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2 Publications visible to you, out of a total of 2
Co-expression of cytochrome P450 reductases modulates the activity and selectivity of human cytochrome P450 enzymes transiently expressed in Nicotiana benthamiana

Abstract (Expand)

The transient co-expression of various redox partners affects the efficiency of human hepatic cytochrome P450 enzymes (CYP) in a plant-based biotransformation system. Using Nicotiana benthamiana as a … host, we investigated the interaction of CYP1A2, CYP2D6, and CYP3A4 with different cytochrome P450 reductases (CPRs) derived from animal and plant sources. While human CPR typically enhance or maintain CYP activity, plant-derived CPRs can either enhance or significantly inhibit the metabolism of specific drugs. Additionally, the co-expression of an alternative redox partner, cytochrome b5, can enhance, inhibit, or have no effect on human CYP catalysis, depending on the specific CYP involved. For the majority of CYP/CPR/substrate combinations, we selected variants beneficial for CYP-mediated biotransformation, resulting in a 1.8-4.3-fold increase in product accumulation. We also developed chimeric human-plant CPR variants by swapping structural domains, thereby allowing identification of specific regions responsible for different levels of CYP2D6 productivity. This approach led to the creation of an enhanced CPR variant with a modified transmembrane domain and improved characteristics compared to the native versions.

Authors: Yuriy V. Sheludko, Iryna M. Gerasymenko, Heribert Warzecha

Date Published: 2026

Publication Type: Preprint

Efficient accumulation of new irregular monoterpene malonyl glucosides in Nicotiana benthamiana achieved by co-expression of isoprenyl diphosphate synthases and substrate-producing enzymes

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Irregular monoterpenes have limited natural sources but possess unique activities applicable in medicine and agriculture. To enable sustainable plant-based production of these compounds, we established … a transient expression procedure to enhance the biosynthetic flux in Nicotiana benthamiana toward dimethylallyl diphosphate (DMAPP), a substrate for isopentenyl diphosphate synthases (IDSs) that generate irregular monoterpene skeletons. Considering the benefits of glycosylation for accumulating and storing monoterpenes in extractable form, we focused on developing a platform for the production of non-volatile glycosylated irregular monoterpenes using three IDS that form branched and cyclic structures. The analysis of methanolic leaf extracts from transiently transformed N. benthamiana plants revealed six major new components, 6-O-malonyl-β-D-glucopyranoside and 6-O-malonyl-β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside derivatives of chrysanthemol, lavandulol and cyclolavandulol, five of which are novel compounds. Alleviating two bottlenecks in the DMAPP formation in plastids by co-expressing 1-deoxyxylulose 5-phosphate synthase and isopentenyl diphosphate isomerases increased the yield of chrysantemyl and lavandulyl glucosides produced by plant-derived IDS to 1.7 ± 0.4 μmol g-1 FW and 1.4 ± 0.3 μmol g-1 FW, respectively. A bacterial cyclolavandulyl diphosphate synthase operated efficiently in chloroplasts and cytoplasm. The highest irregular monoterpene concentrations were achieved in cytoplasm by co-expression of hydroxymethylglutaryl-CoA reductase, the bottleneck enzyme of the mevalonate pathway for DMAPP biosynthesis. The mean level of cyclolavandulyl glucosides reached 3.9 ± 1.5 μmol g-1 FW; the top-performing plants contained 6.6 μmol g-1 FW. This yield represents the highest amount of irregular monoterpenes produced in plant systems.

Authors: Iryna Gerasymenko, Yuriy V. Sheludko, Volker Schmidts, Heribert Warzecha

Date Published: 6th Oct 2025

Publication Type: Journal Article

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