Current Advances on the Structure, Bioactivity, Synthesis, and

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Current advances on the structure, bioactivity, synthesis and metabolic regulation of novel ubiquinone derivatives in the edible and medicinal mushroom Antrodia cinnamomea Bo-Bo Zhang, Peng-Fei Hu, Jing Huang, Yong-Dan Hu, Lei Chen, and Gan-Rong Xu J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.7b04206 • Publication Date (Web): 10 Nov 2017 Downloaded from http://pubs.acs.org on November 11, 2017

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Journal of Agricultural and Food Chemistry

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Current advances on the structure, bioactivity, synthesis and metabolic regulation of novel

2

ubiquinone derivatives in the edible and medicinal mushroom Antrodia cinnamomea

3

Bo-Bo Zhang1, *, Peng-Fei Hu1, Jing Huang1, Yong-Dan Hu2, Lei Chen1, Gan-Rong Xu1

4 5 6

1

7

Jiangnan University, Wuxi 214122, China

Key Laboratory of Carbohydrate Chemistry and Biotechnology, School of Biotechnology,

8 9 10

2

Yunnan Institute of Food Safety, Kunming University of Science and Technology, Kunming

650500, China

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Complete mailing addresses of all authors:

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Bo-Bo Zhang, [email protected];

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Peng-Fei Hu, [email protected];

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Jing Huang, [email protected];

16

Yong-Dan Hu, [email protected];

17

Lei Chen, [email protected];

18

Gan-Rong Xu, [email protected]

19 20

*Corresponding author: Bo-Bo Zhang

21

Tel: +86 510 8591 8202; fax: +86 510 8591 8202.

22

E-mail: [email protected]; 1

ACS Paragon Plus Environment


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Abstract

25

In recent years, Antrodia cinnamomea has attracted great attention around the world as

26

an extremely precious edible and medicinal mushroom. Ubiquinone derivatives, which are

27

characteristic metabolites of A. cinnamomea, have shown great bioactivities. Some of them

28

have been regarded as promising therapeutic agents and approved into clinical trial by US

29

FDA. Although some excellent reviews have been published covering different aspects of A.

30

cinnamomea, this review brings, for the first time, complete information about the structure,

31

bioactivity, chemical synthesis, biosynthesis and metabolic regulation of ubiquinone

32

derivatives in A. cinnamomea. It not only advances our knowledge on the bioactive

33

metabolites especially the ubiquinone derivatives in A. cinnamomea, but also provides

34

valuable information for the investigation on other edible and medicinal mushrooms.

35 36 37

Keywords: Antrodia cinnamomea; edible and medicinal mushroom; ubiquinone derivatives;

38

structure; bioactivity; chemical synthesis; biosynthesis; metabolic regulation

39 40 41 42 43 44 2


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1. Introduction

46

Higher fungi/mushrooms have been regarded as a sustainable cell factory to produce

47

unique bioactive metabolites, which are valued as edible and medicinal provisions for human

48

health.

49

camphoratus, is an exclusive fungus which has been traditionally used in Taiwan as a folk

50

medicine. Previous studies revealed that A. cinnamomea possesses extensive and great

51

biological activities, such as hepatoprotective effect, immunomodulation, anti-cancer,

52

anti-oxidation and anti-inflammation. However, it is extremely difficult to obtain fruiting

53

bodies of A. cinnamomea in wild, due to the slow growth rate and the rarity of parasitic host

54

tree Cinnamomum kanehirai Hay

55

cultivation, solid-state fermentation and submerged fermentation has been applied as

56

substitutes for wild fruiting body of A. cinnamomea to meet the increasing consumption

57

demand 6.

Antrodia

cinnamomea,

also

named

Antrodia

camphorata,

Taiwanofungus

1-5

. Therefore, artificial cultivation including basswood

58

To explore the potential medicinal application, for the first step, multiple

59

pharmacological activities of the crude extracts of A. cinnamomea have been extensively

60

investigated and summarized in Table 1. For example, the crude extracts of A. cinnamomea

61

could induce the apoptosis of tumor cells, including human hepatoma cells Hep G2, Hep 3B,

62

PLC/PRF/5 and B16F10 melanoma cell

63

important function of the extract. It was reported that the aqueous extract of the mycelia

64

could effectively protect human umbilical vein endothelial cells from free-radical damage 11.

65

Although the crude extracts of A. cinnamomea possessed significant pharmacological

66

activities, the bioactive ingredients of A. cinnamomea were still largely unclear.

7-10

. Antioxidant activity was also revealed as an

3



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67 68

Hence, for the second step, many types of bioactive compounds have been identified in

69

fruiting bodies and mycelia of A. cinnamomea, including terpenoids, succinic acid and maleic

70

acid derivatives, polysaccharide, sterol and ubiquinone derivatives, et al 2, 12-18. Triterpenoids

71

are regared as the largest group of phytochemicals and have significant medicinal values 19.

72

Antcins are the typical triterpenoid compounds of A. cinnamomea. Under the stimulation of

73

antcin B and methylantcinate B, NADPH oxidase and both the extrinsic and intrinsic

74

apoptosis pathways were activated and provoked HepG2 cell death

75

Hep 3B cell apoptosis, adhesion, migration and invasion via modifying and adjusting protein

76

expression and mitochondrial membrane permeability

77

from the fruiting bodies of A. cinnamomea could effectively induce autophagy in Hep 3B

78

cells and the IC50 was 18.4 µM 24. Antcamphins A-L are ergosterol-type terpenoids and show

79

IC50 values ranging from 22.0 to 93.5 µM in breast cancer cells (MDA-MB-231) and lung

80

cancer cells (A549) 25. Except these typical terpenoids, polysaccharides are another important

81

class of bioactive compounds which extracted from both the fruiting bodies and mycelia of

82

the A. cinnamomea. They exhibit excellent bioactivity against hepatitis B virus and

83

anti-inflammatory activities

84

important bioactive compositions of A. cinnamomea. which possess anti-cancer and

85

anti-inflammatory activities 29-31. In addition, a number of benzenoids in A. cinnamomea have

86

been reported to possess anti-inflammatory activity. Among the benzenoids, antrocamphin A

87

has been believed to be the main component responsible for the anti-inflammatory activity,

88

which inhibit pro-inflammatory molecule release through down-regulation of inducible nitric

20, 21

. Antcin K mediated

22, 23

. Eburicoic acid which separated

26-28

. Succinic and maleic acid derivatives are also listed as

4


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89

oxide synthase (iNOS) and COX-2 expression via the nuclear factor-kappa B (NF-κB)

90

pathway32-34.

91

Among different types of bioactive compounds, ubiquinone derivatives not only have

92

the particularity in the chemical structure, but also be regarded as one of the most biologically

93

active components in A. cinnamomea. Therefore, the aim of this review is to introduce recent

94

advances on the structure, bioactivity and synthesis of ubiquinone derivatives in the edible

95

and medicinal mushroom A. cinnamomea.

96

97

2. The structure and bioactivity of ubiquinone derivatives

98

Ubiquinone derivatives are the characteristic bioactive compounds in A. cinnamomea,

99

which possess notable anticancer activity and potent anti-inﬂammatory activity. Until now,

100

twelve new kinds of ubiquinone derivatives have been isolated and identified in A.

101

cinnamomea, including Antroquinonol, Antroquinonol B, Antroquinonol C, Antroquinonol D,

102

Antroquinonol L, Antroquinonol M, Antrocamol LT1, Antrocamol LT2, Antrocamol LT3,

103

4-acetyantroquinonol B, 4-acetylantrocamol LT3 and antrocinnamone. The unique structure

104

of each ubiquinone derivative is displayed in Fig. 1, while the molecular formula and

105

bioactivity of different ubiquinone derivatives in A. cinnamomea are summarized in Table 2.

106

As one of the most important ubiquinone derivatives in A. cinnamomea, antroquinonol 35

107

exhibit potent bioactivities for treating Alzheimer's disease

108

cells, including liver cancer, leukemia, lung cancer, breast cancer, pancreatic cancer, et al.

109

In-depth investigation on the anti-cancer mechanisms of antroquinonol reveal that it can

110

inhibit cancer cell proliferation/induce death through altering the signal pathway or activity of 5


and a wide range of cancer


proteins.

Evidence

suggests

that

antroquinonol

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111

key

modulates

Adenosine

112

5'-monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin

113

(mTOR) pathways via inhibiting protein phosphorylation, including mTOR, p70S6K and

114

4E-BP1, stimulating the assembly of the tuberous sclerosis complex (TSC)-1/TSC2 and

115

increasing AMPK activity to against hepatocellular carcinoma 36. Additionally, antroquinonol

116

induced autophagy of human lung cancer, liver cancer and leukemia cells through the

117

inhibition of isoprenyl transferase activity and leading to inhibition of Ras and Rho signaling

118

and Ras-related GTP-binding protein

119

effectively reduce the tumor volume by inhibiting focal adhesion kinase (FAK)/Src complex

120

formation in both N18 neuroblastoma and C6 glioma cell lines

121

participated in the inhibition of non-small lung cancer cells proliferation with a EC50 value of

122

25 µM by down-regulation of Bcl2 protein which associated with a decrease in

123

phosphatidylinositol 3 kinase (PI3K) and mTOR protein levels

124

which based on the patients with metastatic non-small cell lung cancer, had revealed the

125

dose-limiting toxicities (DLT) and maximum tolerable dose (MTD) of antroquinonol and put

126

forward the recommended dose for Phase II studies in different types of cancer

127

tumor MDA-MB-231 cells migration/invasion was suppressed by antroquinonol through

128

inhibiting extracellular-regulated protein kinase (ERK)-activator protein (AP)-1 and

129

AKT-NF-κB dependent matrix metalloproteinase-9 (MMP-9) and epithelial-mesenchymal

130

transition expression, such as N-cadherin, Twist and Snail up-regulations and E-cadherin

131

down-regulations

132

cell-like properties in colon cancer by participating in targets PI3K/AKT/β-catenin signaling

37

. Previous studies found that antroquinonol can

38

. Antroquninonol also

39

. In 2014, a Phase I study

40

. Breast

41

. A recent research reported that antroquinonol suppressed cancer stem

6


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42

133

and regulating downstream target expression

. In addition, antroquinonol can inhibit the

134

proliferation of pancreatic cancer PANC-1 and AsPC-1 cells with a IC50 value of 18.6 and

135

20.2 µM, respectively

136

regarded as a promising therapeutic agent in treatment of cancer cells, and approved into

137

phase 2 clinical trial by US FDA 43.

16

. Due to the prominent bioactivities of antroquinonol, it has been

138

Antroquinonol B and 4-acetyantroquinonol B are the others two ubiquinone derivatives

139

with notable pharmacological activity in A. cinnamomea. In the latest literature, the

140

anti-inflammatory activity of antroquinonol B and 4-acetyantroquinonol B were evaluated

141

through

142

macrophages, with excellent IC50 of 16.2 and 14.7 µg/mL, respectively

143

with three commercial drugs folinic acid, fluorouracil and oxaliplatin (FOLFOX),

144

4-acetyantroquinonol B exhibited better results in the inhibition of tumor proliferation of

145

DLA-1, HCT-116, SW-480, RKO and HT-29 cells

146

significantly reduce the formation of colorectal cells and participate in the regulation of

147

several signal transduction pathways, including Lgr5/Wnt/beta-catenin, JAK-STAT and

148

non-transmembrane receptors amino acid kinase signaling pathway

149

was also significantly inhibited by 4-acetylantroquinonol B via arresting G1 phase of the cell

150

cycle, regulating the p53 and p21 proteins and the mRNA expression of cyclin-dependent

151

kinase (CDK)2, CDK4, p21, p27 and p53 protein 46, 47.

measuring

nitrite

production

from

lipopolysaccharides

(LPS)-stimulated 44

. When compared

45

. 4-acetyantroquinonol B can

45

. HepG2 proliferation

152

Currently, besides of the extensively studied antroquinonol, antroquinonol B and

153

4-acetylantroquinonol B, more and more ubiquinone derivatives in A. cinnamomea have been

154

evaluated to exhibit great bioactivities. For instance, antroquinonol D is not-toxic to normal 7



155

cells while it could inhibit the growth of MCF7, T47D and MDA-MB-231 breast cancer cell

156

with IC50 value of 8.01, 3.57 and 25.08 µM, respectively

157

methyltransferase inhibitor, antroquinonol D induces DNA demethylation and activates a

158

variety of silenced tumor suppressor genes to inhibit cell growth and migration. By recent

159

report of Yen et al., antrocamol LT1, antrocamol LT2 and antrocamol LT3 showed strong and

160

selective cytotoxicity on five human cancer cell lines, with the IC50 ranging from 0.01 to 1.79

161

µΜ

162

been isolated from the mycelia of A. cinnamomea and shown relatively toxicity against three

163

human cancer cell lines 50.

48

. Meanwhile, as a DNA

49

. Two new ubiquinone derivatives antrocinnamone and 4-acetylantrocamol LT3 has

164 165

3. Synthesis and metabolic regulation of ubiquinone derivatives in Antrodia cinnamomea

166

People all around the world are paying more and more attention to the ubiquinone

167

derivatives in A. cinnamomea, due to their significantly biological effects. However, the

168

contents of these ubiquinone derivatives in A. cinnamomea are quite low, which could not

169

meet the increasing demand in both research and commercial purpose. Hence, how to

170

efficiently obtain these valuable compounds with a large quantity is an urgent task. There are

171

two common methods to synthesize these ubiquinone derivatives, one is the chemical total

172

synthesis while the other one is biosynthesis. In this section, the two approaches to synthesize

173

ubiquinone derivatives are comparatively discussed and the emphasis is placed on the

174

biosynthesis and metabolic regulation of these characteristic compounds in the fermentation

175

of A. cinnamomea.

176 8


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177


3.1 Chemical synthesis of ubiquinone derivatives of A. cinnamomea

178

The flexibility of chemical synthesis is used to construct and design new compounds,

179

such as peptides, protein, drug and chemical products 54-56. Among the ubiquinone derivatives

180

of A. cinnamomea, only antroquinonol and antroquinonol D have been successfully

181

synthesized by chemical method recently. Hence, only the chemical synthesis routes of the

182

two compounds are discussed in this section.

183

In 2015, Sulake et al. used an iridium-catalyzed olefin isomerization-Claisen

184

rearrangement reaction to accomplish the first total synthesis of antroquinonol 57. Afterwards,

185

they developed another approach for synthesis of antroquinonol by using D-mannose as the

186

starting material

187

4-methoxyphenol by Rohidas et al. in 2014 52. The framework of quinonol synthesis involved

188

chelation and substrate-controlled diastereoselective reduction of cyclohexenone and

189

lactonization. By subsequent Michael addition of dimethyl malonate on cyclohexadienone,

190

dihydroxylation and Wittig olefination, the sesquiterpene side chain was synthesized through

191

coupling with geranyl phenyl sulfide with Bouveault-Blanc reduction

192

synthesis approach of antroquinonol and antroquinonol D are quite complicated and exist

193

many difference intermediate compounds, researchers are looking for a better way to

194

synthesis these compounds. In 2015, a short synthesis of antroquinonol was proposed to

195

origin from 2,3,4-trimethoxyphenol and undergo seven-step synthesis 60. total synthesis of

196

antroquinonol and antroquinonol D were accomplished by using enantioselective Michael

197

reactions, which require short linear synthetic sequences (only 6 steps) 61. As show in Fig. 2,

198

antroquinonol and antroquinonol D could be synthesized from benzoquinone monoketals by

58

. In terms of antroquinonol D, it was firstly synthesized from

9


52, 59

. Since this


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199

enantioselective Michael reaction as the strategic step. It is worth noting that upon treatment

200

with K2CO3 in MeOH in the sixth step, the chlorine atom was replaced by the methoxy group

201

and the inversion of configuration occurred in C-6 to form antroquinonol. Otherwise,

202

antroquinonol D was obtained when the substituent changes from a chlorine atom to a

203

hydrogen atom and without the methoxy substituent at the C-3 position. Finally, the yield of

204

antroquinonol and antroquinonol D were 10.4% and 15.2%, respectively

205

used a conjugate addition to a substituted quinone through a similar 6-step reaction to

206

synthesize the antroquinonol

207

quinon-monoketal

208

antroquinonol in an overall yield of 13% with 96% e.e. 43. Although the chemical synthesis of

209

ubiquinone derivatives has made great progress, there are still several problems of this

210

approach, such as the generation of by-products and the need for further modification of

211

some substances to restore activity

212

means that chemical synthesis usually involves long linear sequences, which is difficult for

213

purification and to achieve a high yield 64. Comparatively, the production of these bioactive

214

compounds through biosynthesis approach is more natural and sustainable

215

biosynthesis and metabolic regulation of these ubiquinone derivatives in A. cinnamomea will

216

be mainly elaborated in the subsequent section.

from

61

. Villaume et al.

43

. The synthesis commences with the formation of

commercial

benzaldehyde,

resulting

in

enantioenriched

62, 63

. In addition, the complexity of natural products

65

. Thus, the

217 218

3.2 Biosynthesis and the metabolic regulation of ubiquinone derivatives in A.

219

cinnamomea

220

Up to now, the known biosynthetic pathway of ubiquinone compounds is mainly based 10


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221

on bacteria and yeast. Ubiquinone compounds consist of two major structure, benzoquinone

222

rings and polyisoprene side chains. As shown in Fig. 3, it has been reported that the

223

polyisoprene side chain is synthesized through Mevalonate (MVA) pathway or

224

Methylerythritol 4-phosphate (MEP) pathway in eukaryotes or bacteria and then connected

225

with the benzene ring donor

226

ubiquinone

227

microorganisms, the ubiquinone derivatives in A. cinnamomea possess unique structure on

228

both the quinone ring and the polyisoprene side chain. For instance, the hydroxyl

229

modification occurs on the quinone ring of antroquinonol while the γ-lactone ring structure

230

occurs on the polyisoprene side chain of 4-acetyantroquinonol B. Hence, it is indicated that

231

the unique structure of the ubiquinone derivatives in A. cinnamomea may be biosynthesized

232

through novel metabolic pathway. However, the metabolic pathway of these ubiquinone

233

derivatives is still unclear at present. In recent years, some researchers suggested that

234

antroquinonols share the same biosynthetic pathway with ubiquinones, both involving a

235

combinatorial route of the shikimate and MVA pathway 19. Different opinions were supported

236

by the other researchers, in which the polyisoprene side chain was biosynthesized by the

237

same MVA pathway while the quinonoid nucleus was supposed to be synthesized through

238

polyketide pathway

239

these ubiquinone derivatives in A. cinnamomea are comparatively discussed in the following

240

section.

66-68

. The benzene ring is further modified to finally form

69, 70

. Unlike the common ubiquinone compounds synthesized by the model

71-73

. Therefore, the two controversial pathways for the biosynthesis of

241 242

3.2.1 Shikimic acid pathway and related metabolic regulation 11



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243

Two typical ubiquinone derivatives antroquinonol and 4-acetyantroquinonol B, which

244

respectively possess hydroxyl modification on the quinone ring and γ-lactone ring structure

245

on the polyisoprene side chain, were chosen for in-depth discussion on the biosynthesis

246

pathway and metabolic regulation in A. cinnamomea. Although antroquinonol and

247

4-acetylantroquinonol B were isolated and identified from A. cinnamomea in 2007 and 2009,

248

their biosynthesis pathways are still not clear at present 44, 51. A part of researchers suggested

249

that the biosynthesis of ubiquinone derivatives in A. cinnamomea was based on the shikimic

250

acid pathway. As evidence, the production of ubiquinone derivatives was significantly

251

induced by the addition of the precursor material which was associated with coenzyme Q

252

synthesis. Geraniol, 4-hydroxybenzoic acid and oleic acid were precursors of ubiquinone and

253

they can improve the production of antroquinonol and 4-acetylanthraquinone B 74, 75. Some of

254

the volatile compounds such as 2,4,5-trimethoxybenzaldehyde (TMBA) and nerolidol were

255

hypothesized as the precursors of the 4-acetylantroquinonol B by Chiang et al. The TMAB

256

may be produced from phosphoenolpyruvate via the shikimate pathway and finally reacts

257

with farnesyl diphosphate to synthesize 4-acetylantroquinonol B 76. For a short summary, as

258

shown in Fig. 4, it was proposed that the isoprene side chain was synthesized via the MVA

259

pathway while the benzoquinone ring was synthesized via the shikimic acid pathway.

260

Specifically,

261

4-acetylantroquinonol B was from phenylalanine to chorismic acid, modification to form

262

4-hydroxybenzoic acid, and then connect with the isoprene side chain to further produce

263

antroquinonol and 4-acetylantroquinonol. Alternatively, phenylalanine was transformed to

264

cinnamic acid, TMAB, and further form antroquinonol and 4-acetylantroquinonol B 74, 76.

one

possible

route

for

the

biosynthesis

12


of

antroquinonol

and

Page 13 of 42


265 266 267

3.2.2 Polyketide pathway and related metabolic regulation Studies also suggested that ubiquinone derivatives of A. cinnamomea were likely 72, 73

268

synthesized through polyketide synthase

269

supported the speculation of biosynthesis of ubiquinone derivatives through polyketide

270

pathway in A. cinnamomea. Four polyketide synthase (PKS) genes of A. cinnamomea,

271

including three reducing PKSs and one non-reducing PKS (NR-PKS), were identified. Yu et

272

al. revealed that the function of the NR-PKS gene pks63787 associated with the biosynthesis

273

of aromatic metabolites, including five benzenoids and two benzoquinone derivatives such as

274

coenzyme Q0 (CoQ0)

275

as a precursor of ubiquinone derivatives and the in-depth investigation of the mechanisms

276

revealed that addition of CoQ0 could regulate some key proteins involved in the

277

antroquinonol biosynthetic pathway

278

acid sequences of the PKS63787 KS domains and 32 NR-PKSs of representing fungal

279

species revealed that pks63787 was clustered with orsellinic acid synthases which tightly

280

linked with the important precursor of ubiquinone derivatives in A. cinnamomea

281

deletion of pks63787 resulted in the failure of synthesis of antroquinonol and

282

4-acetylantroquinonol B. However, these ubiquinone derivatives could be biosynthesized

283

again when combined with the addition of orsellinic acid during cultivation process 53. Based

284

on the existing studies, the proposed polyketide pathway for the biosynthesis of ubiquinone

285

derivatives

286

4-acetyantroquinonl B both relied on orsellinic acid as the common precursor to form

in

A.

With the application of genomics, it further

77, 78

. Thus, CoQ0, as a common polyketone compound, was selected

cinnamomea

74, 75, 79

. Afterwards, phylogenetic analysis on the amino

was

displayed

in

Fig.

13


5.

53

. Further

Antroquinonol

and


Page 14 of 42

287

benzoquinone ring. Followed the polyketide pathway, the crucial precursor orsellinic acid

288

was farnesylated to form 3-farnesyl-orsellinic acid, undergone a series of reaction to form

289

coenzyme Q3 (CoQ3）, and then finally synthesized to antroquinonol through an unknown

290

process. Alternatively, antroquinonol could be biosynthesized by the ring modification of

291

orsellinic acid though the intermediate product CoQ0

292

the distinct difference was the γ-lactone modification on the farnesyl tail terminal.

53, 80

. In term of 4-acetyantroquinonl B,

293 294

3.2.3 Other biosynthetic regulation

295

Besides the common biosynthetic regulation based on the metabolic pathway, the other

296

kinds of regulation methods were successfully applied for the enhanced production of

297

ubiquinone derivatives in A. cinnamomea. Antroquinonol is hydrophobic and nearly insoluble

298

in the fermentation broth and hence hardly be biosynthesized through ordinary submerged

299

fermentation

300

biosynthesis of antroquinonol by 89.06 mg/L through alleviating the product inhibition

301

Fungal effector is defined as a complex mixture of components that can promote the

302

synthesis of fugal metabolites

303

stimulated by the addition of various effectors such as camphorwood leach liquor, by which

304

the change of morphology and provision of vital precursors as structure donors have been

305

suggested as possible mechanistic actions

306

play important roles in organisms, including regulation of electron transport and inhibition of

307

mitochondrial peroxidation

308

molecules, not only damage cell structure and compromise function, but also play an

75

. Therefore, plant oil was applied as in situ extractant and promoted the 75, 81

.

82

. It was found that the production of antroquinonol was

79, 81

. Additionally, most ubiquinone substances

83-85

. Reactive oxygen species (ROS), a group of highly reactive

14


Page 15 of 42


309

important role in the regulation of cell growth and secondary metabolism on gene

310

transcription levels 86, 87. Thus, based on the intrinsic link between the physiological function

311

of ubiquinone and ROS stimulating effect, addition of hydrogen peroxide (H2O2) could

312

enhance the intracellular ROS content, the oxidative stress and thus stimulating the

313

biosynthesis of antroquinonol and other bioactive compounds during the submerged

314

fermentation process 88.

315

Based on these recent results, the proposed model for the biosynthetic pathway and

316

metabolic regulation of ubiquinone derivatives in A. cinnamomea is shown in Fig 6. In this

317

model, the key points, the mode of action and the underlying mechanisms that have important

318

implications for the biosynthesis and regulation of ubiquinone derivatives have been clearly

319

illustrated.

320 321

4. Future Perspectives

322

During the recent two decades, along with the recognition of the precious value of the

323

edible and medicinal mushroom A. cinnamomea, more and more researchers are paying great

324

attention to the isolation and identification of new chemical compounds, revealing their

325

pharmacological activity and then their biosynthetic aspect. Among these cherished

326

metabolites, ubiquinone derivatives possess excellent biological activities and have been

327

regarded as the dazzling jewels in A. cinnamomea. Therefore, increasing reports have been

328

published covering almost complete information on the structure, bioactivity, chemical

329

synthesis, biosynthesis and metabolic regulation of these new ubiquinone derivatives, which

330

have been comprehensively summarized in this review. However, many intrinsic and 15



331

extrinsic obstacles are still stand in the way to the research progress. This retardation could be

332

attributed to several aspects, such as: (a) Most of the ubiquinone derivatives have been

333

reported to have anticancer activities through inhibiting migration/invasion/proliferation and

334

promoting cell apoptosis to against cancer cells in vitro and in vivo. However, the underlying

335

mechanistic actions of these ubiquinone derivatives such as the pharmacokinetics and

336

pharmacodynamics are still unclear. The purity and the sufficient quantity of these

337

ubiquinone derivatives are the bottlenecks hindering the development. At present, most

338

studies are addressed on laboratory levels and only antroquinonol has entered clinical trials.

339

Therefore, more human and clinical trials are necessary for a full evaluation of these valuable

340

compounds for potential clinical applications to benefit the whole mankind. (b) Although

341

some ubiquinone derivatives have been successfully synthesized by chemical approach,

342

further improvements are still required, such as reducing the generation of different

343

by-products, shortening the synthesis steps and increasing the product yield. (c) Further

344

in-depth investigation on the biosynthetic pathway are largely required. The ubiquinone

345

derivatives in A. cinnamomea possess unique structure on the quinone ring and the

346

polyisoprene side chain. For the polyisoprene side chain, it is believed to be synthesized

347

through MVA pathway. However, for the biosynthesis of quinonoid nucleus, it is still

348

controversial between the polyketide pathway and shikimic acid pathway. With the

349

development and integrated application of different research approaches such as genomics,

350

proteomics and metabolomics, it is promising to pave the way for the understanding on

351

biosynthetic pathway. (d) Based on the illumination on the biosynthetic pathway, more

352

metabolic regulation methods could be used for efficient biosynthesis of these ubiquinone 16


Page 16 of 42

Page 17 of 42


353

derivatives. For instance, a series of regulatory genes has been proved to be activated by

354

ROS. The underlying regulatory mechanisms of extracellular and intracellular stimulus such

355

as in situ extraction and oxidative stress should be further revealed on molecular level with

356

the help of transcriptome and metabolomic analysis. (e) Due to the particular difficulty to

357

obtain fruiting bodies of A. cinnamomea in wild, artificial cultivation especially solid-state

358

fermentation and submerged fermentation will be applied as promising substitutes to meet the

359

increasing consumption demand. However, there is a large gap in the bioactivity between the

360

fruiting body from wild and the mycelia from artificial culture. Hence, how to efficiently

361

enhance the content of characteristic bioactive compounds such as ubiquinone derivatives in

362

the fermented mycelia is an urgent task, which is also significant for the increasing demand in

363

both research and commercial purpose.

364 365

Acknowledgements

366

This work was supported by the National Key Research and Development Program of

367

China (Grant No. 2016YFD0400802), the fund of the Beijing Engineering and Technology

368

Research Center of Food Additives, Beijing Technology & Business University, the Priority

369

Academic Program Development of Jiangsu Higher Education Institutions, the Jiangsu

370

province "Collaborative Innovation Center for Advanced Industrial Fermentation" industry

371

development program, and the Program of Introducing Talents of Discipline to Universities

372

(No. 111-2-06).

373 374 375 17



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618

80. Chou, K. C.; Yang, S. H.; Wu, H. L.; Lin, P. Y.; Chang, T. L.; Sheu, F.; Chen, K. H.;

619

Chiang, B. H. Biosynthesis of antroquinonol and 4-acetylantroquinonol B via a

620

polyketide pathway using orsellinic acid as a ring precursor in Antrodia cinnamomea. J.

621

Agric. Food Chem. 2017, 65, 74-86.

622

81. Hu, Y. D.; Lu, R. Q.; Liao, X. R.; Zhang, B. B.; Xu, G. R. Stimulating the biosynthesis

623

of antroquinonol by addition of effectors and soybean oil in submerged fermentation of

624

Antrodia camphorata. Biotechnol. Appl. Biochem. 2016, 63, 398-406.

625 626

82. Bentinger, M.; Tekle, M.; Brismar, K.; Chojnacki, T.; Swiezewska, E.; Dallner, G. Stimulation of coenzyme Q synthesis. Biofactors. 2008, 32, 99-111.

627

83. Bertsova, Y. V.; Bogachev, A. V.; Skulachev, V. P. Two NADH: ubiquinone

628

oxidoreductases of Azotobacter vinelandii and their role in the respiratory protection.

629

Biochim Biophys, Acta, Bioenerg. 1998, 1363, 125-133.

630 631 632 633

84. Ernster, L.; Dallner, G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim. Biophys. Acta Mol. Basis. Dis. 1995, 1271, 195-204. 85. Mellors, A.; Tappel, A. L. The inhibition of mitochondrial peroxidation by ubiquinone and ubiquinol. J. Biol. Chem. 1966, 241, 4353-4356.

634

86. Wei, Z. H.; Bai, L.; Deng, Z.; Zhong, J. J. Enhanced production of validamycin A by

635

H2O2-induced reactive oxygen species in fermentation of Streptomyces hygroscopicus

636

5008. Bioresour Technol. 2011, 102, 1783-1787.

637 638 639

87. Dixon, S. J.; Stockwell, B. R. The role of iron and reactive oxygen species in cell death. Nat. Chem. Biol. 2014, 10, 9-17. 88. Xia, Y. J.; Zhou, X.; Wang, G. Q.; Zhang, B. B.; Xu, G. R.; Ai, L. Z. Induction of 29



640

antroquinonol production by addition of hydrogen peroxide in the fermentation of

641

Antrodia camphorata S-29. J. Sci. Food Agric. 2017, 97, 595-599.

642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 30


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669

Figure Captions

670

Fig. 1 The structure of different ubiquinone derivatives in A. cinnamomea

671 672

Fig. 2 The chemical total synthesis route for antroquinonol and antroquinonol D 43, 61

673

OTf: trifluormethanesulfonate, LHMDS: lithiumhexamethyldisilazide, THF: tetrahydrofuran,

674

DMF: N,N-dimethylformamide, LS-Selectride: lithium trisiamylborohydride.

675 676

Fig. 3 Biosynthetic pathway of ubiquinone in model organisms

677

IPP:

678

3-Hydroxy-4-methylglutaryl-CoA.

Isoprenenyl

diphosphate,

DMAPP:

Dimethylallyl

diphosphat,

HMG-CoA:

679 680

Fig. 4 Proposed shikimic acid synthesis pathway of ubiquinone derivatives in A. cinnamomea

681

74, 76

682

①: 4-Hydroxybenzoic acid was used as benzoquinone rings precursor.

683

②: 2,4,5-trimethoxybenzaldehyde was used as benzoquinone rings precursor.

684

GPP: Geranyl diphosphate, FPP: Farnesyl pyrophosphate.

685 686

Fig. 5 Proposed polyketide pathway for the biosynthesis of ubiquinone derivatives in A.

687

cinnamomea 53, 78, 80

688

FPPB: Farnesyl pyrophosphate-γ-lactone, CoQ3B: coenzyme Q3-γ-lactone, 5-DMQ3B:

689

5-demethoxy-CoQ3-γ-lactone, FOAB: 3-farnesyl-orsellinic acid-γ-lactone.

690

31



691

Fig. 6 Proposed biosynthesis regulation of ubiquinone derivatives in A. cinnamomea

692

32


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Table 1 The typical bioactive compounds in A. cinnamomea

Crude

Type

Source

Bioactivities

References

Ethyl acetate extract

Fruiting body

Human hepatoma cells Hep G2, Hep 3B and PLC/ PRF/5

7-9

Ethanol extract

Mycelia

B16F10 melanoma cell

10

Aqueous extract

Mycelia

Human umbilical vein endothelial cells

11

Mainly in

Hep G2, Hep 3B, Breast cancer (MDA-MB-231), Lung

fruiting body

cancer (A549)

extracts

20-25

Triterpenoids

Fruiting body Polysaccharides

Against hepatitis B virus and anti-inflammatory

26-28

Anti-cancer, anti-inflammatory

29-31

Anti-inflammatory

32-34

Refer to Table 2 for details

Table 2

and mycelia Isolated Succinic and maleic

Fruiting body

acid

and mycelia

Benzenoids

Fruiting body

Ubiquinone

Mainly in

derivatives

mycelia

compounds

33



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Table 2 The molecular formula and bioactivity of different ubiquinone derivatives in A. cinnamomea Compounds

Molecular

(report year)

formula

Source

Antroquinonol

Form

Bioactivity

References

Yellow oil

Alzheimer's disease, Lung cancer, liver cancer, leukemia, breast cancer, colon cancer, pancreatic cancer, et al.

16, 35-39, 41, 51

Mycelia (solid-state C24H38O4

(2007)

fermentation)

Antroquinonol B

Mycelia (solid-state

Inhibition of NO production in C24H36O6 (2009)

Colorless oil

lipopolysaccharide-activated

44

fermentation) murine macrophages

Antroquinonol C


Pale yellow

fermentation)

oil


Slight

Breast cancer MCF7, T47D and

fermentation)

yellowish oil

MDA-MB-231

Yellowish oil

No reported

C25H40O5 (2008) Antroquinonol D

Breast Cancer

C23H36O3 (2014) Antroquinonol L

48

Mycelia (liquid C23H32O3

(2017)

53

fermentation)

Antroquinonol M (2017)

52

C23H32O3

Mycelia (liquid

Pale-yellowish

fermentation)

oil

No reported

34


53

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Antrocamol LT1

Mycelia (solid-state C24H39O5

(2015)

Colorless oil fermentation)

Antrocamol LT2

Mycelia (solid-state Colorless oil fermentation)

Antrocamol LT3

Colorless oil fermentation) Mycelia (solid-state

C26H38O7 B (2009)

49

DU-145, Madin-Darby canine


4-acetyantroquinonol

HepG2, Human Prostate carcinoma lines PC3 and

C24H39O5 (2015)

49

Human liver carcinoma line

C26H40O6 (2015)

Colon carcinoma line CT26,

kidney normal cell line

49

Colorectal cancer Colorless oil

44-47

fermentation)

HepG2

4-acetylantrocamol C26H40O6

Mycelia

Yellow oil

LT3 (2017)

50 Three human cancer cell lines

Antrocinnamone

(549, HepG2, and PC3) C23H32O3

Mycelia

Yellow oil

(2017)

35


50


Fig. 1

36


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Fig. 2

37



Fig. 3

38


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Fig. 4

39



Fig. 5

40


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Fig. 6

41



Graphic for table of contents

42


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