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Resveratrol, a major stilbene phytoalexin, is a valuable polyphenol that has been recognized for its benefits to human health. Resveratrol has antioxidant and antitumor effects and promotes longevity. It is used in medicine, health care products, cosmetics, and other industries. Therefore, a sustainable source for resveratrol production is required...
Contexts in source publication
Context 1
... is homologous to PAL and can transform tyrosine into p-coumaric acid (Fig. 1). Depending on the precursor added, the PAL, C4H, TAL, 4CL, and STS genes involved in the resveratrol biosynthetic pathway can be effectively recombined in genetically-engineered microorgan- isms, as shown in Table 1. ...
Context 2
... E. coli system contains an artificial stilbene biosynthetic pathway which includes the production of PAL from Rhodotorula rubra, 4-coumarate-CoA ligase from Lithospermum erythrorhizon, tobacco or Arabidopsis, TAL from Saccharothrix, and STS from grape or peanut. Table 1 shows that this system has been constructed by several research groups using p- coumaric acid or tyrosine as the precursor ( Katsuyama et al. 2007a, b;Watts et al. 2006;Beekwilder et al. 2006;Lim et al. 2011;Choi et al. 2011). Katsuyama et al. (2007a, b) constructed a pathway for stilbene biosynthesis in E. coli using PAL from R. rubra, 4CL from Lithospermum and STS from peanut, using tyrosine as the precursor and the system produced a yield of 37 mg resveratrol/l. ...
Citations
... However, the yield of resveratrol production by these metabolically engineered microorganisms is not very high to meet the global demand of 100 tons/year. Additionally, obtaining high-purity resveratrol (98%) is difficult and costly (Mei et al. 2015). ...
In modern times, medicine is predominantly based on evidence-based practices, whereas in ancient times, indigenous people relied on plant-based medicines with factual evidence documented in ancient books or folklore that demonstrated their effectiveness against specific infections. Plants and microbes account for 70% of drugs approved by the USFDA (U.S. Food and Drug Administration). Stilbenes, polyphenolic compounds synthesized by plants under stress conditions, have garnered significant attention for their therapeutic potential, bridging ancient wisdom with modern healthcare. Resveratrol, the most studied stilbene, initially discovered in grapes, red wine, peanuts, and blueberries, exhibits diverse pharmacological properties, including cardiovascular protection, antioxidant effects, anticancer activity, and neuroprotection. Traditional remedies, documented in ancient texts like the Ayurvedic Charak Samhita, foreshadowed the medicinal properties of stilbenes long before their modern scientific validation. Today, stilbenes are integral to the booming wellness and health supplement market, with resveratrol alone projected to reach a market value of 90 million US$ by 2025. However, challenges in stilbene production persist due to limited natural sources and costly extraction methods. Bioprospecting efforts reveal promising candidates for stilbene production, particularly endophytic fungi, which demonstrate high-yield capabilities and genetic modifiability. However, the identification of optimal strains and fermentation processes remains a critical consideration. The current review emphasizes the knowledge of the medicinal properties of Stilbenes (i.e., cardiovascular, antioxidant, anticancer, anti-inflammatory, etc.) isolated from plant and microbial sources, while also discussing strategies for their commercial production and future research directions. This also includes examples of novel stilbenes compounds reported from plant and endophytic fungi.
... As An intriguing approach with promising potential to address the prevailing challenges in resveratrol manufacturing is the bioproduction of resveratrol through the utilization of recombinant microorganisms [29]. According to Thapa et al., heterologous expression of the plant pathway has been successfully used in several hosts to synthesize resveratrol [30,31]. As higher levels of resveratrol inside cells may cause detrimental effects and reduce resveratrol production, the compound produced within the cells was removed and transferred outside via the four endogenous transport mechanisms of E. coli to balance intracellular content and increase production. ...
Natural products have been a long-standing source for exploring health-beneficial components from time immemorial. Modern science has had a renewed interest in natural-products-based drug discovery. The quest for new potential secondary metabolites or exploring enhanced activities for existing molecules remains a pertinent topic for research. Resveratrol belongs to the stilbenoid polyphenols group that encompasses two phenol rings linked by ethylene bonds. Several plant species and foods, including grape skin and seeds, are the primary source of this compound. Resveratrol is known to possess potent anti-inflammatory, antiproliferative, and immunoregulatory properties. Among the notable bioactivities associated with resveratrol, its pivotal role in safeguarding the intestinal barrier is highlighted for its capacity to prevent intestinal inflammation and regulate the gut microbiome. A better understanding of how oxidative stress can be controlled using resveratrol and its capability to protect the intestinal barrier from a gut microbiome perspective can shed more light on associated physiological conditions. Additionally, resveratrol exhibits antitumor activity, proving its potential for cancer treatment and prevention. Moreover, cardioprotective, vasorelaxant, phytoestrogenic, and neuroprotective benefits have also been reported. The pharmaceutical industry continues to encounter difficulties administering resveratrol owing to its inadequate bioavailability and poor solubility, which must be addressed simultaneously. This report summarizes the currently available literature unveiling the pharmacological effects of resveratrol.
... The phenylalanine, tyrosine, and tryptophan pathways were also strengthened in strain XP (Fig. S11). These pathways are associated with the synthesis of aromatic acids such as terpenoids (11,56) and flavonoids (57). This implies that strain XP suits the synthesis of aromatic compounds (Fig. 3B). ...
Robust chassis are critical to facilitate advances in synthetic biology. This study describes a comprehensive characterization of a new yeast isolate Saccharomyces cerevisiae XP that grows faster than commonly used research and industrial S. cerevisiae strains. The genomic, transcriptomic, and metabolomic analyses suggest that the fast growth rate is, in part, due to the efficient electron transport chain and key growth factor synthesis. A toolbox for genetic manipulation of the yeast was developed; we used it to construct l -lactic acid producers for high lactate production. The development of genetically malleable yeast strains that grow faster than currently used strains may significantly enhance the uses of S. cerevisiae in biotechnology.
IMPORTANCE
Yeast is known as an outstanding starting strain for constructing microbial cell factories. However, its growth rate restricts its application. A yeast strain XP, which grows fast in high concentrations of sugar and acidic environments, is revealed to demonstrate the potential in industrial applications. A toolbox was also built for its genetic manipulation including gene insertion, deletion, and ploidy transformation. The knowledge of its metabolism, which could guide the designing of genetic experiments, was generated with multi-omics analyses. This novel strain along with its toolbox was then tested by constructing an l -lactic acid efficient producer, which is conducive to the development of degradable plastics. This study highlights the remarkable competence of nonconventional yeast for applications in biotechnology.
... 11,13,81 In reactions with free radicals, RES yields various oligomers as final products. 54,90,91 The NMR analysis showed that in combination with AA, the oxidation of RES generates viniferins. 92 In this case, the regeneration mechanism of synergistic antioxidant action can be excluded. ...
The antioxidant interactions between several natural phenolic and non-phenolic compounds (catechin, quercetin, rutin, resveratrol, gallic acid and ascorbic acid) and organic acids (tartaric, citric and dihydroxyfumaric acids) were studied using the DPPH method. Main additive and antagonistic interactions have been found for the combinations of catechin, quercetin, resveratrol and gallic acid with tartaric and citric acids; such behavoir can be due to the enhanced stability of the phenolic compounds in acidic media. Rutin and ascorbic acid showed good synergistic effects with tartaric and citric organic acids, which could be due to the polymerization processes in the case of rutin and the change in the mechanism of action in the case of ascorbic acid. In combination with dihydroxyfumaric acid, the mixtures showed dose–dependent synergistic, additive, or antagonistic antioxidant interactions. Good synergistic effects were observed for the binary mixtures of dihydroxyfumaric acid with ascorbic acid, catechin, and rutin.
... Under stress conditions like pathogen invasion, enzymes involved in the biosynthetic pathway become active and produce resveratrol. It is considered to be a potent antioxidant, tumor suppressant, anti-diabetic compound, inducer of neurogenesis (Mei et al. 2015;Piyaratne et al. 2022) and mitochondrial biogenesis (Zhou et al. 2021). Also, resveratrol has been widely used in cosmetic industry due to its anti-ageing property (Rajha et al. 2022). ...
Objective
Assembly and construction of resveratrol production pathway in Saccharomyces cerevisiae for denovo production of resveratrol using seaweed extract as fermentation medium.
Results
Genes involved in the production of resveratrol from tyrosine pathway, tyrosine ammonia lyase (FTAL) gene from Flavobacterium johnsoniae (FjTAL), the 4-coumarate:CoA ligase gene from Arabidopsis thaliana (4CL1) and the stilbene synthase gene from Vitis vinifera (VvSTS) were introduced into low copy, high copy and integrative vector and transformed into S. cerevisiae W303-1a. The resulting strains W303-1a/pARS-res5, W303-1a/2µ-res1 and W303-1a/IntUra-res9 produced a level of 2.39 ± 0.01, 3.33 ± 0.03 and 8.34 ± 0.03 mg resveratrol l⁻¹ respectively. CRISPR mediated integration at the δ locus resulted in 17.13 ± 1.1 mg resveratrol l⁻¹. Gracilaria corticata extract was tested as a substrate for the growth of transformant to produce resveratrol. The strain produced a comparable level, 13.6 ± 0.54 mg resveratrol l⁻¹ when grown in seaweed extract medium.
Conclusions
The strain W303-1a/IntδC-res1 utilized Gracillaria hydrolysate and produced 13.6 ± 0.54 mg resveratrol l⁻¹ and further investigations are being carried out focusing on pathway engineering and optimization of process parameters to enhance resveratrol yield.
... As such, exploring the potential of microbial fermentation for synthesizing RES is a promising avenue to pursue. Endophytic fungi have become a popular research focus due to their ability to produce secondary metabolites with similar biological activities as host plants (Mei et al. 2015). Like fungi, the endophytic bacterium also plays a crucial role in obtaining natural products (Kandasamy and Kathirvel 2022). ...
Resveratrol (RES) is a secondary metabolite synthesized by plants in response to environmental stress and pathogen infection, which is of great significance for the industrial production of RES by fermentation culture. In this study, we aimed to explore the biosynthesis pathway of RES and its key enzymes in the Priestia megaterium PH3, which was isolated and screened from peanut fruit. Through Liquid Chromatography-Mass Spectrometry (LC-MS) analysis, we quantified the RES content and distribution in the culture medium and determined that Priestia megaterium PH3 mainly secreted RES extracellularly. Furthermore, the highest production of RES was observed in YPD, yielding an impressive 127.46 ± 6.11 μg/L. By optimizing the fermentation conditions, we achieved a remarkable RES yield of 946.82 ± 24.74 μg/L within just 2 days, which represents the highest reported yield for a natural isolate produced in such a short time frame. Our investigation revealed that the phenylpropane pathway is responsible for RES synthesis in this bacterium, with cinnamate 4-hydroxylase (C4H) identified as the main rate-limiting enzyme. Overall, our findings highlight the robust RES production capabilities of Priestia megaterium PH3, offering novel insights and potential applications for bacterial fermentation in RES production.
Key points
• RES synthesized by the bacterium was confirmed through the phenylpropane pathway.
• The key rate-limiting enzyme for biosynthesis-RES is C4H.
• RES reached 946.82 ± 24.74 μg/L after fermentation for 2 days.
Graphical Abstract
... Recent advancements in biological tools and techniques has enabled the cost-effective and rapid production of such bioactive plant products in microbial hosts. Although microbial hosts lack resveratrol biosynthetic genes, they offer a promising alternative source for the largescale production of resveratrol and its derivatives using metabolic engineering and synthetic biology approaches [37,38]. However, despite the use of the latest techniques, the overall production of resveratrol and its derivatives remains insufficient [39,40]. ...
... Although both in vitro and in vivo systems are effective in producing resveratrol-Oglucosides, each has its advantages and disadvantages. In vitro systems using DgAS are fast, direct, easy to handle, environmentally friendly, and require fewer steps for product extraction and purification [30,37]. However, these systems require large amounts of protein and a longer time for the purification of enzymes for scale-up production. ...
A biocatalytic system that could produce bioactive resveratrol poly-glucosides, using sucrose as a low-cost source of UDP-glucose donors and amylosucrase DgAS from Deinococcus geothermalis, was developed in this study. This system boasts several advantages, including the rapid and direct conversion of substrates to products, thermostability, regio-stereospecificity, and effectiveness, both in vitro and in vivo, at 40 °C. The results showed that the optimal reaction condition of the production of resveratrol glucosides was obtained by 2.0 µg/mL DgAS and 100 mM sucrose at pH 7.0, incubated at 40 °C for 5 h. With a success rate of around 97.0% in vitro and 95.0% in vivo in a short period of time, resveratrol-O-glucosides showed exciting outcomes in cosmetic applications, including antioxidant, anti-inflammatory, anti-aging, and whitening effects when tested with Raw 264.7, B16, and HS68 cell lines. DgAS is recognized as an important biocatalyst due to its high thermostability, effectiveness, and specificity among all known amylosucrases (ASases) in the production of poly-glucosides in a chain of polyphenols, such as resveratrol, making it an ideal candidate for industrial use in the cost-effective production of cosmetic items.
... Resveratrol is rapidly metabolized in the body and its absorption can reach 70 % (Baur & Sinclair, 2006), being proposed as a food supplement for humans (Mei et al., 2015). However, consumption should be cautious, as resveratrol in low doses stimulates the immune system, but in high doses, it has been shown to induce immunosuppression (Sharma et al., 2007). ...
The purple passion fruit (Passiflora edulis Sims) is a fruit that has an intense and wrinkled purple peel when ripe. In the food industry, the passion fruit pulp is used in the production of juices and nectars, while the peel and seeds are considered waste, although they have great biotechnological potential due to their chemical composition , with emphasis on bioactive compounds. In this study, the profile of 13 phenolics, two alkaloids, the total phenolic content and the antioxidant activity, evaluated by different methods, of the pulp, peel and seed of purple passion fruit at three maturation stages, were evaluated. Fifteen metabolites in the phenolic and alkaloid profile were identified in the different fractions of the fruit, and by their variation, processes of synthesis and degradation along ripening were suggested. As for the content of phenolic compounds and antioxidant activity, the seed stood out compared to the peel and pulp. The results obtained suggest the health benefits of consuming the fruit pulp, and the potential for using the peel and seed as by-products that are also beneficial to health and as candidates for biotechnological use in industries and research centers.
... Just like BY-2 cells, the rice cell suspension cultures are also commonly employed because of a sugar-sensitive α-amylase promoter system (RAmy3D) (Trexler et al., 2005). This promoter is induced by sugar deprivation and results in the increased expression of several pharmacological proteins in rice cells, such as human serum albumin (Liu et al., 2015), interleukin-12 (Shin et al., 2010), hGM-CSF, and α1-antitrypsin (rAAT) (McDonald et al., 2005). However, in contrast to BY-2 cells, the stability of rice cells is less and their vitality is greatly reduced when grown in a sucrosedepleted media (Huang & McDonald, 2009). ...
... It is an important constituent of different nutritional supplements and pharmaceuticals and possesses a range of biological activities against certain nerve-related diseases and cardiovascular problems (Thapa et al., 2019). Even though resveratrol is generated in plants, its content is generally low, with multistep extraction and seasonal occurrence making it commercially nonviable (Mei et al., 2015). Due to its high pharmacological and dietary value, and to make it commercially viable, its production by alternate methods becomes necessary. ...
... Recent advancement in biological tools and techniques has enabled cost-effective and rapid production of such bioactive plant products in microbial hosts. Although microbial hosts lack resveratrol biosynthetic genes, they offer a promising alternative source for large-scale production of resveratrol and its derivatives using metabolic engineering and synthetic biology approaches [33,34]. However, despite the use of latest techniques, the overall production of resveratrol and its derivatives remains insufficient [35,36]. ...
... Although both in vitro and in vivo systems are effective in producing resveratrol-O-glucosides, each has its advantages and disadvantages. In vitro systems using DgAS are fast, direct, easy to handle, environmentally friendly, and requiring fewer steps for product extraction and purification [30,33]. However, these systems require large amounts of protein and a longer time for the purification of enzymes for scale-up production. ...
A biocatalytic system that could produce bioactive resveratrol poly-glucosides using sucrose as a low-cost source of UDP-glucose donors and amylosucrase DgAS from Deinococcus geothermalis was developed in this study. This system boasts several advantages, including fast and direct conversion of substrates to products, thermostable, and regio-stereospecific, and effectiveness in vitro and in vivo at 40°C. With a success rate of around 97.0% in a short period in vitro and 95.0% in vivo, resveratrol-O-glucosides showed exciting outcomes in cosmetic activities, such as antioxidant, anti-inflammatory, anti-aging, and whitening effects when tested with Raw 264.7, B16, and HS68 cell lines. DgAS is recognized as an important biocatalyst due to its higher thermostability, effectiveness, and specificity among all known amylosucrases (ASases) in the production of poly-glucosides in a chain of polyphenols, like resveratrol, making it an ideal candidate for industrial use to cost-effective production of cosmetic items.
