JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Qian Yang,Jinlei Zhu,Xia Yang,Tian Wei,Min Lv,Yongfeng Li
Digitaria ciliaris var. chrysoblephara is a xerophytic weed severely invading rice fields along with the application of rice mechanical direct seeding technology in China. This study identified one resistant population (M5) with an Ile-1781-Leu substitution in ACCase1 showing broad-spectrum resistance to three chemical classes of ACCase-inhibiting herbicides, including metamifop, cyhalofop-butyl, fenoxaprop-p-ethyl, haloxyfop-p-methyl, clethodim, sethoxydim, and pinoxaden. The other two populations, M2 and M4, without any resistance-responsible mutations, only exhibited resistance to aryloxyphenoxypropionate (APP) herbicides cyhalofop-butyl and fenoxaprop-p-ethyl. Pre-treatment with the cytochrome P450 monooxygenase (P450) inhibitor PBO significantly reduced the cyhalofop-butyl resistance by 43% in the M2 population. Pre-emergence weed control with soil-applied herbicides, such as pretilachlor, pendimethalin, and oxadiazon, can effectively inhibit the germination and growth of D. ciliaris var. chrysoblephara. The present study reported a xerophytic weed species invading rice fields featuring broad-spectrum resistance to ACCase-inhibiting herbicides as a result of Ile-1781-Leu mutation of ACCase. Both target- and P450-involved non-target-site mechanisms may be contributing to resistance in D. ciliaris var. chrysoblephara species.
研究领域:
植物学
·
遗传学
·
农学
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PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2024
·
IF 4.2
Zhengsheng Mao,Youjia Yu,Gen Ba,Hongmei Zhao,Qifang Shi,Yue Cao,Weiran Xie,Jinsong Zhang,Hao Sun,Feng Chen
Diquat (DQ) poisoning has garnered attention in recent years, primarily due to the rising incidence of cases worldwide, coupled with the absence of a viable antidote for its treatment. Despite the fact that diquat monopyridone (DQ-M) has been identified as a significant metabolite of DQ, the enzyme responsible for its formation remains unknown. In this study, we have identified aldehyde oxidase (AOX) as a vital enzyme involved in DQ oxidative metabolism . The metabolism of DQ to DQ-M was significantly inhibited by AOX inhibitors including raloxifene and hydralazine . The source of oxygen incorporated into DQ-M was proved to be from water through a H2 18 O incubation experiment which further corroborated DQ-M formation via AOX metabolism. The product of DQ-M in vitro generated by fresh rat tissues co-incubation was consistent with its AOX expression. The result of the molecular docking analysis of DQ and AOX protein showed that DQ is capable of binding to AOX. Furthermore, the cytotoxicity of DQ was significantly higher than DQ-M at the same concentration tested in six cell types. This work is the first to uncover the involvement of aldehyde oxidase, a non-cytochrome P450 enzyme, in the oxidative metabolic pathway of diquat, thus providing a potential target for the development of detoxification treatment.
研究领域:
药理学
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毒理学
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PubMed
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BIOORGANIC CHEMISTRY
·
2026
·
IF 4.7
Yuxin Shen,Jun Wu,Lu Cao,Shiqi Jiang,Yan Chen,Ren-ai Xu,Ling Ji
This study systematically elucidated the metabolic characteristics of the hepatocellular carcinoma (HCC) therapeutic drug donafenib and its drug–drug interaction (DDI) with the antiviral agent arbidol. In vitro phenotyping assays using chemical inhibitors and recombinant CYP enzymes identified CYP3A4 as the primary enzyme catalyzing donafenib N-oxide formation. This was further confirmed by in vivo pharmacokinetic experiments in Cyp3a1/2 knockout rats, where AUC (0-t) , AUC (0-∞) and t 1/2 of donafenib were increased compared with wild-type rats. Additionally, the study was the first to report the effects of 8 CYP3A4 variants (CYP3A4.39-.46) on donafenib metabolism. Among these, 7 variants (except CYP3A4.42) had reduced metabolic catalytic activity compared to wild-type CYP3A4.1, and the intrinsic clearance (CL int ) was 8.60%–97.89% of that of CYP3A4.1. Subsequently, the potential mechanism of enzymatic activity changes was investigated through molecular docking. Finally, the study found that arbidol significantly inhibited donafenib metabolism, where the half-maximum inhibitory concentration (IC 50 ) value of arbidol was 3.16 ± 0.09 μM in rat liver microsome (RLM) and 36.38 ± 1.23 μM in human liver microsome (HLM), respectively. Animal studies have shown that the pharmacokinetics of donafenib were significantly altered following co-administration of arbidol in Sprague-Dawley rats. The results indicated that the AUC (0-t) , AUC (0-∞) and C max of donafenib were increased by 1.19-, 1.05- and 0.54-fold, respectively. Moreover, T max was prolonged by 68.42%, while CL z /F was decreased by 53.85%. These results provided critical references for clinical dosage adjustment, facilitating personalized treatment and reducing the risk of adverse reactions.
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ACS Catalysis
·
2026
·
IF 13.6
Xing Yu,Peng Deng,Sheng Gu,Bu-Bing Zeng,Hui-Lei Yu,Jian-He Xu,Zhi-Jun Zhang
Direct asymmetric α-C−H bond amination of carboxylic acids is an attractive route to optically active α-amino acids from inexpensive, renewable starting materials. However, traditional chemical methods suffer from expensive catalysts and environmental concerns, while recently developed multienzyme cascades are limited by complex auxiliary enzyme requirements and narrow substrate scope. Here, we report an engineered P450 peroxygenase (P450CLA-M5) with enhanced overoxidation promiscuity that enables the direct conversion of fatty acids to α-keto acids. Coupling this enzyme with d-amino acid dehydrogenase and formate dehydrogenase establishes a biocatalytic cascade for the C−H amination of fatty acids to d-amino acids. Saturated, unsaturated, and aromatic fatty acids were converted to the corresponding d-amino acids with yields up to 94% and >99% ee. Specifically, the yield of d-2-aminodecanoic acid represents a 15-fold improvement over previous biocatalytic approaches. This work demonstrates how engineering increased enzyme promiscuity can enhance cascade efficiency for the synthesis of valuable chiral d-amino acids from renewable feedstocks.
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Chemistry-An Asian Journal
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2012
·Vol. 7
·期 10
·2253-2257
·
IF 4.5
Xinrui Zhou,Xian Chen,Yaqin Jin,Istvan E. Markó
Graphical A mild process for the selective oxidation of sulfides is in great demand. Therefore, probing the mechanism underlying the biological oxidation of sulfides under ambient conditions may provide valuable insights for the development of such a reaction. Based on porphyrin models of P450 enzymes, evidence of two key intermediates, Int0 and Int1 , in this reaction is provided. A mild process for the selective oxidation of sulfides is in great demand. Therefore, probing the mechanism underlying the biological oxidation of sulfides under ambient conditions may provide valuable insights for the development of such a reaction. Based on porphyrin models of P450 enzymes, evidence of two key intermediates, Int0 and Int1 , in this reaction is provided. Spectroscopic studies indicated the formation of a hydroperoxide-iron(III) species ( Int0 ) upon addition of H 2 O 2 . This intermediate proved to be highly selective for sulfoxide production. By contrast, a defined porphyrin oxoiron(IV) cation radical ( Int1 ) directly reacted with sulfoxides, leading selectively to the corresponding sulfones. Interestingly, the available sulfoxides reversibly act as a new axial ligand for Int0 forming a more active species Int0 SO . The amount of Int0 increased in the presence of alkyl, aryl, or aromatic sulfides, while Int1 formed in the absence of these sulfides. Thus, sulfoxides and sulfones would selectively form under conditions that favor the corresponding intermediates, which elucidate the biological oxidation pathway.
研究领域:
生物化学
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催化化学
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CHEMICO-BIOLOGICAL INTERACTIONS
·
2022
·
IF 5.168
Zhen Wang,Xiaoyu Wang,Zhe Wang,Xin Lv,Hang Yin,Wei Li,Wenli Li,Lili Jiang,Yong Liu
Thymoquinone is a main bioactive compound of Nigella sativa L. ( N.sativa ), which has been used for clinical studies in the treatment of seizures due to its beneficial neuroprotective activity and antiepileptic effects. It has been evidenced that thymoquinone may inhibit the activity of cytochrome P450 2C9 (CYP2C9). However, little is known about the effect of thymoquinone or N.sativa on the pharmacokinetic behavior of phenytoin , a second-line drug widely used in the management of status epilepticus . In this study, we systematically investigated the risk of the potential pharmacokinetic drug interaction between thymoquinone and phenytoin. The inhibitory effect of thymoquinone on phenytoin hydroxylation activity by CYP2C9 was determined using UPLC-MS/MS by measuring the formation rates for p -hydroxyphenytoin ( p -HPPH). The potential for drug-interaction between thymoquinone and phenytoin was quantitatively predicted by using in vitro-in vivo extrapolation (IVIVE). Our data demonstrated that thymoquinone displayed effective inhibition against phenytoin hydroxylation activity. Enzyme kinetic studies showed that thymoquinone exerted a competitive inhibition against phenytoin hydroxylation with a K i value of 4.45 ± 0.51 μM. The quantitative prediction from IVIVE suggested that the co-administration of thymoquinone (>18 mg/day) or thymoquinone-containing herbs ( N.sativa > 1 g/day or N.sativa oil >1 g/day) might result in a clinically significant herb-drug interactions. Additional caution should be taken when thymoquinone or thymoquinone-containing herbs are co-administered with phenytoin, which may induce unexpected potential herb-drug interactions via the inhibition of CYP2C9.
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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高影响因子
PLoS One
·
2013
·Vol. 8
·期 3
·e59882
·
IF 3.73
Lushan Yu,Yan Jiang,Lu Wang,Rong Sheng,Yongzhou Hu,Su Zeng
BYZX, [(E)-2-(4-((diethylamino)methyl)benzylidene)-5,6-dimethoxy-2,3-dihydroinden-one], belongs to a series of novel acetylcholinesterase inhibitors and has been synthesized as a new chemical entity for the treatment of Alzheimer’s disease symptoms. When incubated with human liver microsomes (HLMs), BYZX was rapidly transformed into its metabolites M1, M2, and M3. The chemical structures of these metabolites were identified using liquid chromatography tandem mass spectrometry and nuclear magnetic resonance, which indicated that M1 was an N -desethylated and C = C hydrogenation metabolite of BYZX. M2 and M3 were 2 precursor metabolites, which resulted from the hydrogenation and desethylation of BYZX, respectively. Further studies with chemical inhibitors and human recombinant cytochrome P450s (CYPs), and correlation studies were performed. The results indicated that the N -desethylation of BYZX and M2 was mediated by CYP3A4 and CYP2C8. The reduced form of β-nicotinamide adenine dinucleotide 2′-phosphate was involved in the hydrogenation of BYZX and M3, and this reaction occurred in the HLMs and in the human liver cytosol. The hydrogenation reaction was not inhibited by any chemical inhibitors of CYPs, but it was significantly inhibited by some substrates of α,β-ketoalkene C = C reductases and their inhibitors such as benzylideneacetone, dicoumarol, and indomethacin. Our results suggest that α,β-ketoalkene C = C reductases may play a role in the hydrogenation reaction, but this issue requires further clarification.
研究领域:
药理学
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生物化学
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阿尔茨海默病研究
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2021
·
IF 4.36
Yuanyuan Chai,Yunxia Xu,Ziyin Xia,Xin Huang,Luyong Zhang,Zhenzhou Jiang
Ethnopharmacological relevance Zhuanggu Guanjie Pill (ZGGJP), a modern Chinese medicine formula, is composed of 12 herbs and has been used to treat osteoporosis in China for almost 30 years. However, no in vivo study of the influences of ZGGJP on the cytochrome P450 (CYP) activities have been reported. Aim of the study The aim of this study was to evaluate the effects of ZGGJP on the activities and the mRNA expression of CYP enzymes (CYP1A2, CYP2B6 , CYP2C9 , CYP2C19 , CYP2D6 , CYP2E1 and CYP3A) and their corresponding nuclear receptor levels in rats. Materials and methods After 7 days oral treatment of ZGGJP at low- and high-dose, cocktail solution was given to rats. Blood samples were collected at series of time points. The plasma concentrations of probe drugs and their corresponding metabolites were determined by UPLC-MS/MS. The influence of ZGGJP on the activities of seven CYPs were evaluated the metabolic ratios (C max and AUC 0-t) for metabolites/probe drugs. In addition, the effects of ZGGJP on the mRNA expression of CYPs and their corresponding nuclear receptors in rat liver were evaluated by real-time PCR. Results ZGGJP showed significant inductive effects on CYP1A2 and CYP2B6 of both male and female rats. The influence of ZGGJP on CYP2C9 and CYP3A showed gender difference. ZGGJP could induce the activities of CYP2C9 and CYP3A in female rats, but have no influence on the activities in male rats. ZGGJP had no effects on CYP2D6, CYP2C19 and CYP2E1. The mRNA expression results of CYPs were in accordance with the pharmacokinetic results. The mRNA expression levels of constitutive androstane receptor (CAR) and vitamin D receptor (VDR) were increased significantly in female rats at high dosage, but no significant changes were observed in male rats. Conclusion ZGGJP had inductive effects on CYP1A2 and CYP2B6 in both male and female rats. The results showed that ZGGJP could induce the activities of CYP2C9 and CYP3A in female rats, but had no effect in male rats. This may suggest that the influence of ZGGJP on CYP2C9 and CYP3A exhibit gender difference. The inductive effects of ZGGJP on the activities of CYPs, exhibiting gender difference, may be regulated by CAR and VDR. Therefore, co-administration of ZGGJP with other drugs, especially using CYP2C9 and CYP3A substrates in females, may need dose adjustment to avoid herb-drug interaction.
研究领域:
民族药理学
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药物代谢
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分子生物学
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高影响因子
International Journal of Environmental Research and Public Health
·
2022
·Vol. 19
·期 24
·17012
·
IF 4.614
Dingfan Hu,Juan Wu,Luosheng Fan,Shunyao Li,Rong Jia
Complex bacteria communities that comprisedBrevibacillussp. (M1) andAchromobactersp. (M2) with effective abilities of degrading decabromodiphenyl ether (BDE-209) were investigated for their degradation characteristics and mechanisms under aerobic conditions. The experimental results indicated that 88.4% of 10 mg L−1BDE-209 could be degraded after incubation for 120 h under the optimum conditions of pH 7.0, 30 °C and 15% of the inoculation volume, and the addition ratio of two bacterial suspensions was 1:1. Based on the identification of BDE-209 degradation products via liquid chromatography–mass spectrometry (LC–MS) analysis, the biodegradation pathway of BDE-209 was proposed. The debromination, hydroxylation, deprotonation, breakage of ether bonds and ring-opening processes were included in the degradation process. Furthermore, intracellular enzymes had the greatest contribution to BDE-209 biodegradation, and the inhibition of piperyl butoxide (PB) for BDE-209 degradation revealed that the cytochrome P450 (CYP) enzyme was likely the key enzyme during BDE-209 degradation by bacteria M (1+2). Our study provided alternative ideas for the microbial degradation of BDE-209 by aerobic complex bacteria communities in a water system.Keywords:decabromodiphenyl ether;complex bacteria community;degradation efficiency;pathway;crude enzyme;cytochrome P450
研究领域:
环境科学
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微生物学
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生物技术
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PubMed
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 8
·3472
·
IF 4.6
Chao Shi,Yan Wang,Xiangge Tian,Xia Lv,Yue An,Jing Ning,Xiulan Xin,Li Dai,Xiaochi Ma,Lei Feng
Cytochrome P450 1A is one of the vital subfamilies of heme-containing cytochrome P450 enzymes belonging to an important exogenous metabolizing CYP in human. The abnormal of endoplasmic reticulum (ER) may directly affect the functional activity of ER-located CYP1A and be associated with the occurrence and development of various diseases. In the present study, we constructed a selective two-photon fluorescent probeERNMfor rapid and visual detection of endogenous CYP1A that was localized in the ER.ERNMcould target the ER and detect the enzymatically active CYP1A in living cells and tissues. The monitoring ability ofERNMfor the fluctuations in functionality level of CYP1A was confirmed using ER stressed A549 cell. Based on the ER-targeting two-photon probe for CYP1A, the close association of ER state and the functional activity of ER-locating CYP1A was confirmed, which would promote the deep understanding of the biofunction of CYP1A in various ER-related diseases.Keywords:cytochrome P450 1A;fluorescent probe;endoplasmic reticulum-targeting;enzymatically active probe;two-photon
研究领域:
生物化学
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分子生物学
·
药理学
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PubMed
高影响因子
JACS Au
·
2026
·
IF 8.5
Yu Qin,Huiling Liu,Yan Zhang,Fei Li,Zhiwei Deng,Zhengshan Luo,Yuhao Zhuang,Kai Fu,Zhenbo Yuan,Yijian Rao
Sustainable and scalable production of plant natural products remains a major challenge at the interface of synthetic biology, metabolic engineering, and drug discovery, often constrained by plant-membrane-bound cytochrome P450s. To overcome the bottleneck in P450-catalyzed methylenedioxy-bridge (MDB) formation, we designed a concise, modular Escherichia coli pathway to the alkaloid berberine that bypasses multiple native steps and enables high-level accumulation of the P450-dependent intermediate. We then implemented integrated engineering of CjCYP719A1, including expression optimization, structure-guided design, consensus mutagenesis, and machine learning, to obtain a variant with 8.9-fold higher activity and improved thermostability. This enabled a berberine titer of 353 mg/L in scaled-up preparations, the highest reported to date, demonstrating industrial potential. Furthermore, mechanistic studies reveal their improved catalytic activity and thermostability. Together, this work provides a practical framework for functional expression and systematic optimization of plant-derived P450s to enable efficient production of plant natural products in E. coli.
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ANALYTICAL CHEMISTRY
·
2026
·
IF 7.3
Yifan Li,Junbo Li,Yang Yang,Chunyi Wei,Yuting Song,Bo Jiang,Yunfei Xie,Wei Ji
Exploring the metabolic kinetics mediated by cytochrome P450 (CYP) enzymes is essential for understanding pharmacokinetic and toxicological mechanisms. However, real-time monitoring of CYP-mediated enzymatic reactions remains challenging for conventional techniques. Here, we report the first attempt to develop a surface-enhanced Raman scattering (SERS)-based analytical platform for the direct, real-time tracking of enzymatic metabolism and extraction of critical kinetic parameters. An in vitro CYP enzyme system was constructed to emulate hepatic microsomal activity, using pyrene (Pyr) as a model and polycyclic aromatic hydrocarbon (PAH) as the model substrate. Cetyltrimethylammonium bromide (CTAB)-induced Ag aggregates enabled simultaneous detection of Pyr (408 cm–1) and its metabolite 1-hydroxypyrene (1-OHPyr; 426/617 cm–1) directly within the reaction medium. The hydrophobic CTAB self-assembled monolayer enhanced analyte enrichment and suppressed protein interference, while the intrinsic Raman band of CTAB at 760 cm–1 served as a reliable internal standard for quantitative kinetic assessment. This platform allowed real-time monitoring of CYP-catalyzed oxidation of Pyr, yielding pseudo-first-order kinetics (k = 0.00501 min–1) and the Michaelis constant Km of 13 μM. Furthermore, inhibition studies identified CYP1A2 as the principal isoform responsible for Pyr metabolism, corroborated by the potent inhibitory activity of α-naphthoflavone (with calculated IC50). To our knowledge, this work represents the first instance of SERS for time-resolved monitoring of CYP-mediated metabolism, expanding its capability from static detection to dynamic biochemical analysis. The proposed strategy provides a simple, label-free, and time-resolved approach for enzyme kinetic studies, inhibitor screening, and metabolic analysis.
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