The very well-known bioactive natural product, resveratrol (3,5,4′-trihydroxystilbene), is a highly studied secondary metabolite produced by several plants, particularly grapes, passion fruit, white tea, and berries. It is in high demand not only because of its wide range of biological activities against various kinds of cardiovascular and nerve-related diseases, but also as important ingredients in pharmaceuticals and nutritional supplements. Due to its very low content in plants, multi-step isolation and purification processes, and environmental and chemical hazards issues, resveratrol extraction from plants is difficult, time consuming, impracticable, and unsustainable. Therefore, microbial hosts, such as Escherichia coli, Saccharomyces cerevisiae, and Corynebacterium glutamicum, are commonly used as an alternative production source by improvising resveratrol biosynthetic genes in them. The biosynthesis genes are rewired applying combinatorial biosynthetic systems, including metabolic engineering and synthetic biology, while optimizing the various production processes. The native biosynthesis of resveratrol is not present in microbes, which are easy to manipulate genetically, so the use of microbial hosts is increasing these days. This review will mainly focus on the recent biotechnological advances for the production of resveratrol, including the various strategies used to produce its chemically diverse derivatives.

No abstract

A promiscuous Bacillus glycosyltransferase (YjiC) was explored for the enzymatic synthesis of monoterpene O -glycosides in vitro and in vivo. YjiC converted seven monoterpenes into 41 different sugar-conjugated novel glycoside derivatives. The whole-cell biotransformation of the same set of monoterpenes exhibited robust enzyme activity to synthesize O -glucosyl derivatives from Escherichia coli . These newly synthesized selected monoterpene- O -glucosyl derivatives exhibited enhanced antibacterial activities against human pathogenic bacteria and antinematodal activities against pine wood nematode Bursaphelenchus xylophilus .

Glycosylation is a well-characterized glycosyltransferase (GT) enzyme-catalyzed reaction, in cells, involved in metabolism, cell integrity, molecular recognition and pathogenicity, and post-modification of secondary metabolites during biosynthesis [1][2][3][4]. GTs are ubiquitous in nature and transfer sugar moieties from activated nucleotide diphosphate sugars (NDP-D/L-sugars) to acceptor molecules. Leloir GTs are NDP-sugar dependent and transfer sugar units to lipid, nucleic acid, natural products, and other small molecules at nucleophilic oxygen (O-), nitrogen (N-), sulfur (S-), or carbon (C-). According to the recent CAZy classification (http://www.cazy.org/), GTs are classified into 110 different families. Among them, GT1 family proteins are inverting enzymes having GT-B type 3D structure transferring diverse sugars to small molecules [5,6]. The glycosylation of natural products (NPs) influences the physical, chemical and biological properties of the parent molecules. Especially, the sugar conjugation to therapeutically important NPs alters the pharmacological and pharmacokinetic properties including water solubility, stability, specificity, as well as biological actions of the compounds [7,8].Due to the emerging resistance to the different therapeutics, recent research has been focused on designing/ developing bioactive molecules by modification of previously known compounds using various approaches such as by applying microbial enzymes and cells as biocatalysts. Glycosylation is one of the most prominent tools to create glycoside libraries of bioactive small molecules as glycosylation results in an alteration in the pharmacokinetic properties of the parent compounds [9]. In this context, the search for novel glycosyltransferases with tolerance to diverse sets of donor substrates and acceptor compounds is expanding in importance. GTs from various organisms have been used to glucosylate diverse sets of plant natural products, specifically flavonoids [10,11].In this study, we have investigated the application of a GT, YjiC from non-pathogenic Bacillus licheniformis DSM 13 strain for glycosylation of various industrially important amino (NH 2 ) and thiol (SH) functional groupcontaining acceptor substrates. YjiC has been extensively studied for its donor and acceptor substrate promiscuity towards nucleophilic O-glycosylation of diverse sets of natural products using NDP-D/L-sugars as donor substrates [12,13]. Nucleophilic N-, S-, C-glycosylation is regarded as rare in comparison to O-glycosylation of natural products. This puts the emphasis on research with those GTs capable of not only O-glycosylation but also able to generate other natural products with uncommon glycosidic linkages. GTs able to form C-C glycosydic linkages are gaining attention because of the stability of C-C bonds, and the resulting activity of both glycosyl and aglycone parts [14]. Likewise, N-and S-linked glycosidic linkages are also equally important for developing novel natural products with potential biological activity. In this study, ...

Background; Glucosylation is a well-known approach to improve the solubility, pharmacological and biological properties of flavonoids. In recent years, efforts such as enzymatic synthesis have been developed to enhance the production of flavonoid glucosides. However, the low yield of products coupled with the requirement of expensive UDP-sugars limits the application of these systems for large-scale synthesis for human needs. C. glutamicum is a Gram-positive and generally regarded as safe (GRAS) bacteria frequently employed for the large-scale production of amino acids and bio-fuels. Due to the versatility of its cell factory system and its non-endotoxin producing properties, it has become an attractive system for the industrial-scale biosynthesis of alternate products. Here, we explored the cell factory of C. glutamicum for efficient glucosylation of flavonoids using apigenin as a model flavonoid. Results; For the production of apigenin glucosides, a promiscuous glycosyltransferase, YdhE from Bacillus licheniformis was successfully expressed in C. glutamicum. Additionally, the endogenous C. glutamicum genes galU1 encoding UDP-glucose pyrophosphorylase and pgm encoding phosphoglucomutase genes involved in the synthesis of UDP-glucose were overexpressed to create a C. glutamicum cell factory system capable of efficiently glucosylating apigenin with a high yield of glucosides in a comparatively short time. Consequently, the production of various apigenin glucosides was controlled under different temperatures yielding almost 4.2 mM of APG1(apigenin 4’-O-β-glucoside), 0.6 mM of APG2 (apigenin-7-O-β-glucoside), 1.7 mM of APG3 (apigenin 4’,7-O-β-diglucoside) and 2.1 mM of APG4 (apigenin 4’,5-O-β-diglucoside) after 40 h of incubation with the supplementation of 5 mM of apigenin. Conclusion; The developed C. glutamicum cell factory system highly glucosylated apigenin with higher efficiency and the high substrate susceptibility of C. glutamicum makes it the best alternative for large-scale biosynthesis of flavonoid glucosides. The developed system could be used to modify a wide range of plant secondary metabolites with increased pharmacokinetic activities on a large scale without the use of expensive UDP-sugars, thus making a cost-effective system.

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.

The name of the author "Yamaguchi Tokutaro" is incorrect for the first and last name has been interchanged. The correct presentation is "Tokutaro Yamaguchi". The original article has been corrected. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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.