Song
SUMMARY Cold and drought stress are the most critical stresses encountered by crops and occur simultaneously under field conditions. However, it is unclear whether volatiles contribute to both cold and drought tolerance, and if so, by what mechanisms they act. Here, we show that airborne eugenol can be taken up by the tea ( Camellia sinensis ) plant and metabolized into glycosides, thus enhancing cold and drought tolerance of tea plants. A uridine diphosphate (UDP)-glucosyltransferase, UGT71A59, was discovered, whose expression is strongly induced by multiple abiotic stresses. UGT71A59 specifically catalyzes glucosylation of eugenol glucoside in vitro and in vivo . Suppression of UGT71A59 expression in tea reduced the accumulation of eugenol glucoside, lowered reactive oxygen species (ROS) scavenging capacity, and ultimately impaired cold and drought stress tolerance. Exposure to airborne eugenol triggered a marked increase in UGT71A59 expression, eugenol glucoside accumulation, and cold tolerance by modulating ROS accumulation and CBF1 expression. It also promoted drought tolerance by altering abscisic acid homeostasis and stomatal closure. CBF1 and CBF3 play positive roles in eugenol-induced cold tolerance and CBF2 may be a negative regulator of eugenol-induced cold tolerance in tea plants. These results provide evidence that eugenol functions as a signal in cold and drought tolerance regulation and shed new light on the biological functions of volatiles in the response to multiple abiotic stresses in plants.
研究领域:
植物学
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分子生物学
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环境科学
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DOI
高影响因子
ENZYME AND MICROBIAL TECHNOLOGY
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2025
·
IF 3.7
Chen-Xin Guo,Jiyan Li,Yu Wang,Tang Li,Heng Yin
Stevia rebaudiana , a perennial herb, is recognized not only for its sweet steviol glycosides but also for its rich flavonoid content, which confer pharmacological properties including anti-inflammatory, antimicrobial, and anticancer activities. However, the enzymatic basis underlying flavonoid modification in S. rebaudiana remains poorly understood. In this study, we identified, cloned, and heterologously expressed a novel flavonoid glycosyltransferase gene, SrUGT72B1 in E. coli . The recombinant SrUGT72B1 catalyzed the glycosylation of multiple flavonoids using UDP-glucose as the primary sugar donor, and exhibited broad substrate promiscuity toward apigenin, luteolin, phloretin and kaempferol. In addition to UDP-glucose, SrUGT72B1 also accepted UDP-xylose and UDP-rhamnose, with UDP-glucose exhibiting the highest catalytic efficiency. Biochemical characterization revealed that the enzyme functions optimally at pH 9.0 and 50 °C. Notably, SrUGT72B1 demonstrates regioselective 5-O-glycosylation toward apigenin, a rare activity among plant glycosyltransferases. Molecular docking and molecular dynamics simulations provided structural insights into this unique regioselectivity and substrate recognition. Together, these findings establish SrUGT72B1 as a previously uncharacterized flavonoid 5-O-glycosyltransferase, expanding the functional landscape of plant UGTs and offering potential applications in the biosynthesis of value-added flavonoid glycosides.
研究领域:
植物学
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生物化学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Shichao Xiao,Hang Yin,Xin Lv,Zhen Wang,Lili Jiang,Yangliu Xia,Yong Liu
Darolutamide is a potent second-generation, selective nonsteroidal androgen receptor inhibitor (ARI), which has been approved by the US Food and Drug Administration (FDA) in treating castrate-resistant, non-metastatic prostate cancer (nmCRPC). Whether darolutamide affects the activity of UDP-glucuronosyltransferases (UGTs) is unknown. The purpose of the present study is to evaluate the inhibitory effect of darolutamide on recombinant human UGTs and pooled human liver microsomes (HLMs), and explore the potential for drug-drug interactions (DDIs) mediated by darolutamide through UGTs inhibition. The product formation rate of UGTs substrates with or without darolutamide was determined by HPLC or UPLC-MS/MS to estimate the inhibitory effect and inhibition modes of darolutamide on UGTs were evaluated by using the inhibition kinetics experiments. The results showed that 100 μM darolutamide exhibited inhibitory effects on most of the 12 UGTs tested. Inhibition kinetic studies of the enzyme revealed that darolutamide noncompetitively inhibited UGT1A1 and competitively inhibited UGT1A7 and 2B15, with the K i of 14.75 ± 0.78 μM, 14.05 ± 0.42 μM, and 6.60 ± 0.08 μM, respectively. In particular, it also potently inhibited SN-38, the active metabolite of irinotecan, glucuronidation in HLMs with an IC 50 value of 3.84 ± 0.46 μM. In addition, the in vitro-in vivo extrapolation (IVIVE) method was used to quantitatively predict the risk of darolutamide-mediated DDI via inhibiting UGTs. The prediction results showed that darolutamide may increase the risk of DDIs when administered in combination with substrates of UGT1A1, UGT1A7, or UGT2B15. Therefore, the combined administration of darolutamide and drugs metabolized by the above UGTs should be used with caution to avoid the occurrence of potential DDIs.
研究领域:
药理学
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临床医学
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生物化学
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DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2016
·
IF 3.847
Xia Lv,Xin-Xin Wang,Jie Hou,Zhong-Ze Fang,Jing-Jing Wu,Yun-Feng Cao,Shu-Wen Liu,Guang-Bo Ge,Ling Yang
Tolcapone and entacapone are two potent catechol- O -methyltransferase (COMT) inhibitors with a similar skeleton and displaying similar pharmacological activities . However, entacapone is a very safe drug used widely in the treatment of Parkinson's disease , while tolcapone is only in limited use for Parkinson's patients and needs careful monitoring of hepatic functions due to hepatotoxicity. This study aims to investigate and compare the inhibitory effects of entacapone and tolcapone on human UDP-glucosyltransferases (UGTs), as well as to evaluate the potential risks from the view of drug-drug interactions (DDI). The results demonstrated that both tolcapone and entacapone exhibited inhibitory effects on UGT1A1, UGT1A7, UGT1A9 and UGT1A10. In contrast to entacapone, tolcapone exhibited more potent inhibitory effects on UGT1A1, UGT1A7, and UGT1A10, while their inhibitory potentials against UGT1A9 were comparable. It is noteworthy that the inhibition constants ( K i ) of tolcapone and entacapone against bilirubin- O -glucuronidation in human liver microsomes (HLM) are determined as 0.68 μM and 30.82 μM, respectively, which means that the inhibition potency of tolcapone on UGT1A1 mediated bilirubin- O -glucuronidation in HLM is much higher than that of entacapone. Furthermore, the potential risks of tolcapone or entacapone via inhibition of human UGT1A1 were quantitatively predicted by the ratio of the areas under the plasma drug concentration-time curve (AUC). The results indicate that tolcapone may result in significant increase in AUC of bilirubin or the drugs primarily metabolized by UGT1A1, while entacapone is unlikely to cause a significant DDI through inhibition of UGT1A1.
研究领域:
药理学
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生物化学
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临床医学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2011
·Vol. 26
·期 1
·86-90
·
IF 1.878
Rui-Hua Dong,Zhong-Ze Fang,Liang-Liang Zhu,Si-Cheng Liang,Guang-Bo Ge,Ling Yang,Ze-Yuan Liu
UDP-glucuronosyltransferases (UGTs), the most important phase II drug metabolizing enzymes (DMEs), could metabolize many drugs and various endogenous substances including bilirubin, steroid hormones, thyroid hormones, bile acids and fat-soluble vitamins. Evaluation of the inhibitory effects of compounds on UGTs is clinically important because inhibition of UGT isoforms could not only result in serious drug–drug interactions (DDIs), but also induce metabolic disorders of endogenous substances. The aim of the present study was to investigate the inhibitory effects of carvacrol on major UGT isoforms. The results showed that carvacrol could inhibit the activity of UGT1A9 with negligible effects on other UGT isoforms. When 4-methylumbelliferone (4-MU) was used as a nonspecific probe substrate and recombinant UGT enzymes were utilized as an enzyme resource, the inhibition of UGT1A9 was best fit to the competitive type and the inhibition kinetic parameter ( K i ) was calculated to be 5.7 µ m . Furthermore, another specific probe substrate, propofol, was employed to determine the inhibitory kinetics of UGT1A9, and the results demonstrated that the inhibitory type was noncompetitive. The inhibition kinetic parameter ( K i ) was determined to be 25.0 µ m . Because this substrate-dependent inhibition of UGT1A9 might confuse the in vitro–in vivo extrapolation, these in vitro inhibition kinetic parameters should be interpreted with special caution. Copyright © 2011 John Wiley & Sons, Ltd.
研究领域:
药理学
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生物化学
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PubMed
高影响因子
PHARMAZIE
·
2012
·Vol. 67
·期 8
·715-717
·
IF 1.006
Fu Jian-Fang,Ren Qin-You,Zhang Nan-Yan,Gao Bin,Tu Yan-Yang,Fu Guo-Qiang,Li Dao-Hai,Zhang Yong-Sheng
The aim of the present study was to investigate the inhibitory potential of glimepiride towards important UDP-glucuronosyltransferase (UGT) isoforms in human liver, which play a key role in the elimination of drugs. The recombinant UGT enzymes were used as enzyme source, and a nonspecific
substrate 4-methylumbelliferone (4-MU) was utilized as substrate. The results showed that 100 μM of glimepiride inhibited UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B7 and UGT2B15 by 54.7%, 43.1%, 100%, 70.5%, 32.7 and 37.2%, respectively. Given that glimepiride exhibited strong inhibition towards
UGT1A6, further inhibitory kinetic behaviour was determined. Glimepiride exerted concentration-dependent inhibition towards UGT1A6. Both Dixon and Lineweaver-Burk plots demonstrated that inhibition of UGT1A6 was best fit for noncompetitive inhibition type, and the inhibition kinetic parameter
(Ki) was calculated to be 59.8 μM. Given that UGT1A6 plays a key role in detoxification of many drugs, more attention should be given when glimepiride was co-administered with the drugs mainly undergoing UGT1A6-mediated metabolism.
研究领域:
药理学
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临床医学
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产品关联
DOI
高影响因子
JOURNAL OF PHARMACEUTICAL SCIENCES
·
2016
·
IF 2.641
Hua Sun,Tianpeng Zhang,Zhufeng Wu,Baojian Wu
ABSTRACT: In this study, we aimed to determine the modulatory effects of warfarin (an extensively used anticoagulant drug) and its metabolites on UDP-glucuronosyltransferase (UGT) activity and to assess the potential of warfarin to alter the pharmacokinetics of zidovudine (AZT). The effects of warfarin and its metabolites on glucuronidation were determined using human and rat liver microsomes (HLM and RLM) as well as expressed UGTs. The mechanisms of warfarin–UGT interactions were explored through kinetic characterization and modeling. Pharmacokinetic studies with rats were performed to evaluate the potential of warfarin to alter the pharmacokinetics of AZT. We found that warfarin was an effective modifier of a panel of UGT enzymes. The effects of warfarin on glucuronidation were inhibitory for UGT1A1, 2B7, and 2B17, but activating for UGT1A3. Mixed effects were observed for UGT1A7 and 1A9. Consistent with its inhibitory effects on UGT2B7 activity, warfarin inhibited AZT glucuronidation in HLM ( K i = 74.9–96.3 μM) and RLM ( K i = 190–230 μM). Inhibition of AZT glucuronidation by UGT2B7, HLM, and RLM was also observed with several hydroxylated metabolites of warfarin. Moreover, the systemic exposure (AUC) of AZT in rats was increased by a 1.5- to 2.1-fold upon warfarin coadministration. The elevated AUC was associated with suppressed glucuronidation that was probably attained through a combined action of warfarin and its hydroxylated metabolites. In conclusion, the activities of multiple UGT enzymes can be modulated by warfarin and the nature of modulation was isoform dependent. Also, pharmacokinetic interactions of zidovudine with warfarin were highly possible through inhibition of UGT metabolism.
研究领域:
药理学
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生物化学
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临床医学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Shuaibing Liu,Shiyu Zhao,XueXia Zhang,Eric Chun Yong Chan,Ziteng Wang,Hang Li,Xin Tian
Infigratinib, an oral FGFR inhibitor for advanced cholangiocarcinoma, yielded two active metabolites, BHS697 and CQM157, with similar receptor affinity. Our study characterized P450s that are responsible for the metabolism of infigratinib to its two major active metabolites, BHS697 and CQM157. In vitro inhibition of P450s and UGTs by infigratinib, BHS697 or CQM157 was further investigated. The unbound apparent K m values for metabolism of infigratinib to BHS697 by HLM, human recombinant CYP2C8, CYP2C19, CYP2D6 and CYP3A4 enzymes are 4.47, 0.65, 2.50, 30.6 and 2.08 μM, while V max values are 90.0 pmol/min/mg protein, 0.13, 0.027, 0.81, and 0.56 pmol/min/pmol protein, respectively. The unbound apparent K m value for metabolism of infigratinib to CQM157 by HLM is 0.049 μM, while the V max value is 0.32 pmol/min/mg protein respectively. In HLM, infigratinib displayed moderate inhibition of CYP3A4 and CYP2C19 and weak or negligible inhibition of other P450 isoforms. BHS697 exhibited weak inhibition of CYP2B6, CYP2C9, CYP2C19 and CYP3A4, and no inhibition of CYP2C8 and CYP2D6. CQM157 moderately inhibited CYP2C9 and CYP3A4, and weakly or negligibly inhibited other P450 isoforms. Regarding UGTs, infigratinib moderately inhibited UGT1A4 and weakly inhibited UGT1A1, respectively. BHS697 weakly inhibited UGT1A1. In contrast, CQM157 moderately inhibited both UGT1A1 and UGT1A4. Our findings provide novel insights into the metabolism of and potential DDIs implicating infigratinib.
研究领域:
药理学
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临床医学
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生物化学
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产品关联
DOI
PubMed
高影响因子
BIOPHARMACEUTICS & DRUG DISPOSITION
·
2024
·Vol. 45
·期 3
·149-158
·
IF 1.7
Yi Rong,Nanxi Li,Xuan Qiao,Lei Yang,Peng Han,Zhiyun Meng,Hui Gan,Zhuona Wu,Xiaoxia Zhu,Yunbo Sun,Shuchen Liu,Guifang Dou,Ruolan Gu
Icaritin is a prenylflavonoid derivative of the genus Epimedium (Berberidaceae) and has a variety of pharmacological actions. Icaritin is approved by the National Medical Products Administration as an anticancer drug that exhibits efficacy and safety advantages in patients with hepatocellular carcinoma cells. This study aimed to evaluate the inhibitory effects of icaritin on UDP-glucuronosyltransferase (UGT) isoforms. 4-Methylumbelliferone (4-MU) was employed as a probe drug for all the tested UGT isoforms using in vitro human liver microsomes (HLM). The inhibition potentials of UGT1A1 and 1A9 in HLM were further tested by employing 17β-estradiol (E2) and propofol (PRO) as probe substrates, respectively. The results showed that icaritin inhibits UGT1A1, 1A3, 1A4, 1A7, 1A8, 1A10, 2B7, and 2B15. Furthermore, icaritin exhibited a mixed inhibition of UGT1A1, 1A3, and 1A9, and the inhibition kinetic parameters (K i ) were calculated to be 3.538, 2.117, and 0.306 (μM), respectively. The inhibition of human liver microsomal UGT1A1 and 1A9 both followed mixed mechanism, with K i values of 2.694 and 1.431 (μM). This study provides supporting information for understanding the drug–drug interaction (DDI) potential of the flavonoid icaritin and other UGT-metabolized drugs in clinical settings. In addition, the findings provide safety evidence for DDI when liver cancer patients receive a combination therapy including icaritin.
研究领域:
药理学
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临床医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）