Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1069246 | ENA |
REPOSITORIES: ENA
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Project description:Digoxin extracted from the foxglove plant is a widely prescribed natural product for treating heart failure. It is listed as an essential medicine by the World Health Organization. However, how the foxglove plant synthesizes digoxin is mostly unknown, especially the cytochrome P450 sterol side chain cleaving enzyme (P450<sub>scc</sub>), which catalyzes the first and rate-limiting step. Here we identify the long-speculated foxglove P450<sub>scc</sub> through differential transcriptomic analysis. This enzyme converts cholesterol and campesterol to pregnenolone, suggesting that digoxin biosynthesis starts from both sterols, unlike previously reported. Phylogenetic analysis indicates that this enzyme arises from a duplicated cytochrome P450 CYP87A gene and is distinct from the well-characterized mammalian P450<sub>scc</sub>. Protein structural analysis reveals two amino acids in the active site critical for the foxglove P450<sub>scc</sub>'s sterol cleavage ability. Identifying the foxglove P450<sub>scc</sub> is a crucial step toward completely elucidating digoxin biosynthesis and expanding the therapeutic applications of digoxin analogs in future work.
2025-07-03 | MTBLS7993 | MetaboLights
Project description:This study provides transcriptomic insights into the degradation of butyl benzyl phthalate (BBP) by the white-rot fungus Pleurotus ostreatus. RNA-seq was conducted for samples treated with BBP alone or in combination with the cytochrome P450 inhibitor piperonyl butoxide (PB). The aim was to investigate the role of fungal enzymes in BBP metabolism. Differentially expressed genes related to xenobiotic degradation, oxidative stress, and P450 activity were identified and analyzed.
2025-08-01 | GSE302615 | GEO
Project description:Eukaryotic cytochrome P450 enzymes, generally colocalizing with their redox partner cytochrome P450 reductase (CPR) on the cytoplasmic surface of organelle membranes, often perform poorly in prokaryotic cells, whether expressed with CPR as a tandem chimera or free-floating individuals, causing a low titer of heterologous chemicals. To improve their biosynthetic performance in Escherichia coli, we here architecturally design self-assembled alternatives of eukaryotic P450 system using reconstructed P450 and CPR, and create a set of N-termini-bridged P450-CPR heterodimers as the counterparts of eukaryotic P450 system with N-terminus-guided colocalization. The covalent counterparts show superior and robust biosynthetic performance; the N-termini-bridged architecture is validated to improve the biosynthesis of both plant and human P450 systems. Furthermore, the architectural configuration of protein assemblies has an inherent effect on the biosynthesis of N-termini-bridged P450-CPR heterodimers. The results suggest that spatial architecture-guided protein assembly could serve as an efficient strategy for improving the biosynthesis of protein complexes, particularly those related to eukaryotic membranes, in prokaryotic and even eukaryotic hosts.
2024-10-29 | PXD056539 | Pride
Project description:NADPH-cytochrome P450 reductase (CPR) is important for the functions of many enzymes, such as microsomal cytochrome P450 (P450) monooxygenases and heme oxygenases. Two mouse models with deficient CPR expression in adults were recently generated in this laboratory: liver-Cpr-null (with liver-specific Cpr deletion) (Gu et al., J. Biol. Chem., 278, 25895–25901, 2003) and Cpr-low (with reduced CPR expression in all organs examined) (Wu et al. J. Pharmacol. Expt. Ther. 312, 35-43, 2005). The phenotypes included a reduced serum cholesterol level and an induction of hepatic P450 in both models, and hepatomegaly and fatty liver in the liver-Cpr-null mouse alone. Our aim was to identify hepatic gene-expression changes related to these phenotypes. Cpr-lox mice, which have normal CPR expression (Wu et al., Genesis, 36, 177-181, 2003.), were used as the control in microarray analysis. A detailed analysis of the gene-expression changes in lipid metabolism and transport pathways revealed potential mechanisms, such as an increased activation of constitutive androstane receptor (CAR) and a decreased activation of peroxisomal proliferators activated receptor alpha (PPAR-gamma) by precursors of cholesterol biosynthesis, that underlie common changes (e.g., induction of multiple P450s and inhibition of genes for fatty acids metabolism) in response to CPR-loss in the two mouse models. Moreover, we also uncovered model-specific gene-expression changes, such as the induction of a lipid translocase (CD36 antigen) and the suppression of carnitine O-palmitoyltransferase 1 (CPT1a) and acyl-CoA synthetase long-chain family member 1 (Acsl1), that are potentially responsible for the severe hepatic lipidosis observed in liver-Cpr-null, but not Cpr-low mice. Keywords = Cytochrome P450 Keywords = NADPH-cytochrome P450 reductase Keywords = transgenic mice Keywords = liver Keywords = nuclear receptor Keywords: other
2005-07-16 | GSE2362 | GEO
Project description:Microarray analysis to examine the relationship between hepatic phenotype and changes in gene expression in cytochrome P450 reductase (CPR) null mice. Keywords: ordered
2004-07-11 | GSE1468 | GEO