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Advances in the Production of Minor Ginsenosides Using Microorganisms and Their Enzymes

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Advances in the Production of Minor Ginsenosides Using Microorganisms and Their Enzymes Review Advances in the Production of Minor Ginsenosides Using Microorganisms and Their Enzymes Almando Geraldi1,2,* Abstract 1Department of Biology, Faculty of Science and Minor ginsenodes are of great interest due to their diverse pharmacological activities such as their anti-cancer, anti-diabetic, neuroprotective, immunomodulator, and anti-inflammatory effects. The miniscule amount Technology, Universitas of minor ginsenosides in ginseng plants has driven the development of their mass production methods. Airlangga, Surabaya, 60115, Among the various production methods for minor ginsenosides, the utilization of microorganisms and their Indonesia enzymes are considered as highly specific, safe, and environmentally friendly. In this review, various minor ginsenosides production strategies, namely utilizing microorganisms and recombinant microbial enzymes, 2Research Center for for biotransforming major ginsenosides into minor ginsenoside, as well as constructing synthetic minor Bio-Molecule Engineering, ginsenosides production pathways in yeast cell factories, are described and discussed. Furthermore, the Universitas Airlangga, present challenges and future research direction for producing minor ginsenosides using those approaches Surabaya, 60115, Indonesia are discussed. Keywords biotransformation, biosynthesis, β-glucosidase, Ginsenosides, minor ginsenosides. *Correspondence: Almando Geraldi, Tel: +62-31-5936501; E-mail: almando.geraldi@fst. unair.ac.id Introduction and C-20 positions in the case of PPT-type Received: February 29 2020 ginsenosides [9, 10]. Revised: March 19 2020 Ginseng, a plant belonging to the Meanwhile, based on their abundance in Accepted: April 27 2020 Araliaceae family and the genus Panax, ginseng, ginsenosides can be classified as Published Online: May 29 has been used to treat different kinds of major ginsenoside and minor ginsenosides. 2020 ailments and disease in East Asian coun- Major ginsenosides [i.e., Rd, Rc, Rb , and 2 Available at: tries for millennia [1, 2]. Recently, the Rb1 (PPD-type); Rg1, Rf, and Re (PPT-type)] https://bio-integration.org/ popularity of ginseng as a nutraceutical constitute more than 90% of the total ginse- and alternative medicine has been increas- nosides, while minor ginsenosides [i.e. F2, ing worldwide [3, 4]. The global ginseng Rg3, Rh2, and Compound K (PPD-type); Rg2, market has been reported to be valued Rh1, and F1 (PPT-type)] are only present in at over two billion U.S. dollars and is small quantities in ginseng [50, 51]. Despite expected to grow exponentially [5]. showing some therapeutic effects such as, The beneficial health effects of ginseng anti-inflammatory, anti- diabetic, and neuro- are mainly attributed to ginsenosides, the protective effects, major ginsenosides are not major bioactive compound of ginseng easily absorbed by the human body [52]. On [6, 7]. Various in vitro and in vivo studies the other hand, while they are only present in have demonstrated the diverse pharmaco- very low amounts in ginseng, minor ginseno- logical activities of ginsenosides such as sides are considered as being more pharma- anti-microbial, antioxidant, anti-inflamma- cologically active than major ginsenosides tory, skin-protective, neuroprotective, anti- due to their smaller molecule size, better per- cancer, and anti-diabetic effects (Table 1). meability across the cell membrane, and thus Most of ginsenosides are classified as their higher bioavailability [53, 54]. protopanaxadiol (PPD), and protopanaxat- Minor ginsenosides are of commercial riol (PPT) types [8]. Both types consist of interest due to their diverse biological activ- an aglycon (a non-sugar component) of a ities and high pharmacological activities. dammarane skeleton (PPD or PPT) as an However, the miniscule amount of minor aglycon and one to four molecules of sugar ginsenosides extracted from ginseng can- moieties at C-3 and C-20 positions in the not satisfy the needs of scientific and clini- case of PPD-type ginsenosides or at C-6 cal studies, as well as commercial purposes BIOI 2020, Vol 1, No. 1, 15–24 15 https://bio-integration.org doi: 10.15212/bioi-2020-0007 BIOI 2020 Table 1 Example of PPD- and PPT-type Ginsenosides with Their Health Benefits Review 20(S)-Protopanaxadiol-type ginsenoside Name R1 (C3) R3 (C20) Health Benefits References 1 2 1 6 Rb1 Major Glc – Glc Glc – Glc Neuroprotective and anti-diabetic effects [11, 12] ginsenosides 1 2 1 6 Rb2 Glc – Glc Ara(p) – Glc Neuroprotective and anti-inflammatory effects [13, 14] Rc Glc1–2Glc Ara(f)1–6Glc Anti-inflammatory and skin-protective effects [15, 16] Rd Glc1–2Glc Glc– Anti-cancer and neuroprotective effects [17, 18] F2 Minor ginse- Glc– Glc– Anti-oxidant, anti-cancer, and skin-protective effects [19–21] nosides 1 2 Rg3 Glc – Glc H Anti-depressant, anti-virus, and anti-cancer effects [22–24] Gypenoside XVII Glc– Glc1–6Glc Cardioprotective and neuroprotective effects [25, 26] (GypXVII) Gypenoside H– Glc1–6Glc Skin-protective and anti-cancer effects [27, 28] LXXV (GypLXXV) Rh2 Glc– H– Skin protective, immunomodulator, anti-virus, and [29–32] anti-cancer effects Compound K H Glc– Anti-epileptic, anti-cancer, and skin-protective [33–35] (CK) effects 20(S)-Protopanaxatriol-type ginsenoside Name R2 (C6) R3 (C20) Health Benefit References Re Major Rha1–2Glc Glc– Anti-diabetic, kidney-, and heart-protective effects [36–38] Rf ginsenosides Glc1–2Glc H Neuroprotective and anti-inflammatory effects [39, 40] Rg1 Glc– Glc– Neuroprotective and hepatoprotective effects [41, 42] 1 2 Rg2 Minor Rha – Glc H- Skin-protective, antidepressant, and anti- [43–45] ginsenosides inflammatory effects Rh1 Glc- H Anti-oxidant, anti-inflammatory, immunomodulator, [46, 47] and anti-cancer F1 H Glc- Anti-aging, anti-oxidant, skin-protective, [48, 49] immunomodulator Ara(f): α-l-arabinofuranosyl; Ara(p): α-l-arabinopyranosyl; Glc: α-d-glucopyranosyl; Rha: α-l-ahamnopyranosyl. 16 A. Geraldi: Advances in the Production of Minor Ginsenosides Review BIOI 2020 [55, 56]. Therefore, it is very important to develop useful methods for the mass production of minor ginsenosides. Biotransformation of major ginsenosides into minor ginsenosides using Minor ginsenosides production microorganisms methods A wide variety of microorganisms have been used in the biotransformation of major ginsenosides into minor gin- The most common approach to producing minor ginseno- senosides (Table 2). The biotransformation activities are sides is by hydrolyzing the sugar moieties of major gin- mainly attributed to β-glucosidases (β-d-glucopyranoside senosides [57]. The hydrolysis can be conducted through glucohydrolase) [E.C.3.2.1.21] which hydrolyze the gly- physical (heat and microwave transformation), chemical cosidic bonds of the sugar moieties of the major ginseno- (acid and alkali hydrolysis), and biological (biotransforma- sides at the C-3, C-6, and C-20 positions [62]. However, tion) methods. Heat transformation via baking and steam- due to specific structures of the aglycon (dammarane skel- ing transforms PPD-type major ginsenosides Rb1, Rb2, and eton), only specific β-glucosidases, thus specific micro- Rc2 into Rd, and finally into minor ginsenosides Rg3, F2, organisms are able to hydrolyze ginsenoside-β-glucoside compound K, and Rh2, as well as PPT-type major ginseno- linkages [63]. sides Re and Rf into minor ginsenosides Rh1 and F1, with Ginseng plantation fields are one of the main sources of by-products of acetyl-ginsenosides [58, 59]. Meanwhile, microorganisms with major ginsenoside-biotransforming acid hydrolysis using hydrochloric acid transformed Rb1 activities. Endophytic microorganisms, spend all or part into Rg3 [60]. The physical and chemical methods are con- of their life cycle inside ginseng plants without damaging sidered to be fast and simple; however, the use of those the plant tissues or inducing defense responses, for exam- methods often results in the formation of undesirable ple, Burkholderia sp. GE 17-7 and Flavobacterium sp. GE by-products due to the low specificity. Moreover, there are 32, as well as fungi Arthrinium sp. GE 17-18 [64]. Those safety and environmental issues, for example, due to the use microorganisms exhibit hydrolysis activities on PPD-type of high temperature in the heat transformation approach, or ginsenosides. Flavobacterium sp. GE 32 has been reported strong acid/base in the acid/alkali hydrolysis methods. On to hydrolyze the outer glycosidic linkage of Rb1 at C-3 to the other hand, biological methods which involve enzymes produce Gypenoside XVII and the C-20 position to produce offer higher reaction specificity, can be conducted in mild Rd. The bacteria also showed hydrolysis activities on the conditions minimizing safety risks, and are more environ- glycosidic linkage at the C-20 position of Rd to generate mentally friendly [61]. Thus, there is growing interest in Rg3 [65]. Similar hydrolysis activities on the terminal and using biological methods for the mass production of minor inner glucopyranosyl moieties at the C-20 position of Rb1 to ginsenosides. produce Rg3 were also shown by Burkholderia sp. GE 17-7 In general, the biological methods for producing minor [66]. Meanwhile Arthrinium sp. GE 17-18 was shown to ginsenosides can be categorized as; the use of microbial have hydrolysis activity on terminal and inner glucopyrano- cells and enzymes for hydrolyzing sugar moieties of major syl moieties at the C-3 position and terminal glucopyranosyl ginsenosides, and the emerging biosynthesis methods, where moieties at the C-20 position of Rb1 to generate
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