Biotechnological production of hyperforin for pharmaceutical formulation

Gaid, Mariam; Biedermann, Eline; Füller, Jendrik; Haas, Paul; Behrends, Sönke; Krull, Rainer; Scholl, Stephan; Wittstock, Ute; Müller‐Goymann, Christel C.; Beerhues, Ludger

doi:10.1016/j.ejpb.2017.03.024

Cited by 25 publications

(15 citation statements)

References 196 publications

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“…H. perforatum contains a number of bioactive constituents, which act additively and/or synergetically (Schmidt & Butterweck, 2015). The major classes are hypericins, hyperforins, flavonoids and xanthones, which invariably stem from the polyketide metabolism (Beerhues, 2011;Gaid et al, 2017). Their scaffolds are synthesized by type III polyketide synthases, which are known to catalyse the formation of a diversity of natural products by varying the starter substrate, the number of chain extensions and the mode of intramolecular cyclization (Austin & Noel, 2003; Abe & Morita, 2010).…”

Section: Introductionmentioning

confidence: 99%

Exodermis and endodermis are the sites of xanthone biosynthesis in Hypericum perforatum roots

et al. 2017

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Xanthones are specialized metabolites with antimicrobial properties, which accumulate in roots of Hypericum perforatum. This medicinal plant provides widely taken remedies for depressive episodes and skin disorders. Owing to the array of pharmacological activities, xanthone derivatives attract attention for drug design. Little is known about the sites of biosynthesis and accumulation of xanthones in roots. Xanthone biosynthesis is localized at the transcript, protein, and product levels using in situ mRNA hybridization, indirect immunofluorescence detection, and high lateral and mass resolution mass spectrometry imaging (AP-SMALDI-FT-Orbitrap MSI), respectively. The carbon skeleton of xanthones is formed by benzophenone synthase (BPS), for which a cDNA was cloned from root cultures of H. perforatum var. angustifolium. Both the BPS protein and the BPS transcripts are localized to the exodermis and the endodermis of roots. The xanthone compounds as the BPS products are detected in the same tissues. The exodermis and the endodermis, which are the outermost and innermost cell layers of the root cortex, respectively, are not only highly specialized barriers for controlling the passage of water and solutes but also preformed lines of defence against soilborne pathogens and predators.

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Section: Introductionmentioning

confidence: 99%

Exodermis and endodermis are the sites of xanthone biosynthesis in Hypericum perforatum roots

et al. 2017

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“…To our knowledge, the same is true for the intact plant. Isobutyryl‐CoA is the precursor for the biosynthesis of hyperforins (Beerhues, 2006; Gaid et al ., 2018). However, H. calycinum cell cultures contain only traces of this metabolite inside the cells (approximately 0.003% of dry mass; Klingauf et al ., 2005).…”

Section: Discussionmentioning

confidence: 99%

A promiscuous coenzyme A ligase provides benzoyl‐coenzyme A for xanthone biosynthesis in Hypericum

et al. 2020

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Benzoic acid-derived compounds, such as polyprenylated benzophenones and xanthones, attract the interest of scientists due to challenging chemical structures and diverse biological activities. The genus Hypericum is of high medicinal value, as exemplified by H. perforatum. It is rich in benzophenone and xanthone derivatives, the biosynthesis of which requires the catalytic activity of benzoate-coenzyme A (benzoate-CoA) ligase (BZL), which activates benzoic acid to benzoyl-CoA. Despite remarkable research so far done on benzoic acid biosynthesis in planta, all previous structural studies of BZL genes and proteins are exclusively related to benzoate-degrading microorganisms. Here, a transcript for a plant acyl-activating enzyme (AAE) was cloned from xanthone-producing Hypericum calycinum cell cultures using transcriptomic resources. An increase in the HcAAE1 transcript level preceded xanthone accumulation after elicitor treatment, as previously observed with other pathway-related genes. Subcellular localization of reporter fusions revealed the dual localization of HcAAE1 to cytosol and peroxisomes owing to a type 2 peroxisomal targeting signal. This result suggests the generation of benzoyl-CoA in Hypericum by the CoA-dependent non-b-oxidative route. A luciferase-based substrate specificity assay and the kinetic characterization indicated that HcAAE1 exhibits promiscuous substrate preference, with benzoic acid being the sole aromatic substrate accepted. Unlike 4coumarate-CoA ligase and cinnamate-CoA ligase enzymes, HcAAE1 did not accept 4-coumaric and cinnamic acids, respectively. The substrate preference was corroborated by in silico modeling, which indicated valid docking of both benzoic acid and its adenosine monophosphate intermediate in the HcAAE1/BZL active site cavity.

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“…The growth kinetic during the linear phase was expressed via the volumetric biomass formation rate r X (Figure 4). The maximum r X was observed within the linear phase (days [16][17][18][19][20][21][22] to be between 6.3-9.0 g L −1 day −1 (Figures 3A, 4A). Similar growth patterns were observed for H. perforatum and Echinacea purpurea root cultures [32,33].…”

Section: The Growth Characteristics Of Sjw Root Culturesmentioning

confidence: 94%

“…Thus, in vitro cultivation of SJW offers a promising biotechnological tool for long‐term supply of stable elite clones . Despite the reported plethora of trials for in vitro tissue and organ cultures, systems with hyperforin forming properties are scarce . Previously, SJW in vitro‐grown root cultures were successfully established in our laboratory .…”

Section: Introductionmentioning

confidence: 99%

Toward enhanced hyperforin production in St. John's wort root cultures

Gaid

Grosch

Möller

et al. 2019

Engineering in Life Sciences

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During the past decades, several trials targeted a stable, sustainable and economic production of St. John's wort (Hypericum perforatum) extract. The value of this extract stems from its use to treat depression and skin irritation due to its hyperforin content. Previously, hyperforin‐forming in vitro root cultures were established. Here, detailed growth and production kinetics have been analyzed over 40 days of cultivation. In the first 10 days, sucrose was completely hydrolyzed to glucose and fructose. The ammonium consumption supported the increase in the biomass and hyperforin production. When sucrose was replaced with glucose/fructose, the linear growth phase started 6 days earlier and resulted in a higher space‐time‐yield. The maximum hyperforin production was 0.82 mg L−1 day−1, which was 67 % higher than in the sucrose‐supplemented standard cultivation. Buffering the sucrose‐supplemented medium with phosphate caused a 2.7‐fold increase in the product to biomass yield coefficient. However, the combination of monosaccharides and buffering conditions did not cause an appreciable improvements in the production performance of the shake flask approaches. A potential scalability from flask to lab‐scale stirred bioreactors has been demonstrated. The results obtained offer a basis for a scalable production of hyperforin and a sustainable source for a tissue culture‐based phytomedicine.

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Biotechnological production of hyperforin for pharmaceutical formulation

Cited by 25 publications

References 196 publications

Exodermis and endodermis are the sites of xanthone biosynthesis in Hypericum perforatum roots

Exodermis and endodermis are the sites of xanthone biosynthesis in Hypericum perforatum roots

A promiscuous coenzyme A ligase provides benzoyl‐coenzyme A for xanthone biosynthesis in Hypericum

Toward enhanced hyperforin production in St. John's wort root cultures

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