Biosynthetic approach to combine the first steps of cardenolide formation in <i>Saccharomyces cerevisiae</i>

Rieck, Christoph; Geiger, Daniel; Munkert, Jennifer; Messerschmidt, Katrin; Petersen, Jan; Strasser, Juliane; Meitinger, Nadine; Kreis, Wolfgang

doi:10.1002/mbo3.925

Cited by 13 publications

(12 citation statements)

References 34 publications

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“…Genomic and biotechnological advances make fungal fermentation‐based processes ideal to produce bioactive compounds from fungi and plants (Pyne, Narcross, & Martin, 2019). Yeast cell factories enable production of medicinally valuable plant alkaloids (Galanie et al, 2015; Srinivasan & Smolke, 2019), steroids (Rieck et al., 2019), and coumarins (Zhao et al., 2019). A successful example of this approach is the heterologous expression of the precursor artemisinic acid in yeast, with yields appropriate for industrial‐scale production; it can be converted to the antimalarial artemisinin using a chemical source of singlet oxygen (Paddon et al., 2013).…”

Section: Advances In Research Technology: Harmonization For Humanity mentioning

confidence: 99%

Molecules from nature: Reconciling biodiversity conservation and global healthcare imperatives for sustainable use of medicinal plants and fungi

Howes

Quave

Collemare

et al. 2020

Plants People Planet

127

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Plants and fungi have provided, or inspired, key pharmaceuticals for global health challenges, including cancer, heart disease, dementia, and malaria, and are valued as traditional medicines worldwide. Global demand for medicinal plants and fungi has threatened certain species, contributing to biodiversity loss and depletion of natural resources that are important for the health of humanity. We consider the evolving role of plants and fungi in global healthcare as new challenges to human health and to biodiversity arise. We present current and emerging scientific approaches, to uncover and preserve nature‐based health solutions for the future, through harmonization with biodiversity conservation strategies.

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Section: Advances In Research Technology: Harmonization For Humanity mentioning

confidence: 99%

Molecules from nature: Reconciling biodiversity conservation and global healthcare imperatives for sustainable use of medicinal plants and fungi

Howes

Quave

Collemare

et al. 2020

Plants People Planet

127

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“…This time-consuming process is necessary as the chemical synthesis of cardenolides is not economically feasible. Only parts of their biosynthesis in planta are known which makes it difficult to design alternative biotechnological production systems using yeast or bacteria (Rieck et al 2019 ).…”

Section: Introductionmentioning

confidence: 99%

RNAi-mediated gene knockdown of progesterone 5β-reductases in Digitalis lanata reduces 5β-cardenolide content

et al. 2021

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Key message Studying RNAi-mediated DlP5βR1 and DlP5βR2 knockdown shoot culture lines of Digitalis lanata, we here provide direct evidence for the participation of PRISEs (progesterone 5β-reductase/iridoid synthase-like enzymes) in 5β-cardenolide formation. Abstract Progesterone 5β-reductases (P5βR) are assumed to catalyze the reduction of progesterone to 5β-pregnane-3,20-dione, which is a crucial step in the biosynthesis of the 5β-cardenolides. P5βRs are encoded by VEP1-like genes occurring ubiquitously in embryophytes. P5βRs are substrate-promiscuous enone-1,4-reductases recently termed PRISEs (progesterone 5β-reductase/iridoid synthase-like enzymes). Two PRISE genes, termed DlP5βR1 (AY585867.1) and DlP5βR2 (HM210089.1) were isolated from Digitalis lanata. To give experimental evidence for the participation of PRISEs in 5β-cardenolide formation, we here established several RNAi-mediated DlP5βR1 and DlP5βR2 knockdown shoot culture lines of D. lanata. Cardenolide contents were lower in D. lanata P5βR-RNAi lines than in wild-type shoots. We considered that the gene knockdowns may have had pleiotropic effects such as an increase in glutathione (GSH) which is known to inhibit cardenolide formation. GSH levels and expression of glutathione reductase (GR) were measured. Both were higher in the Dl P5βR-RNAi lines than in the wild-type shoots. Cardenolide biosynthesis was restored by buthionine sulfoximine (BSO) treatment in Dl P5βR2-RNAi lines but not in Dl P5βR1-RNAi lines. Since progesterone is a precursor of cardenolides but can also act as a reactive electrophile species (RES), we here discriminated between these by comparing the effects of progesterone and methyl vinyl ketone, a small RES but not a precursor of cardenolides. To the best of our knowledge, we here demonstrated for the first time that P5βR1 is involved in cardenolide formation. We also provide further evidence that PRISEs are also important for plants dealing with stress by detoxifying reactive electrophile species (RES).

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“…Recently, genes coding selected enzymes from Digitalis lanata , Arabidopsis thaliana, bacterium Comamonas testosteronii , mouse ( Mus musculus ), and cattle ( Bos taurus ) were cloned into two vectors, which were inserted into yeast cells ( Saccharomyces cerevisiae ). These cells were then able to produce 3β,21-dihydroxy-5β-pregnan-20-one [ 59 ].…”

Section: Production Of Cardiac Glycosidesmentioning

confidence: 99%

Quo vadis Cardiac Glycoside Research?

Bejček

Jurášek

Spiwok

et al. 2021

Toxins

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Cardiac glycosides (CGs), toxins well-known for numerous human and cattle poisoning, are natural compounds, the biosynthesis of which occurs in various plants and animals as a self-protective mechanism to prevent grazing and predation. Interestingly, some insect species can take advantage of the CG’s toxicity and by absorbing them, they are also protected from predation. The mechanism of action of CG´s toxicity is inhibition of Na+/K+-ATPase (the sodium-potassium pump, NKA), which disrupts the ionic homeostasis leading to elevated Ca2+ concentration resulting in cell death. Thus, NKA serves as a molecular target for CGs (although it is not the only one) and even though CGs are toxic for humans and some animals, they can also be used as remedies for various diseases, such as cardiovascular ones, and possibly cancer. Although the anticancer mechanism of CGs has not been fully elucidated, yet, it is thought to be connected with the second role of NKA being a receptor that can induce several cell signaling cascades and even serve as a growth factor and, thus, inhibit cancer cell proliferation at low nontoxic concentrations. These growth inhibitory effects are often observed only in cancer cells, thereby, offering a possibility for CGs to be repositioned for cancer treatment serving not only as chemotherapeutic agents but also as immunogenic cell death triggers. Therefore, here, we report on CG´s chemical structures, production optimization, and biological activity with possible use in cancer therapy, as well as, discuss their antiviral potential which was discovered quite recently. Special attention has been devoted to digitoxin, digoxin, and ouabain.

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Biosynthetic approach to combine the first steps of cardenolide formation in Saccharomyces cerevisiae

Cited by 13 publications

References 34 publications

Molecules from nature: Reconciling biodiversity conservation and global healthcare imperatives for sustainable use of medicinal plants and fungi

Molecules from nature: Reconciling biodiversity conservation and global healthcare imperatives for sustainable use of medicinal plants and fungi

RNAi-mediated gene knockdown of progesterone 5β-reductases in Digitalis lanata reduces 5β-cardenolide content

Quo vadis Cardiac Glycoside Research?

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