Engineering cytochrome P450 enzyme systems for biomedical and biotechnological applications

Li, Zhong; Jiang, Yuanyuan; Guengerich, F. Peter; Ma, Li; Li, Shengying; Zhang, Wei

doi:10.1074/jbc.rev119.008758

Cited by 118 publications

(93 citation statements)

References 169 publications

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“…Therefore, further investigation is needed. The cytochrome P450 (CYP) enzymes are membrane-bound hemoproteins that play a pivotal role in the natural product biosynthesis, drug metabolism, cellular metabolism and homeostasis [58, 59]. Anti-cancer drugs and herbs undergo metabolism mediated by CYP enzymes in the body to form numerous stable metabolites and this metabolism may significantly alter their therapeutic potential [60].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of DNA methylation and gene expression profiles in cholangiocarcinoma

Zhang

Meng

et al. 2019

Cancer Cell Int

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Background: The incidence of cholangiocarcinoma (CCA) has risen in recent years, and it has become a significant health burden worldwide. However, the mechanisms underlying tumorigenesis and progression of this disease remain largely unknown. An increasing number of studies have demonstrated crucial biological functions of epigenetic modifications, especially DNA methylation, in CCA. The present study aimed to identify and analyze methylationregulated differentially expressed genes (MeDEGs) involved in CCA tumorigenesis and progression by bioinformatics analysis. Methods:The gene expression profiling dataset (GSE119336) and gene methylation profiling dataset (GSE38860) were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and differentially methylated genes (DMGs) were identified using the limma packages of R and GEO2R, respectively. The MeDEGs were obtained by overlapping the DEGs and DMGs. Functional enrichment analyses of these genes were then carried out. Protein-protein interaction (PPI) networks were constructed using STRING and visualized in Cytoscape to determine hub genes. Finally, the results were verified based on The Cancer Genome Atlas (TCGA) database. Results:We identified 98 hypermethylated, downregulated genes and 93 hypomethylated, upregulated genes after overlapping the DEGs and DMGs. These genes were mainly enriched in the biological processes of the cell cycle, nuclear division, xenobiotic metabolism, drug catabolism, and negative regulation of proteolysis. The top nine hub genes of the PPI network were F2, AHSG, RRM2, AURKB, CCNA2, TOP2A, BIRC5, PLK1, and ASPM. Moreover, the expression and methylation status of the hub genes were significantly altered in TCGA. Conclusions:Our study identified novel methylation-regulated differentially expressed genes (MeDEGs) and explored their related pathways and functions in CCA, which may provide novel insights into a further understanding of methylation-mediated regulatory mechanisms in CCA.

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Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of DNA methylation and gene expression profiles in cholangiocarcinoma

Zhang

Meng

et al. 2019

Cancer Cell Int

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“…This is even more remarkable given their conserved fold that achieves substrate specificity through diverse active sites yet conserves a general mechanism of catalysis and preventing unregulated solvent access and diffusion of radicals. Because of their versatility and the unique oxygen chemistry they catalyze, many studies are focused on developing strategies to exploit P450s as biocatalysts for biotechnological and biomedical applications [ 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Dissecting the Cytochrome P450 OleP Substrate Specificity: Evidence for a Preferential Substrate

et al. 2020

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The cytochrome P450 OleP catalyzes the epoxidation of aliphatic carbons on both the aglycone 8.8a-deoxyoleandolide (DEO) and the monoglycosylated L-olivosyl-8.8a-deoxyoleandolide (L-O-DEO) intermediates of oleandomycin biosynthesis. We investigated the substrate versatility of the enzyme. X-ray and equilibrium binding data show that the aglycone DEO loosely fits the OleP active site, triggering the closure that prepares it for catalysis only on a minor population of enzyme. The open-to-closed state transition allows solvent molecules to accumulate in a cavity that forms upon closure, mediating protein–substrate interactions. In silico docking of the monoglycosylated L-O-DEO in the closed OleP–DEO structure shows that the L-olivosyl moiety can be hosted in the same cavity, replacing solvent molecules and directly contacting structural elements involved in the transition. X-ray structures of aglycone-bound OleP in the presence of L-rhamnose confirm the cavity as a potential site for sugar binding. All considered, we propose L-O-DEO as the optimal substrate of OleP, the L-olivosyl moiety possibly representing the molecular wedge that triggers a more efficient structural response upon substrate binding, favoring and stabilizing the enzyme closure before catalysis. OleP substrate versatility is supported by structural solvent molecules that compensate for the absence of a glycosyl unit when the aglycone is bound.

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“…CYPs are predominantly expressed in the liver, and play important roles in biosynthetic pathways for natural products, drug metabolism, and degradation of xenobiotics. 17,18 Treatment with ZnO QDs induced dysregulation of Cyp2b10, Cyp2b13, Cyp2c40, Cyp4a12b and Cyp4a32 genes in the liver. CYP1, CYP2 and CYP3 families mediated metabolism of xenobiotics, and excess expression of related genes suggested that the mice were in a stressed condition.…”

Section: Discussionmentioning

confidence: 99%

<p>Gene Expression Profiling of the Liver and Lung in Mice After Exposure to ZnO Quantum Dots</p>

Yang¹,

Li²,

Lin³

et al. 2020

IJN

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Introduction: ZnO quantum dots (QDs) have drawn much attention recently as they are Cd-free, low-cost, and have excellent optical properties. With the expanded production and application of ZnO nanoparticles, concerns about their potential toxicity have also been raised. Materials and Methods: We used RNA sequencing (RNA-seq) to analyze the global gene expression of liver and lung tissues after ZnO QDs treatment. Differentially expressed genes (DEGs) were screened, with a fold change >1.5 and padj <0.05. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed, and padj <0.05 was considered significantly enriched. The RNA-seq results were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Results: A total of 47 and 218 genes were significantly differentially expressed in the liver and lung. Eight GO terms were enriched in the liver and lung, and retinol metabolism and the peroxisome proliferator-activated receptor (PPAR) signaling pathway were shared in different tissues. Discussion: According to DEGs and pathway enrichment analyses, inflammation might be induced in liver and lung tissues after intravenous injection of ZnO QDs. These findings will be helpful for future research and application of ZnO QDs.

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Engineering cytochrome P450 enzyme systems for biomedical and biotechnological applications

Cited by 118 publications

References 169 publications

Comprehensive analysis of DNA methylation and gene expression profiles in cholangiocarcinoma

Comprehensive analysis of DNA methylation and gene expression profiles in cholangiocarcinoma

Dissecting the Cytochrome P450 OleP Substrate Specificity: Evidence for a Preferential Substrate

<p>Gene Expression Profiling of the Liver and Lung in Mice After Exposure to ZnO Quantum Dots</p>

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