Endophytes from Ginkgo biloba and their secondary …...Ginkgo biloba is a medicinal plant which...
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Yuan et al. Chin Med (2019) 14:51 https://doi.org/10.1186/s13020-019-0271-8 REVIEW Endophytes from Ginkgo biloba and their secondary metabolites Zhihui Yuan 1,3 , Yun Tian 1 , Fulin He 2,3* and Haiyan Zhou 1* Abstract Ginkgo biloba is a medicinal plant which contains abundant endophytes and various secondary metabolites. Accord- ing to the literary about the information of endophytics from Ginkgo biloba, Chaetomium, Aspergillus, Alternaria, Penicillium and Charobacter were isolated from the root, stem, leaf, seed and bark of G. biloba. The endophytics could produce lots of phytochemicals like flavonoids, terpenoids, and other compounds. These compounds have antibac- teria, antioxidation, anticardiovascular, anticancer, antimicrobial and some novel functions. This paper set forth the development of active extracts isolated from endophytes of Ginkgo biloba and will help to improve the resources of Ginkgo biloba to be used in a broader field. Keywords: Ginkgo biloba, Chinese medical plant, Endophytes, Secondary metabolites © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Background Ginkgo biloba (G. biloba) is a deciduous tree belonging to the ginkgo genus, which is also known as Gongsun- shu, etc. G. biloba is one of the most ancient plants on earth dating back more than 200 million years. Com- monly Ginkgo biloba has been used for a medicinal plant and its seeds, leaves and fruits can be used for medicines with biological activities involving antibacteria, antioxi- dation, anticardiovascular and others. However, Ginkgo trees grow slowly and under natural conditions they need more than 20 years from planting to fruiting, which is a restricting point for its development; while its endophyt- ics provide physiological metabolic pathways to pro- duce numerous novel medicinal compounds which have become a hotspot [1]. e endophytics play important roles in the process of host plant growth and systematic evolution [1, 2]. During the whole life, endophytics protect their host from infec- tious diseases and also help to survive in adverse environ- ment [3]. Since the unique relationships between the host plant and associated endophytes, endophytes in G. biloba have been recognized as important sources of a variety of novel secondary metabolites with anticancer, antimicro- bial and other biological activities [4, 5]. Secondary metabolites are the chemical bank which provides a huge quantity of diverse commercial products for human medicines. First report about endophytics is that Stierle et al. isolated Taxomyces andreanae from phloem of Taxus brevifolia, which can produce taxol and related chemicals at the concentration of 24–50 ng/L [6]. From then on, more and more endophytics from phar- maceutical plants, such as Camptotheca acuminata [7], pine [8] and Taxus plants [9–11] were isolated. As to G. biloba, various endophytics including Chaetomium, Aspergillus, Alternaria, Penicillium and Charobacter were isolated from the root, stem, leaf, seed and bark of G. biloba. ey produce lots of phytochemicals like fla- vonoids, terpenoids, and other compounds [12, 13]. 50% of these isolates showed antimicrobial activities against various pathogens. Some secondary metabolites such as 2-hexenal have been involved in the plant’s defense against pests. ese bioactive metabolites are attractive to developing the commercial prodrugs and agricultural/ industrial production. Most importantly, as a therapeutic drug, G. biloba has no side effects even after long periods of use and its phytopharmaceuticals are readily accessible throughout the world. For better using endophytic and Open Access Chinese Medicine *Correspondence: [email protected]; [email protected] 1 College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China 3 College of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yongzhou 425199, China Full list of author information is available at the end of the article
Transcript of Endophytes from Ginkgo biloba and their secondary …...Ginkgo biloba is a medicinal plant which...
Yuan et al. Chin Med (2019) 14:51 https://doi.org/10.1186/s13020-019-0271-8
REVIEW
Endophytes from Ginkgo biloba and their secondary metabolitesZhihui Yuan1,3, Yun Tian1, Fulin He2,3* and Haiyan Zhou1*
Abstract
Ginkgo biloba is a medicinal plant which contains abundant endophytes and various secondary metabolites. Accord-ing to the literary about the information of endophytics from Ginkgo biloba, Chaetomium, Aspergillus, Alternaria, Penicillium and Charobacter were isolated from the root, stem, leaf, seed and bark of G. biloba. The endophytics could produce lots of phytochemicals like flavonoids, terpenoids, and other compounds. These compounds have antibac-teria, antioxidation, anticardiovascular, anticancer, antimicrobial and some novel functions. This paper set forth the development of active extracts isolated from endophytes of Ginkgo biloba and will help to improve the resources of Ginkgo biloba to be used in a broader field.
Keywords: Ginkgo biloba, Chinese medical plant, Endophytes, Secondary metabolites
© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
BackgroundGinkgo biloba (G. biloba) is a deciduous tree belonging to the ginkgo genus, which is also known as Gongsun-shu, etc. G. biloba is one of the most ancient plants on earth dating back more than 200 million years. Com-monly Ginkgo biloba has been used for a medicinal plant and its seeds, leaves and fruits can be used for medicines with biological activities involving antibacteria, antioxi-dation, anticardiovascular and others. However, Ginkgo trees grow slowly and under natural conditions they need more than 20 years from planting to fruiting, which is a restricting point for its development; while its endophyt-ics provide physiological metabolic pathways to pro-duce numerous novel medicinal compounds which have become a hotspot [1].
The endophytics play important roles in the process of host plant growth and systematic evolution [1, 2]. During the whole life, endophytics protect their host from infec-tious diseases and also help to survive in adverse environ-ment [3]. Since the unique relationships between the host plant and associated endophytes, endophytes in G. biloba
have been recognized as important sources of a variety of novel secondary metabolites with anticancer, antimicro-bial and other biological activities [4, 5].
Secondary metabolites are the chemical bank which provides a huge quantity of diverse commercial products for human medicines. First report about endophytics is that Stierle et al. isolated Taxomyces andreanae from phloem of Taxus brevifolia, which can produce taxol and related chemicals at the concentration of 24–50 ng/L [6]. From then on, more and more endophytics from phar-maceutical plants, such as Camptotheca acuminata [7], pine [8] and Taxus plants [9–11] were isolated. As to G. biloba, various endophytics including Chaetomium, Aspergillus, Alternaria, Penicillium and Charobacter were isolated from the root, stem, leaf, seed and bark of G. biloba. They produce lots of phytochemicals like fla-vonoids, terpenoids, and other compounds [12, 13]. 50% of these isolates showed antimicrobial activities against various pathogens. Some secondary metabolites such as 2-hexenal have been involved in the plant’s defense against pests. These bioactive metabolites are attractive to developing the commercial prodrugs and agricultural/industrial production. Most importantly, as a therapeutic drug, G. biloba has no side effects even after long periods of use and its phytopharmaceuticals are readily accessible throughout the world. For better using endophytic and
Open Access
Chinese Medicine
*Correspondence: [email protected]; [email protected] College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China3 College of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yongzhou 425199, ChinaFull list of author information is available at the end of the article
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secondary metabolites from ginkgo trees, we summarize the data previously reported.
Endophytes in Ginkgo bilobaThe whole plant of G. biloba can be used as medicine. In its root, stem, leaf, seed and bark of Ginkgo biloba, vari-ous endophytes have been isolated and their biological function was investigated. The conventional procedure of endophytes isolation is to wash the roots, stems or leaves of ginkgo firstly with 75% alcohol for 3 min, rinse with sterile water 3–5 times, 0.1% mercury sterilized for 2 min, rinsed with sterile water 3–5 times, cut into 0.5 cm × 0.5 cm pieces. The cutting pieces were inocu-lated in PDA medium at 28 °C for 4 days. After purifica-tion, ginkgo endophytes were isolated.
For the endophytic procaryotes, on the total DNA as the template, 27F(AGA GTT TGATC-CTG GGT CAG)/1492R(GGT TAC CTT GTT ACG ACT T) as a primer, 16S rDNA was amplified. For the endophytic eukarya, ITS5 (GAAG TAA AAG TCG TAA CAAGG)/ITS4 (TCC TCC GC TTA TTGA TATGC) as a primer, ITS rDNA was amplified. According to the culturing and molecular analysis between different species, the endo-phytics residing in G. biloba belong to Chaetomium, Aspergillus, Alternaria, Penicillium, Charobacter, etc.
Endophytic procaryotes in Ginkgo bilobaFrom the previous reports, around 50 species of endo-phytic procaryotes were found including Bacillus subtilis, Lactobacillus sp., Fusobacterium sp., Gemella sp., Neisse-ria sp., Pseudomonas sp., Rothia sp., Veillonella sp., etc. Basing on 16S RNA sequence of endophytic procaryotes from previous literatures, the phylogenetic tree was con-structed in Fig. 1. Amongst these procaryotes, the com-munity structure or compositional differences at different taxonomic levels was presented in Fig. 2.
Sphingomonadaceae are a family of the Alphaproteo-bacteria and most abundant in G. biloba. An impor-tant feature is the presence of sphingolipids in the outer membrane of the cell wall [14]. In this family, some spe-cies are phototrophic which may have high nutritional value. The phototrophic bacteria are rich in amino acids, folic acid and vitamins, especially vitamin B12, biotin and coenzyme Q. Some other species are known as the abil-ity to degrade some aromatic compounds which has the interests for environmental remediation [11].
Other abundant species are family Hyphomicrobiaceae, Burkholderiaceae, Methylobacteriaceae, Enterobacte-riaceae, Neisseriaceae and Micrococcaceae. The family Hyphomicrobiaceae is affiliated with Alphaproteobacteria and members of this family are distributed everywhere in soils, freshwater, and also under the marine. This fam-ily is highly diverse morphologically and physiologically.
Most are aerobic chemoheterotrophs and a few can grow anaerobically by denitrification or mixed-acid fermentation.
The Methylobacteriaceae comprises a large family of Alphaproteobacteria and contains three genera including Methylobacterium, Microvirga, and Meganema. Methylo-bacterium species are ubiquitous in the natural environ-ment. Some species induce plant leaf and root nodule formation, and can promote plant growth by production of auxins [15]. Most of Methylobacterium are methylo-trophs and they can use methanol or other one-carbon compounds as energy sources to produce proteins [16]. Otherwise, in Methylobacterium, common fatty acids were contained especially ubiquinone Q-10, a popular dietary supplement.
Family Enterobacteriaceae contains a large number of genera that are biochemically and genetically related to one another. Many of them are pathogens, such as Sal-monella, Shigella or Yersinia, because they produce endo-toxins. Endotoxins reside in the cell wall and when the cell dies and the cell wall disintegrates, endotoxins are released [9].
Family Burkholderiaceae belongs to the order Bur-kholderiales within the class Betaproteobacteria. This family is characterized by the presence of ecologically extremely diverse organisms and contains truly environ-mental saprophytic organisms, phytopathogens, oppor-tunistic pathogens, as well as primary pathogens for humans and animals.
Family Neisseriaceae and Micrococcaceae are wide-spread in soil, subterranean cave silts, sea, glacier silts, sewage, water sludge, aerial surfaces of plants, vegetables, and various animal species and are even more distantly related to the human pathogens.
Endophytic eukarya in Ginkgo bilobaThe phylogenetic tree of endophytic eukarya (Fig. 3) was constructed basing on ITS sequence of roots and leaves of Ginkgo biloba from previous literatures. Amongst these endophytic eukarya, the community structure at different taxonomic levels was presented in Fig. 4.
Amongst eukarya, family Pleosporaceae belongs to sac fungi. The taxonomic relationship of this family to associ-ated genera is still not determined. The classification of Pleosporaceae has been a challenge because of the lack of the importance of morphological characters and ref-erence strains. From the present knowledge, the family Pleosporaceae includes numerous saprobic, opportunistic human and plant pathogenic taxa [17].
Phaeosphaeriaceae is a large and important family of fungi in the order Pleosporales. Species in this fam-ily have a cosmopolitan distribution, and are generally
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nectrotrophic or saprobic on a wide range of plants [18]. This family includes economically important plant patho-gens and previously accommodated 35 sexual and asex-ual genera and comprised more than 300 species with a range of morphological characters [19].
The Xylariaceae are a family of mostly small ascomyce-tous fungi. It is one of the most commonly encountered groups of ascomycetes and is found throughout the tem-perate and tropical regions of the world. They are typi-cally found on wood, seeds, fruits, or plant leaves, some even associated with insect nests. Most decay wood and many are plant pathogens. Phylogenetic analyses suggest that there are two main lineages in this family, Hypoxy-loideae and Xylarioideae [20, 21].
Secondary metabolites of endophytics in Ginkgo bilobaA series of compounds were obtained by fermentation, extraction, and isolation from endophytics of G. biloba, amongst which 115 metabolites were found in the fer-mentation broth of Chaetomium fungi, 44 metabolites were found from Aspergillus, 43 metabolites found in the genus Xylaria. The amount from these three genera accounted for 72% of the secondary metabolites from endophytic procaryotes and 21% were isolated from Fusarium, Alternaria and Penicillium. The number of metabolites of each genus is shown in Fig. 5.
Many metabolic products from G. biloba have strong inhibitory effects on pathogenic bacteria Staphylococcus
Fig. 1 The phylogenetic tree of endophytic procaryotes from soil, root and leaf of Ginkgo biloba. 50 most abundant OTUs are used for display. If a number appears before the species name, it represents the total number of sequences of this OTU. If it is a graph, the graph size represents the relative abundance (percentage), and the black dot on the branch represents the bootstrap confidence greater than 95%
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aureus, Enterococcus faecalis, and Pseudomonas aerugi-nosa. The secondary metabolites of Ginkgo, such as fla-vonoids and ginkgolides, are drugs or prodrugs used in
the treatment of peripheral arterial diseases, neurologi-cal disorders, sclerosis of cerebral arteries, and cerebral ageing.
Fig. 2 The community structure at different taxonomic levels. (1) The community structure at different phylums; (2) the community structure at different classes; (3) the community structure at different families; (4) the community structure at different genus. The percentage in parentheses indicates that only the group with the average abundance greater than this ratio is listed. All other groups are classified in others
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Secondary metabolites of ChaetomiumChaetomium is the largest type of endophytic fungus from G. biloba and its secondary metabolites are bio-logically diverse. Chaetomium globosum is one of main endophytics. A total of 115 metabolites were isolated from the fermentation broth of Chaetomium globosum (see Fig. 6 and Table 1). Among them, chaetoglobosin A, chaetoglobosin C, chaetoglobosin E, chaetoglobo-sin G, chaetoglobosin Vb, chaetomugilin A, chaetomu-gilin D and ergosterol peroxide (peroxyergosterol; 5α,
8α-peroxy-(22E, 24R)-ergot-6,22-diene-3β-ol), which has been reported in many literatures, may be a research hotspot. Among these compounds, chaetomugilin A, chaetomugilin D, chaetoglobosin A and chaetoglobosin C have strong cytotoxic activity [22].
Chaetomugilin A and D, both are a kind of azaphilone isolated from Chaetomium globosum and has been shown to exhibit inhibitory activity against the brine shrimp (Artemia salina) and Mucor miehei [22]. Chaetomugilide A isolated from Chaetomium globosum
Fig. 3 The phylogenetic tree of endophytic eukarya from soil, root and leaf of Ginkgo biloba. 50 most abundant OTUs are used for display. If a number appears before the species name, it represents the total number of sequences of this OTU. If it is a graph, the graph size represents the relative abundance (percentage), and the black dot on the branch represents the bootstrap confidence greater than 95%
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TY1 has strong activity against hepatoma cell HepG-2, and the IC50 value is only 1.7 μmol/L [23]. Chaetoglo-bosin A is a Chaetomium secretion with the anticancer activity in vitro [24] and it derivates into other bilobalide
compounds MBJ-0038, MBJ-0039, and MBJ-0040 [25]. Chaetoglobosin E is a cytochalasan alkaloid found in Chaetomium globosum and Chaetomium subaffine. It is a cytochalasan alkaloid, a member of indoles, a macrocycle
Fig. 4 The community structure at different taxonomic levels. (1) The community structure at different phylums; (2) The community structure at different classes; (3) The community structure at different families; (4) the community structure at different genus. The percentage in parentheses indicates that only the group with the average abundance greater than this ratio is listed. All other groups are classified in others
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and a secondary alpha-hydroxy ketone. It has a role as a Chaetomium metabolite and an antineoplastic agent.
One new cytochalasan alkaloid, chaetoglobosin V(b), together with two structurally related known com-pounds, chaetoglobosin V and chaetoglobosin G, were isolated from the ethyl acetate extract of a culture of the endophytic fungus Chaetomium globosum, associated with the leaves of G. biloba tree. The structures of the isolated compounds were elucidated by spectroscopic methods including 1D and 2D NMR and mass spec-trometry. The absolute conStruration of chaetoglobo-sin V(b) was established by means of electronic circular dichroism (CD) spectroscopy. The correlation between compounds was demonstrated by a biomimetic trans-formation of chaetoglobosin G under mild conditions
in chaetoglobosins V and V(b). The isolated metabolites were tested against some phytopathogens [22].
The compound flavipin isolated from Chaetomium globosum CDW 7 has strong antioxidant activity [23]. Chaetomium globosum ZY-22 could produce two poly-hydroxylated steroids [24] and two other important com-pounds bilobalide, ginkgolides are to be beneficial to human health [26]. Bilobalide has neuroprotective effects [27] as well as inducing the liver enzymes CYP3A1 and 1A2 which may be partially responsible for interactions between gingko and other herbal medicines or pharma-ceutical drugs; while ginkgolide has been investigated for its potential to reducing migraine frequency [28]. Ergosterol peroxide (5α,8α-epidioxy-22E-ergosta-6,22-dien-3β-ol) is a steroid derivative. It has been reported to
Fig. 5 a The metabolite quantity of some major endophytics in Ginkgo biloba; b the metabolite quantity of some minor endophytics in Ginkgo biloba
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exhibit immune- suppressive, anti-inflammatory, antivi-ral, trypanocidal and antitumor activities in vitro [27].
Secondary metabolites of AspergillusAspergillus is the dominant flora of endophytic fungi of G. biloba and was isolated from different parts of G. biloba which cultivated in various areas. A total of 44 metabolites were found in the fermentation broth of Aspergillus (see Table 2), among which 3-hydroxy-ter-phenyl, 4,5-dimethoxycandidusin A, prenylcandidusin C, and prenylterphenyllin were studied most popularly. For 4″-Deoxycandidusin A, 4″-deoxytripentin, 4′-deoxy-3-hydroxyrisperidone, aspergiloid A, coumarin A, and tribenzine, three articles reported about each compound, respectively. Among these metabolites, 3-hydroxy-ter-phenyl and 4″-deoxycandidusin A, 4″-deoxytripentin have strong inhibitory activity against neuraminidase [29]; 4′-deoxy-3-hydroxytripentin, 3-hydroxy-terphenyl, 4″-deoxycandidusin has moderate activity against human nasopharyngeal carcinoma cell KB, human gastric can-cer cell SGC-7901, human colon cancer cell SW1116 and human lung cancer cell A549 [30].
Secondary metabolites of AlternariaAlternaria is a very common fungus. It is an important pathogen for plants, human and animal diseases. It is a biological resource with great application potential as well. According to the existing literatures, 17 metabolites were isolated from the fermentation products of Alter-naria (see Table 3). Alterperylenol inhibits human tel-omerase activity. Alterperylenol can inhibit telomerase
activity (IC50 = 30 μM), but altertoxin I (dihydroalterper-ylenol), a structurally related compound, did not affect activity at 1 mM. Moreover, alterperylenol and altertoxin I show phytotoxic and antifungal activity [31].
In these metabolites, botulinum toxin and botuli-num toxin II have strong cytotoxic activity. When the concentration is 10 μg/mL, the mortality rate of brine shrimp is 68.9% and 73.6%, respectively [32]. Alternaria No. 28 could produce cytotoxic metabolites which have inhibitory potential against some different protein kinases [7].
Secondary metabolites of PenicilliumPenicillium is widely distributed in nature and generally has a strong biological activity. According to the exist-ing literatures, 17 secondary metabolites were found from the fermentation products of Penicillium sp. in G. biloba (Table 4), and some metabolites were biologically active. The compound arcacic acid is isolated from the fermentation broth of Penicillium commune, which has antibacterial activity and has inhibition activities on 12 kinds of plant pathogens, especially has strong inhibi-tory activity against Bacillus licheniformis and Sclerotinia sclerotiorum, and the IC50 values are only 39.28 mg/L and 60.62 mg/L [33].
The compounds adenosine, deoxyadenosine and ade-nine which were isolated from the fermentation prod-uct of Penicillium sp. YY-20 have a strong scavenging capacity for DPPH free radical [34]. Wu isolated Penicil-lium cataractum SYPF 7131 from 58 endophytic fungi obtained from the leaves, stems and roots of G. biloba.
Fig. 6 The quantity of different kinds of metabolites from Chaetomium
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Tabl
e 1
Seco
ndar
y m
etab
olit
es o
f Cha
etom
ium
in G
inkg
o bi
loba
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
1(2
2E, 2
4R)-
ergo
sta-
7,22
-die
ne-
3β,5
α,6β
-trio
l/cer
evis
tero
l51
6-37
-0Ch
aeto
miu
m g
lobo
sum
[33]
2(2
2E, 2
4R)-
ergo
sta-
7,22
-die
ne-
3β,5
α,6β
,9α-
tetr
aol
8819
1-06
-4Ch
aeto
miu
m g
lobo
sum
[44]
3(7
Z,11
E)-7
,11-
Hex
adec
adie
n-1-
yl
acet
ate
5304
2-79
-8Ch
aeto
miu
m g
lobo
sum
N
o. 1
6Pe
stic
ide
[45]
4(E
,E)-2
,4-D
ecad
iena
l25
152-
84-5
Chae
tom
ium
glo
bosu
m
No.
16
Food
_add
itive
; fra
gran
ce[4
5]
5(Z
)-9-H
exad
ecen
oic
acid
, met
hyl
este
r11
20-2
5-8
Chae
tom
ium
glo
bosu
m
No.
16
[45]
6(Z
,Z)-9
,12-
Oct
adec
adie
noic
aci
d60
-33-
3Ch
aeto
miu
m g
lobo
sum
N
o. 1
6Bi
osyn
thes
is o
f pro
stag
land
ins
and
cell
mem
bran
es[4
5]
71-
(3-A
cety
l-2,2
-di
met
hylc
yclo
prop
yl)-2
-met
hyl-1
-pr
opan
one
7714
2-84
-8Ch
aeto
miu
m g
lobo
sum
T1
6[4
9]
81-
(3-M
etho
xy-2
-pyr
azin
yl)-2
-met
hyl-
1-pr
opan
one
9861
8-81
-6Ch
aeto
miu
m g
lobo
sum
T1
6[4
6]
91,
3-D
ioxo
lane
, 2-m
etho
xy19
693-
75-5
Chae
tom
ium
glo
bosu
m
T16
[46]
101-
Eico
sene
3452
-07-
1Ch
aeto
miu
m g
lobo
sum
N
o. 1
6[4
5]
111-
Trim
ethy
lsily
l met
hano
l32
19-6
3-4
Chae
tom
ium
glo
bosu
m
T16
[46]
122,
3,4-
Trim
ethy
l-5,7
-dih
ydro
xy-2
,3-d
i-hy
drob
enzo
fura
n18
2458
4-79
-3Ch
aeto
miu
m g
lobo
sum
[47]
132,
4,5-
Trim
ethy
l-1,3
-dio
xola
ne32
99-3
2-9
Chae
tom
ium
glo
bosu
m
T16
Flav
ors
[46]
142,
4-D
ecad
iena
l23
63-8
8-4
Chae
tom
ium
glo
bosu
m
No.
16Fo
od a
dditi
ve[2
0, 2
1]
Page 10 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 1
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
152′
-O-M
ethy
lade
nosi
ne21
40-7
9-6
Chae
tom
ium
glo
bosu
mIn
hibi
tion
of v
acci
nia
viru
s gr
owth
[47]
162′
-Deo
xyad
enos
ine
958-
09-8
Chae
tom
ium
glo
bosu
mA
nti-t
umor
and
ant
ivira
l nu
cleo
side
dru
gs (c
ladr
ibin
e)[4
4]
1720
-Dih
ydro
chae
togl
obos
in A
1495
60-9
8-5
Chae
tom
ium
glo
bosu
m[4
7]
1821
Met
hoxy
-Cha
etog
lobo
sin
FCh
aeto
miu
m g
lobo
sum
[47]
182-
Cycl
ohex
yl-h
ex-5
-en-
2-ol
9592
61-1
7-7
Chae
tom
ium
glo
bosu
m
T16
[46]
192-
Ethy
l-5-p
ropy
lphe
nol
7238
6-20
-0Ch
aeto
miu
m g
lobo
sum
T1
6[4
6]
202-
Met
hyl-5
-pro
pyl-2
,4-d
ihyd
ro-
3H-p
yraz
ol-3
-one
3127
2-04
-5Ch
aeto
miu
m g
lobo
sum
T1
6[4
6]
212-
Oct
yl-c
yclo
prop
aneo
ctan
al56
196-
06-6
Chae
tom
ium
glo
bosu
m
No.
16[4
5]
223,
4-D
ihyd
roxy
phen
yl a
cetic
aci
d10
2-32
-9Ch
aeto
miu
m g
lobo
sum
A m
etab
olite
of d
opam
ine,
Cy
topl
asm
, Enc
epha
litis
, H
ypot
hyro
idis
m, A
lzhe
imer
’s di
seas
e, C
olor
ecta
l can
cer
[47]
233-
Met
hylo
rsel
linic
aci
d47
07-4
6-4
Chae
tom
ium
glo
bosu
m
ZY-2
2N
euro
prot
ectiv
e A
ctiv
ity[4
6]
244-
Am
inop
heny
lace
tic a
cid/
p-am
i-no
phen
ylac
etic
aci
d/4-
amin
ophe
-ny
lace
tic a
cid
1197
-55-
3Ch
aeto
miu
m g
lobo
sum
Ant
i-infl
amm
ator
y In
hibi
tion
colit
is[4
7]
254-
Met
hyl-1
-hep
ten-
5-on
e26
118-
97-8
Chae
tom
ium
glo
bosu
m[4
6]
Page 11 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 1
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
265-
(hyd
roxy
met
hyl)-
1H-p
yrro
le-
2-ca
rbal
dehy
de67
350-
50-9
Chae
tom
ium
glo
bosu
mH
apte
n, p
rodu
ces
adva
nced
gl
ycat
ion
end-
prod
ucts
(A
GEs
)
[47]
275′
-Epi
chae
tovi
rdin
A13
0867
1-17
-1Ch
aeto
miu
m g
lobo
sum
N
o. 1
2[4
5]
285′
-Deo
xy-5′-m
ethy
lam
ino-
aden
osin
eN
o ca
s no
.Ch
aeto
miu
m g
lobo
sum
[47]
299(
11)-
dehy
oerg
oste
rol p
erox
ide
8636
3-50
-0Ch
aeto
miu
m g
lobo
sum
ZY
-22
[44]
309,
12-O
ctad
ecad
ien-
1-ol
1577
-52-
2Ch
aeto
miu
m g
lobo
sum
N
o. 1
6[4
5]
31A
ceta
ldeh
yde,
die
thyl
ace
tal
105-
57-7
Chae
tom
ium
glo
bosu
m
T16
Use
d in
frui
t, ru
m a
nd w
hisk
y fla
vour
[46]
32A
deno
sine
58-6
1-7
Chae
tom
ium
glo
bosu
m
ZY-2
2Va
sodi
lato
ry, a
nti-a
rrhy
thm
ic
and
anal
gesi
c ac
tiviti
es
aden
osin
e is
an
aden
osin
e re
cept
or a
goni
st
[46]
33A
llant
oin
97-5
9-6
Chae
tom
ium
glo
bosu
mH
ealin
g, s
ooth
ing,
and
ant
i-irr
i-ta
ting
prop
ertie
s an
ti-ac
ne
prod
ucts
, sun
car
e pr
oduc
ts,
and
clar
ifyin
g lo
tions
[48]
34al
pha-
Met
hyls
tyre
ne98
-83-
9Ch
aeto
miu
m g
lobo
sum
Mem
bran
e ad
hesi
ves
and
seal
-an
t che
mic
als
[48]
35A
nthr
anili
c ac
id11
8-92
-3Ch
aeto
miu
m g
lobo
sum
M
X-05
10A
wat
er-s
olub
le v
itam
in[3
3]
36Be
nzen
eace
tic a
cid
103-
82-2
Chae
tom
ium
glo
bosu
m
No.
16
Use
d in
the
man
ufac
ture
of
pen
icill
in a
nd b
enda
zol
[45]
37Be
nzen
eace
tic a
cid,
met
hyl e
ster
101-
41-7
Chae
tom
ium
glo
bosu
m
No.
16
Use
d in
the
man
ufac
ture
of
atro
pine
[45]
38Be
nzen
eeth
anol
/phe
nyle
thyl
al
coho
l60
-12-
8Ch
aeto
miu
m g
lobo
sum
Esse
nce
[45]
Page 12 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 1
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
39Bu
tyra
ldeh
yde,
4-p
heny
l18
328-
11-5
Chae
tom
ium
glo
bosu
m
T16
[46]
40Ce
rebr
osid
e B
8864
2-46
-0Ch
aeto
miu
m g
lobo
sum
ZY
-22
[46]
41Ce
rebr
osid
e C
9867
7-33
-9Ch
aeto
miu
m g
lobo
sum
ZY
-22
[46]
42C
haet
oglo
bosi
n A
5033
5-03
-0Ch
aeto
miu
m g
lobo
sum
[44,
49]
43C
haet
oglo
bosi
n B
5033
5-04
-1Ch
aeto
miu
m g
lobo
sum
C
DW
7[4
8]
44C
haet
oglo
bosi
n C
5064
5-76
-6Ch
aeto
miu
m g
lobo
sum
[26,
28]
45C
haet
oglo
bosi
n D
5594
5-73
-8Ch
aeto
miu
m g
lobo
sum
[49]
46C
haet
oglo
bosi
n E
5594
5-74
-9Ch
aeto
miu
m g
lobo
sum
(C
DW
7)[4
9]
47C
haet
oglo
bosi
n F
5594
5-75
-0Ch
aeto
miu
m g
lobo
sum
(C
DW
7)[4
7]
48C
haet
oglo
bosi
n Fa
1599
426-
06-8
Chae
tom
ium
glo
bosu
m[4
7]
Page 13 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 1
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
49C
haet
oglo
bosi
n Fe
x14
9457
-95-
4Ch
aeto
miu
m g
lobo
sum
[47]
50C
haet
oglo
bosi
n G
6577
3-98
-0Ch
aeto
miu
m g
lobo
sum
(N
M00
66)
[47]
51C
haet
oglo
bosi
n R
7779
39-3
0-7
Chae
tom
ium
glo
bosu
m[4
9]
52C
haet
oglo
bosi
n V
1399
682-
37-1
Chae
tom
ium
glo
bosu
m[4
7]
53C
haet
oglo
bosi
n Vb
1399
690-
75-5
Chae
tom
ium
glo
bosu
m
(CD
W7)
[48]
54C
haet
oglo
bosi
n Y
1608
108-
89-9
Chae
tom
ium
glo
bosu
m[4
8]
55C
haet
omug
ilide
A14
1813
8-71
-2Ch
aeto
miu
m g
lobo
sum
[45,
47]
56C
haet
omug
ilide
B14
3397
6-48
-7Ch
aeto
miu
m g
lobo
sum
[45]
57C
haet
omug
ilide
C14
1813
8-70
-1Ch
aeto
miu
m g
lobo
sum
[45,
47]
58C
haet
omug
ilin
A10
4164
0-66
-7Ch
aeto
miu
m g
lobo
sum
[45]
Page 14 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 1
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
59C
haet
omug
ilin
D10
9808
1-38
-9Ch
aeto
miu
m g
lobo
sum
[25]
60C
haet
omug
ilin
I11
8784
8-00
-5Ch
aeto
miu
m g
lobo
sum
[25]
61C
haet
omug
ilin
J11
8784
8-01
-6Ch
aeto
miu
m g
lobo
sum
[25]
62C
haet
omug
ilin
O11
8784
8-06
-1Ch
aeto
miu
m g
lobo
sum
[25]
63C
haet
omug
ilin
Q13
1972
9-85
-5Ch
aeto
miu
m g
lobo
sum
[25]
64C
haet
omug
ilin
S13
9909
3-77
-6Ch
aeto
miu
m g
lobo
sum
[25]
65C
haet
oviri
din
C12
8230
-02-
4Ch
aeto
miu
m g
lobo
sum
[15]
66C
haet
oviri
din
D12
8230
-04-
6Ch
aeto
miu
m g
lobo
sum
[33]
67C
haet
oviri
din
E11
7887
5-15
-4Ch
aeto
miu
m g
lobo
sum
[33]
68Cy
clo-
(Phe
-Gly
)50
37-7
5-2
Chae
tom
ium
glo
bosu
m[3
3]
Page 15 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 1
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
69Cy
clop
enta
deca
ne29
5-48
-7Ch
aeto
miu
m g
lobo
sum
N
o.16
[45]
70D
imet
hyl p
htha
late
131-
11-3
Chae
tom
ium
glo
bosu
m
No.
16U
sed
in p
last
ics,
inse
ct
repe
llent
s, sa
fety
gla
ss, a
nd
lacq
uer c
oatin
gs
[45]
71Ep
imw
soko
rwno
ne A
1073
-96-
7Ch
aeto
miu
m g
lobo
sum
[33]
72Er
gost
a-4
6,8,
22-t
etra
en-3
-one
/er
gost
a-4,
6,8,
22-t
etra
en-3
-one
1947
21-7
5-0
Chae
tom
ium
glo
bosu
m
(ZY-
22)
[33]
73Er
gost
erol
57-8
7-4
Chae
tom
ium
glo
bosu
mFo
rmat
ion
of v
itam
in D
2[4
9]
74Er
gost
erol
per
oxid
e (5
α,8α
-epi
-di
oxy-
(22E
,24R
) -er
gost
a-6,
22-
dien
-3β-
ol)
2061
-64-
5Ch
aeto
miu
m g
lobo
sum
An
antin
eopl
astic
age
nt, a
n an
timyc
obac
teria
l dru
g an
d a
tryp
anoc
idal
dru
g
[33]
75Et
hano
ic a
cid
64-1
9-7
Chae
tom
ium
glo
bosu
m
T16
Food
add
itive
, and
in p
etro
-le
um p
rodu
ctio
n[4
6]
76Et
hyl 1
3-m
ethy
l-tet
rade
cano
ate
6431
7-63
-1Ch
aeto
miu
m g
lobo
sum
N
o. 1
6[4
5]
77Et
hyl 2
-hep
teno
ate
2351
-88-
4Ch
aeto
miu
m g
lobo
sum
T1
6[4
5]
Page 16 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 1
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
78Et
hylid
ene
acet
ate
542-
10-9
Chae
tom
ium
glo
bosu
m
T16
[45]
79fla
vipi
n (1
,2-b
enze
nedi
carb
oxal
de-
hyde
-3,4
,5-t
rihyd
roxy
-6-m
ethy
l)48
3-53
-4Ch
aeto
miu
m g
lobo
sum
C
DW
7A
ntio
xida
nt fu
ngic
ides
[22]
80Fu
mig
acla
vine
B68
79-9
3-2
Chae
tom
ium
glo
bosu
m[4
7]
81Fu
mitr
emor
gin
C11
8974
-02-
0Ch
aeto
miu
m g
lobo
sum
(N
M00
66)
A m
ycot
oxin
and
a b
reas
t ca
ncer
resi
stan
ce p
rote
in
inhi
bito
r
[33]
82G
lioto
xin
67-9
9-2
Chae
tom
ium
glo
bosu
m
(NM
0066
)A
myc
otox
in, a
n im
mun
osup
-pr
essi
ve a
gent
, an
prot
ein
farn
esyl
tran
sfer
ase
inhi
bito
r, a
prot
easo
me
inhi
bito
r and
an
ant
ifung
al a
gent
[33]
83G
lobo
ster
ol11
9331
9-70
-8Ch
aeto
miu
m g
lobo
sum
ZY
-22
[44]
84G
lyce
rol f
orm
al54
64-2
8-8
Chae
tom
ium
glo
bosu
m
T16
[46]
85H
exad
ecan
e54
4-76
-3Ch
aeto
miu
m g
lobo
sum
Use
d as
a s
olve
nt a
nd a
n in
gred
ient
in g
asol
ine
and
dies
el a
nd je
t fue
ls
[45]
86H
exad
ecan
oic
acid
, eth
yl e
ster
628-
97-7
Chae
tom
ium
glo
bosu
m
No.
16
Use
d as
sof
tene
r, lu
bric
ant,
food
add
itive
[45]
87H
exad
ecan
oic
acid
, met
hyl e
ster
112-
39-0
Chae
tom
ium
glo
bosu
m
No.
16
Use
d as
inte
rmed
iate
of
emul
sifie
r, w
ettin
g ag
ent,
stab
ilize
r and
pla
stic
izer
[45]
88In
dole
-3- c
arbo
xylic
aci
d77
1-50
-6Ch
aeto
miu
m g
lobo
sum
ZY
-22
Use
d fo
r syn
thes
is o
f to
rise
tron
and
ant
ivira
l dru
gs[3
3]
89In
dole
-3-a
cetic
aci
d87
-51-
4Ch
aeto
miu
m g
lobo
sum
Plan
t gro
wth
stim
ulat
ing
horm
one
[33]
90Is
open
tyl a
lcoh
ol, a
ceta
te12
3-92
-2Ch
aeto
miu
m g
lobo
sum
T1
6U
sed
as a
sol
vent
and
pre
para
-tio
n of
a v
arie
ty o
f flav
or
food
flav
or
[22]
Page 17 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 1
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
91La
ctic
aci
d50
-21-
5Ch
aeto
miu
m g
lobo
sum
T1
6U
sed
to m
ake
som
e pl
astic
iz-
ers,
adhe
sive
s, ph
arm
aceu
-tic
als
and
salts
, use
d in
the
leat
her t
anni
ng in
dust
ry a
nd
as a
sol
vent
[46]
92La
ctic
aci
d, 2
-met
hyl-,
ethy
l est
er80
-55-
7Ch
aeto
miu
m g
lobo
sum
T1
6[4
6]
93M
alto
l11
8-71
-8Ch
aeto
miu
m g
lobo
sum
M
X-05
10Fo
od a
dditi
ve[3
3]
94M
anni
tol
87-7
8-5
Chae
tom
ium
glo
bosu
mU
sed
as a
n os
mot
ic d
iure
tic[3
3]
95M
ethy
l 13-
met
hylte
trad
ecan
oate
5129
-59-
9Ch
aeto
miu
m g
lobo
sum
N
o. 1
6[4
5]
96M
ethy
l 9,1
2-he
ptad
ecad
ieno
ate
1562
0-59
-4Ch
aeto
miu
m g
lobo
sum
N
o. 1
6[4
5]
97M
ethy
l vin
ylca
rbin
ol59
8-32
-3Ch
aeto
miu
m g
lobo
sum
Food
add
itive
[46]
98M
ethy
lthio
glio
toxi
n74
149-
38-5
Chae
tom
ium
glo
bosu
m
(NM
0066
)[3
3]
99o-
Coum
aric
aci
d58
3-17
-5Ch
aeto
miu
m g
lobo
sum
ZY
-22
An
antio
xida
nt a
nd is
bel
ieve
d to
redu
ce th
e ris
k of
sto
mac
h ca
ncer
by
redu
cing
the
form
atio
n of
car
cino
geni
c ni
tros
amin
es
[33]
100
Oct
anoi
c ac
id, m
ethy
l est
er11
1-11
-5Ch
aeto
miu
m g
lobo
sum
N
o. 1
6Fo
od a
dditi
ve[4
5]
101
Pent
adec
ane
629-
62-9
Chae
tom
ium
glo
bosu
m
No.
16
Use
d as
a s
olve
nt a
nd in
som
e ho
useh
old
pest
icid
es[4
5]
102
Pent
adec
anoi
c ac
id, m
ethy
l est
er71
32-6
4-1
Chae
tom
ium
glo
bosu
m
No.
16
Fuel
s an
d fu
el a
dditi
ves
Inte
rmed
iate
s, pe
stic
ide
[45]
103
p-H
ydro
xybe
nzoi
c ac
id99
-96-
7Ch
aeto
miu
m g
lobo
sum
Use
d as
pre
serv
ativ
es, f
ungi
-ci
des
[33]
104
Pseu
rotin
A58
523-
30-1
Chae
tom
ium
glo
bosu
m
(NM
0066
)A
n az
aspi
ro c
ompo
und,
an
oxas
piro
com
poun
d an
d a
lact
am
[33]
Page 18 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 1
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
105
Que
rcet
in11
7-39
-5Ch
aeto
miu
m g
lobo
sum
G
CZX
015
Com
bine
d w
ith c
hem
o-th
erap
eutic
dru
gs, p
rodu
ces
anti-
infla
mm
ator
y an
d an
ti-al
lerg
y eff
ects
[33]
106
Squa
lene
111-
02-4
Chae
tom
ium
glo
bosu
m
(NM
0066
)In
vest
igat
ed a
s an
adj
unct
ive
canc
er th
erap
y, a
lso
used
as
cosm
etic
s an
d di
etar
y su
p-pl
emen
t
[33]
107
S-Te
trac
hlor
oeth
ane
79-3
4-5
Chae
tom
ium
glo
bosu
m
T16
Use
d to
mak
e pa
int,
varn
ish
and
rust
rem
over
s, as
a
solv
ent a
nd a
s an
ingr
edie
nt
in p
estic
ides
[45]
108
Succ
inic
aci
d11
0-15
-6Ch
aeto
miu
m g
lobo
sum
A ra
diat
ion
prot
ectiv
e ag
ent,
an a
nti-u
lcer
dru
g[3
3]
109
Tetr
adec
ane
629-
59-4
Chae
tom
ium
glo
bosu
m
No.
16U
sed
as a
sol
vent
and
som
e pe
stic
ide
spra
ys[4
5]
110
Thym
ine
65-7
1-4
Chae
tom
ium
glo
bosu
m
ZY-2
2A
pyr
imid
ine
nucl
eoba
se a
nd a
py
rimid
one
[33]
111
Trid
ecan
e62
9-50
-5Ch
aeto
miu
m g
lobo
sum
N
o. 1
6U
sed
as a
sol
vent
and
as
an
ingr
edie
nt in
gas
olin
e an
d di
esel
and
jet f
uel
[45]
112
Trie
thyl
ene
glyc
ol m
onom
ethy
l et
her a
ceta
te36
10-2
7-3
Chae
tom
ium
glo
bosu
m
T16
[46]
113
Ura
cil
66-2
2-8
Chae
tom
ium
glo
bosu
m
ZY-2
2U
se in
the
body
to h
elp
syn-
thes
is o
f man
y en
zym
es, a
nd
the
bios
ynth
esis
of p
olys
ac-
char
ides
and
the
tran
spor
ta-
tion
of s
ugar
s co
ntai
ning
al
dehy
des
[49]
114
α-G
uaje
ne36
91-1
2-1
Chae
tom
ium
glo
bosu
m
No.
16
[45]
Page 19 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 2
Seco
ndar
y m
etab
olit
es o
f Asp
ergi
lus i
n G
inkg
o bi
loba
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
13-
Hyd
roxy
terp
heny
llin
6616
3-76
-6As
perg
illus
sp.
Indu
ces
apop
tosi
s an
d S
phas
e ar
rest
in
hum
an o
varia
n ca
rcin
oma
cells
[28,
50]
24″
-Deo
xyca
ndid
usin
A13
5454
9-88
-4As
perg
illus
sp.
[51,
52]
34″
-Deo
xyte
rphe
nylli
n59
904-
04-0
Aspe
rgill
us s
p.[5
0]
44,
5-D
imet
hoxy
cand
idus
in A
/3,4
-di
met
hoxy
cand
idus
in A
1354
549-
89-5
Aspe
rgill
us s
p.[5
0, 5
2]
54′
-Deo
xy- 3
-hyd
roxy
terp
heny
llin
1296
205-
84-9
Aspe
rgill
us s
p.[5
0, 5
2]
64′
’-Deo
xy-5′-d
esm
ethy
l-ter
phen
yllin
1354
549-
87-3
Aspe
rgill
us s
p.[5
0]
74′
’-Deo
xypr
enyl
terp
heny
llin
9591
24-8
7-9
Aspe
rgill
us s
p. IF
B-YX
SPo
tent
ial a
ntic
ance
r lea
d m
olec
ules
[50]
84-
Hyd
roxy
-3-(3
′-met
hyl-2′-b
uten
yl)
benz
oic
acid
1138
-41-
6As
perg
illus
sp.
YXf
3Sh
ow p
oten
t inh
ibiti
on o
f HLE
[50]
95′
-Des
met
hylte
rphe
nylli
n12
9948
5-87
-2As
perg
illus
sp.
An
alph
a-gl
ucos
idas
e in
hibi
tor
[50]
10A
ltern
ario
l64
1-38
-3As
perg
illus
sp.
YXf
3A
n ch
olin
este
rase
inhi
bito
r and
a
myc
otox
in[5
2]
Page 20 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 2
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
11A
ltern
ario
l mon
omet
hyl e
ther
/al
tern
ario
l-4-m
ethy
l eth
er23
452-
05-3
Aspe
rgill
us s
p. Y
Xf3
An
antif
unga
l age
nt[5
2]
12A
sper
gilo
id A
1354
549-
91-9
Aspe
rgill
us s
p.[5
0]
13A
sper
gilo
id B
1354
549-
92-0
Aspe
rgill
us s
p.[5
0]
14A
sper
gilo
id C
1354
549-
93-1
Aspe
rgill
us s
p.[5
0]
15A
sper
gilo
id D
1354
549-
94-2
Aspe
rgill
us s
p.[5
0]
16A
sper
gilo
id E
1579
256-
33-9
Aspe
rgill
us s
p. Y
Xf3
[52]
17A
sper
gilo
id F
1579
256-
35-1
Aspe
rgill
us s
p. Y
Xf3
[52]
18A
sper
gilo
id G
1579
256-
37-3
Aspe
rgill
us s
p. Y
Xf3
[52]
Page 21 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 2
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
19A
sper
gilo
id H
1579
256-
39-5
Aspe
rgill
us s
p. Y
Xf3
[52]
20A
sper
gilo
id I
1887
750-
59-5
Aspe
rgill
us s
p. Y
Xf3
Ant
i-can
cer a
nd in
hibi
tion
of p
lant
pa
thog
ens
[50]
21Ca
ndid
usin
A81
474-
59-1
Aspe
rgill
us s
p.[5
0]
22Ca
ndid
usin
C/4″-
met
hoxy
cand
idus
in
A26
7007
-58-
9As
perg
illus
sp.
[50]
23C
hlor
flavo
nin
2336
3-64
-6As
perg
illus
sp.
(str
ain
no. Y
Xf3)
An
antif
unga
l age
nt[5
0]
24C
hlor
flavo
nin
A14
4305
5-96
-6As
perg
illus
sp.
(str
ain
no. Y
Xf3)
An
antif
unga
l age
nt[5
0]
25Cy
clo-
(L-L
eu-L
-Trp
)15
136-
34-2
Aspe
rgill
us s
p. Y
Xf3
[50]
26G
inkg
olid
e B
1529
1-77
-7As
perg
illus
.fum
igat
us v
ar.
fum
igat
us F
G 0
5G
inkg
olid
e B
prot
ects
hum
an u
mbi
lical
ve
in e
ndot
helia
l cel
ls a
gain
st x
enob
i-ot
ic in
jurie
s vi
a PX
R ac
tivat
ion
[52]
27G
inkg
olid
e C
1529
1-76
-6As
perg
illus
[32]
28Pr
enyl
cand
idus
in B
1297
472-
19-5
Aspe
rgill
us s
p. IF
B-YX
SA
n an
tineo
plas
tic a
gent
[53]
29Pr
enyl
cand
idus
in C
1297
472-
20-8
Aspe
rgill
us s
p.A
n an
tineo
plas
tic a
gent
[53]
30Pr
enyl
terp
heny
llin
9591
24-8
5-7
Aspe
rgill
us s
p.Ex
hibi
ts c
ytot
oxic
act
ivity
, an
antin
eo-
plas
tic a
gent
[53]
Page 22 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 2
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
31Pr
enyl
terp
heny
llin
B12
9747
2-16
-2As
perg
illus
sp.
IFB-
YXS
Exhi
bits
cyt
otox
ic a
ctiv
ity, a
n an
tineo
-pl
astic
age
nt[5
3]
32Sp
haer
opsi
din
A38
991-
80-9
Aspe
rgill
us s
p. Y
Xf3
larv
icid
al a
nd b
iting
det
erre
nts
agai
nst
Aede
s aeg
ypti
[50]
33Sp
haer
opsi
din
B39
022-
38-3
Aspe
rgill
us s
p. Y
Xf3
[50]
34Te
rphe
nolid
e13
5454
9-90
-8As
perg
illus
sp.
[50]
35Te
rphe
nylli
n52
452-
60-5
Aspe
rgill
us s
p.A
myc
otox
in[5
0]
36Te
rrei
nol
6690
73-6
7-0
Aspe
rgill
us s
p. Y
Xf3
[31]
37Xa
ntho
asci
n61
391-
08-0
Aspe
rgill
us s
p. IF
B-YX
S[5
3]
38Pr
enyl
terp
heny
llin
D20
7997
9-59
-0As
perg
illus
sp.
IFB-
YXS
Ant
ibac
teria
l act
iviti
es, a
nti-p
hyto
path
o-ge
nic
activ
ities
[31]
39Pr
enyl
terp
heny
llin
E20
7997
9-60
-3As
perg
illus
sp.
IFB-
YXS
Ant
ibac
teria
l act
iviti
es, a
nti-p
hyto
path
o-ge
nic
activ
ities
[31]
402′
-O-M
ethy
lpre
nylte
rphe
nylli
n20
7997
9-61
-4As
perg
illus
sp.
IFB-
YXS
Ant
ibac
teria
l act
iviti
es, a
nti-p
hyto
path
o-ge
nic
activ
ities
[31]
Page 23 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 2
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
414-
O-M
ethy
lpre
nylte
rphe
nylli
n20
7997
9-62
-5As
perg
illus
sp.
IFB-
YXS
[31]
42[1
,1′:4′,1′’-
Terp
heny
l]-4,
4′’-d
iol,
2′,3′,5′-t
rimet
hoxy
-(9C
I)59
914-
89-5
Aspe
rgill
us s
p. IF
B-YX
S[3
1]
43[1
,1′:4′,1′’-
Terp
heny
l]-2′
,4′’-
diol
,3′,4
,6′-
trim
etho
xy-(9
CI)
5990
3-93
-4As
perg
illus
sp.
IFB-
YXS
[31]
44[1
,1′:4′,1′’-
Terp
heny
l]-2′
,4-d
iol,3′,4′’,6′-
trim
etho
xy-(9
CI)
5990
3-92
-3As
perg
illus
sp.
IFB-
YXS
[31]
Page 24 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 3
Seco
ndar
y m
etab
olit
es o
f Alte
rnar
ia in
Gin
kgo
bilo
ba
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
1(2
2E,2
4R)-
ergo
sta-
7,22
-die
ne-3
β,5α
,6β-
trio
l/cer
evis
tero
l51
6-37
-0Al
tern
aria
tenu
issim
a SY
-P-0
7[2
9]
2(2
R,3R
)-3,5
,7,3′,5′-p
enta
hydr
oxyfl
avan
e87
592-
94-7
Alte
rnar
ia te
nuiss
ima
SY-P
-07
[29]
33β
,5α,
9α-T
rihyd
roxy
-(22E
,24R
)-er
gost
a-7,
22-d
ien-
6-on
e88
191-
14-4
Alte
rnar
ia te
nuiss
ima
SY-P
-07
[29]
46-
Epi-s
tem
phyt
riol
1262
797-
65-8
Alte
rnar
ia te
nuiss
ima
SY-P
-07
[29]
57-
Epi-8
-hyd
roxy
alte
rtox
in I
1262
797-
64-7
Alte
rnar
ia te
nuiss
ima
SY-P
-07
[29]
6A
ltern
ario
l64
1-38
-3Al
tern
aria
No.
28
An
chol
ines
tera
se
inhi
bito
r[2
9]
7A
ltern
ario
l mon
omet
hyl e
ther
/alte
rnar
iol-
4-m
ethy
l eth
er23
452-
05-3
Alte
rnar
ia N
o. 2
8A
n an
tifun
gal a
gent
[29]
8A
lterp
eryl
enol
8889
9-62
-1Al
tern
aria
tenu
issim
a[4
5]
9A
ltert
oxin
I (d
ihyd
roal
terp
eryl
enol
)56
258-
32-3
Alte
rnar
ia s
p.[2
9]
10Er
gost
a-4,
6,8,
22-t
etra
en-3
-one
/erg
osta
-4,
6,8,
22-t
etra
en-3
-one
1947
21-7
5-0
Alte
rnar
ia N
o. 2
8[2
9]
11Er
gost
erol
57-8
7-4
Alte
rnar
ia s
p.Fo
rmat
ion
of v
itam
in D
2[2
9]
Page 25 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 3
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
12Fl
azin
1000
41-0
5-2
Alte
rnar
ia te
nuiss
ima
SY-P
-07
[47]
13So
lana
pyro
ne G
2209
24-5
1-6
Alte
rnar
ia te
nuiss
ima
SY-P
-07
[47]
14St
emph
yper
ylen
ol10
2694
-33-
7Al
tern
aria
tenu
issim
a SY
-P-0
7A
n an
tifun
gal a
gent
[47]
15Te
nuaz
onic
aci
d61
0-88
-8Al
tern
aria
No.
28
An
antib
iotic
with
ant
ivi-
ral a
nd a
ntin
eopl
astic
, al
so a
s a
myc
otox
in
[29]
16Vi
voto
xin
II12
6126
7-71
-3Al
tern
aria
No.
28
[29]
Page 26 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 4
Seco
ndar
y m
etab
olit
e of
Pen
icill
ium
in G
inkg
o bi
loba
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
12′
-Deo
xyur
idin
e/ur
acil
deox
yrib
osid
e95
1-78
-0Pe
nici
llium
sp.
YY-
25A
ntim
etab
olite
[29]
23-
Met
hylo
rsel
linic
aci
d47
07-4
6-4
Peni
cilli
um N
o. 9
7A
ntib
acte
rial a
ctiv
ity[2
9]
33-
Met
hylp
iper
azin
e-2,
5-di
-on
e60
62-4
6-0
Peni
cilli
um s
p. Y
Y-24
[29]
4A
deni
ne73
-24-
5Pe
nici
llium
sp.
YY-
22D
ieta
ry s
uppl
emen
t[2
9]
5A
deno
sine
58-6
1-7
Peni
cilli
um s
p. Y
Y-20
Ana
lges
ic, a
ntia
rrhy
thm
ic[2
9]
6A
nthr
anila
mid
e88
-68-
6Pe
nici
llium
No.
97
Fluo
resc
ent d
yes
[54]
7A
nthr
anili
c ac
id11
8-92
-3Pe
nici
llium
No.
97
Ant
icon
vuls
ants
[55]
8Cy
clop
aldi
c ac
id47
7-99
-6Pe
nici
llium
com
mun
e (T
MSF
169)
[56]
9Fe
rulic
aci
d11
35-2
4-6
Peni
cilli
um N
o. 9
7Fr
ee ra
dica
l sca
veng
ers,
anti-
infla
mm
a-to
ry a
gent
s, an
tihyp
erte
nsiv
e ag
ents
, an
ticoa
gula
nts
[55]
10Fr
uctig
enin
e A
1446
06-9
6-2
Peni
cilli
um N
o. 9
7In
hibi
ts th
e gr
owth
of l
euke
mia
cel
ls[5
5]
Page 27 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 4
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
11In
dole
-3-a
cetic
aci
d87
-51-
4Pe
nici
llium
No.
97
Use
d fo
r pre
vent
ing,
des
troy
ing
or
miti
gatin
g pe
sts
[55]
12M
ethy
l β- d
-rib
ofur
anos
ide
7473
-45-
2Pe
nici
llium
sp.
YY-
21U
sed
to s
ynth
esiz
e no
vel a
lpha
-am
ino
acid
est
ers
agai
nst h
erpe
s si
mpl
ex
viru
s 1
(hsv
-1) a
nd h
epat
itis
b vi
rus
[29]
13O
rsel
linic
aci
d48
0-64
-8Pe
nici
llium
No.
97
[29]
14p-
Hyd
roxy
benz
oic
acid
99-9
6-7
Peni
cilli
um N
o. 9
7[5
5]
15β-
sito
ster
ol83
-46-
5Pe
nici
llium
No.
97
Hyp
olip
idem
ic a
gent
s[5
5]
16Q
uerc
etin
gly
cosi
de (o
rang
e pi
gmen
t)35
20-7
2-7
Peni
cilli
um s
p.[3
4]
Page 28 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 5
Seco
ndar
y m
etab
olit
e of
Xyl
aria
in G
inkg
o bi
loba
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
17-
Am
ino-
4-m
ethy
lcou
mar
in26
093-
31-2
Xyla
ria s
p. Y
X-28
A fl
uore
scen
t dye
use
d to
sta
in b
io-
logi
cal s
peci
men
s[5
7]
2Pe
ntad
ecan
e62
9-62
-9Xy
laria
sp.
YX-
28Tr
eatm
ent o
f pla
ntar
ker
atos
is w
ith
med
icin
al p
lant
in d
iabe
tic p
atie
nts
[57]
3Q
uerc
etin
117-
39-5
Xyla
ria C
olle
totr
ichu
mC
hem
othe
rapy
indu
ced
oral
m
ucos
itis;
trea
tmen
t of e
rosi
ve a
nd
atro
phic
ora
l lic
hen
plan
us; c
hron
ic
obst
ruct
ive
pulm
onar
y di
seas
e;
gast
roes
opha
geal
reflu
x di
seas
e
[57]
4Te
trad
ecan
e62
9-59
-4Xy
laria
sp.
YX-2
8[5
7]
5Tr
idec
ane
629-
50-5
Xyla
ria s
p. Y
X-28
[57]
6D
ibut
yl p
htha
late
84-7
4-2
Xyla
ria s
p. Y
X-28
Aga
inst
the
larv
al tr
ombi
culid
mite
; pr
even
ting
scru
b ty
phus
of t
opic
al
appl
icat
ion
in tr
oops
[57]
71,
3-D
iphe
nyl-2
-pyr
azol
ine
2538
-52-
5Xy
laria
sp.
YX-
28[5
7]
81-
Ace
tyl-1
,2,3
,4-t
etra
hydr
opyr
idin
e19
615-
27-1
Xyla
ria s
p. Y
X-28
[57]
9Z,
Z-7,
11-H
exad
ecad
ien-
1-ol
5396
3-06
-7Xy
laria
sp.
YX-
28[5
7]
10Is
osor
bide
652-
67-5
Xyla
ria s
p. Y
X-28
Prev
entio
n of
ang
ina
pect
oris
due
to
coro
nary
art
ery
dise
ase;
sho
rt-t
erm
re
duct
ion
of in
trao
cula
r pre
ssur
e
[57]
11D
imet
hoxy
-phe
nol
91-1
0-1
Xyla
ria s
p.YX
-28
Food
Fla
vorin
g A
gent
s[5
7]
121-
hydr
oxym
ethy
l-1,2
,3,4
,-tet
rahy
dro-
naph
thal
en-
2-ol
8728
24-4
3-6
Xyla
ria s
p. Y
X-28
[57]
13(1
,4-D
imet
hylp
ent-
2-en
yl)b
enze
ne95
1288
-80-
5Xy
laria
sp.
YX-
28[5
7]
142,
4-Bi
s(1,
1-di
met
hyle
thyl
)phe
nol
96-7
6-4
Xyla
ria s
p. Y
X-28
[57]
153-
Phen
yl-4
-met
hyl-i
soxa
zol-5
(4)-
one
8752
44-9
0-9
Xyla
ria s
p. Y
X-28
[57]
Page 29 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 5
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
163,
4-D
ihyd
ro-8
-hyd
roxy
-3-m
ethy
l-iso
coum
arin
1200
-93-
7Xy
laria
sp.
YX-
28[5
7]
17[l(
3-bu
teny
lthio
)-2-n
itroe
thyl
]-ben
zene
1288
69-5
0-1
Xyla
ria s
p. Y
X-28
[57]
18Pe
ntad
ecan
oic
acid
, met
hyl e
ster
7132
-64-
1Xy
laria
sp.
YX-
28pe
stic
ide
[57]
1914
-Oct
adec
enal
5655
4-89
-3Xy
laria
sp.
YX-
28[5
7]
20E-
11,1
3-D
imet
hyl-1
2-te
trad
ecen
-1-o
l ace
tate
4000
37-0
0-5
Xyla
ria s
p. Y
X-28
[57]
21H
exad
ecan
oic
acid
, met
hyl e
ster
112-
39-0
Xyla
ria s
p. Y
X-28
Food
flav
orin
g ag
ents
[57]
22n-
Hex
adec
anoi
c ac
id57
-10-
3Xy
laria
sp.
YX-
28In
hibi
ts H
IV-1
infe
ctio
n; a
pot
entia
l ca
ndid
ate
for s
peci
fical
ly a
ttac
k m
ultip
le m
yelo
ma
cells
[57]
232-
Und
ecen
al24
63-7
7-6
Xyla
ria s
p. Y
X-28
[57]
24H
exad
ecan
oic
acid
, 14-
met
hyl-m
ethy
l est
er24
90-4
9-5
Xyla
ria s
p. Y
X-28
[57]
259,
12-O
ctad
ecad
ieno
ic a
cid(
Z,Z)
-met
hyl e
ster
112-
63-0
Xyla
ria s
p. Y
X-28
Flav
orin
g ag
ent o
r adj
uvan
t[5
7]
269-
Oct
adec
enoi
c ac
id (Z
)-,m
ethy
l est
er11
2-62
-9Xy
laria
sp.
YX-
28So
lven
ts[5
7]
273,
7,11
-trim
ethy
l-2,6
,10-
Dod
ecat
rien-
1-ol
4602
-84-
0Xy
laria
sp.
YX-
28In
hibi
ts p
rolif
erat
ion
and
indu
ces
apop
tosi
s of
tum
our-
deriv
ed b
ut
not n
on-t
rans
form
ed c
ell l
ines
[57]
289,
12-O
ctad
ecad
ieno
ic a
cid
(Z,Z
)21
97-3
7-7
Xyla
ria s
p. Y
X-28
Trea
ts th
e pr
even
tion
of p
reec
lam
p-si
a;[5
7]
299-
Oct
adec
enam
ide
(Z)
3322
-62-
1Xy
laria
sp.
YX-
28In
duce
dro
wsi
ness
or s
leep
or t
o re
duce
psy
chol
ogic
al e
xcite
men
t or
anx
iety
[57]
30Pe
ntad
ecan
oic
acid
,2-h
ydro
xym
ethy
l es
ter
9886
3-01
-5Xy
laria
sp.
YX-
28Em
ulsi
fier
[57]
31Fe
rrug
inol
514-
62-5
Xyla
ria s
p. Y
X-28
An
antin
eopl
astic
age
nt; a
ntib
acte
rial
agen
t; pr
otec
tive
agen
t[5
7]
329,
12-O
ctad
ecad
ieno
ic a
cid(
Z,Z)
-,2-h
ydro
xy-1
-(h
ydro
xy m
ethy
l)eth
yl e
ster
544-
35-4
Xyla
ria s
p. Y
X-28
Flav
orin
g ag
ents
[57]
33H
exad
ecan
oic
acid
, 2-h
ydro
xy-1
-(hyd
roxy
met
hyl)
ethy
l est
er23
470-
00-0
Xyla
ria s
p. Y
X-28
Lipi
d m
aps
clas
sific
atio
n[5
7]
Page 30 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 5
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
34Bi
s(2-
ethy
lhex
yl)p
htha
late
117-
81-7
Xyla
ria s
p.YX
-28
[57]
355,
6,8,
9,10
,11-
Hex
ahyd
robe
nz[A
]ant
hrac
ene
6706
4-61
-3Xy
laria
sp.
YX-
28[5
7]
361,
2,3,
4-Te
trah
ydro
-Trip
heny
lene
5981
-10-
2Xy
laria
sp.
YX-
28[5
7]
Page 31 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 6
Seco
ndar
y m
etab
olit
e of
Fus
ariu
m in
Gin
kgo
bilo
ba
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
1A
deno
sine
58-6
1-7
Fusa
rium
sola
ni G
BT07
GBT
07Te
rmin
ate
paro
xysm
al s
upra
vent
ricul
ar ta
chyc
ar-
dia;
term
inat
ing
stab
le a
nd n
arro
w-c
ompl
ex
supr
aven
tric
ular
tach
ycar
dias
; adj
unct
to
thal
lous
chl
orid
e TI
201
myo
card
ial p
erfu
sion
sc
intig
raph
y an
d va
gal m
aneu
vers
and
clin
ical
as
sess
men
t
[11]
2Be
nzen
eeth
anol
/Phe
nyle
thyl
al
coho
l60
-12-
8Fu
sariu
m s
p. G
1024
Ant
i-inf
ectiv
e ag
ents
, loc
al; d
isin
fect
ants
; pre
-se
rvat
ives
, pha
rmac
eutic
al[1
1]
3En
niat
in B
917-
13-5
Fusa
rium
sp.
[58]
4G
inkg
olid
e B
1529
1-77
-7Fu
sariu
m o
xysp
orum
[59,
60]
5H
exad
ecan
e54
4-76
-3Fu
sariu
m s
p. G
1024
[11]
6Ka
empf
erid
e49
1-54
-3Fu
sariu
m so
lani
An
antih
yper
tens
ive
agen
t[6
1]
7Ka
empf
erol
520-
18-3
Fusa
rium
oxy
spor
umA
pos
sibl
e ca
ncer
trea
tmen
t; an
tibac
teria
l age
nt[6
1]
8Q
uerc
etin
117-
39-5
Fusa
rium
oxy
spor
um[5
7]
9Ru
tin15
3-18
-4Fu
sariu
m o
xysp
orum
A ro
le a
s an
ant
ioxi
dant
; ant
ialle
rgic
; ant
i-infl
am-
mat
ory;
ant
ipro
lifer
ativ
e; a
nd a
ntic
arci
noge
nic
prop
ertie
s
[61]
10So
yasa
poge
nol B
595-
15-3
Fusa
rium
oxy
spor
um S
chle
cht
GB-
1(3)
[61]
11Te
trad
ecan
e62
9-59
-4Fu
sariu
m s
p. G
1024
[11]
12β-
Sito
ster
ol83
-46-
5Fu
sariu
m o
xysp
orum
Sch
lech
t G
B-1(
3)A
s an
ticho
lest
erem
ic d
rug;
ant
ioxi
dant
; tre
ats
hype
rlipi
dem
ia.
[61]
Page 32 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 6
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
13Is
orha
mne
tin48
0-19
-3Fu
sariu
m s
pW
arni
ng; (
tyro
sina
se in
hibi
tor;
an a
ntic
oagu
lant
)[6
2]
14D
ecan
e12
4-18
-5Fu
sariu
m s
p. G
1024
[11]
152-
Ethy
l-1-h
exan
ol10
4-76
-7Fu
sariu
m s
p. G
1024
[11]
162-
Buta
nol,3
,3′-o
xybi
s-4-
ethy
lphe
nol
123-
07-9
Fusa
rium
sp.
G10
24Fl
avor
ing
Age
nts
[11]
17D
odec
ane
112-
40-3
Fusa
rium
sp.
G10
24In
crea
se th
e ris
k of
neo
plas
ms
in h
uman
s or
an
imal
s[1
1]
181,
2-be
nzis
othi
azol
e27
2-16
-2Fu
sariu
m s
p. G
1024
[11]
194-
Ethy
l-2-m
etho
xyph
enol
2785
-89-
9Fu
sariu
m s
p. G
1024
Flav
orin
g ag
ents
[11]
20p-
Nitr
oace
toph
enon
e10
0-19
-6Fu
sariu
m s
p. G
1024
Pote
ntia
te th
e eff
ectiv
enes
s of
radi
atio
n th
erap
y in
des
troy
ing
unw
ante
d ce
lls[1
1]
212,
3,5,
6-Te
tram
ethy
l-p-b
enzo
-qu
inon
e52
7-17
-3Fu
sariu
m s
p. G
1024
prod
uct q
uino
nes
duro
quin
one
[11]
22Ei
cosa
ne11
2-95
-8Fu
sariu
m s
p. G
1024
Flav
orin
g A
gent
s.[1
1]
231,
2-Be
nzen
edic
arbo
xylic
aci
d bi
s(2-
met
hylp
ropy
l)est
er88
-99-
3Fu
sariu
m s
p. G
1024
[11]
24D
ibut
yl p
htha
late
84-7
4-2
Fusa
rium
sp.
G10
24A
gain
st th
e la
rval
trom
bicu
lid m
ite; p
reve
ntin
g sc
rub
typh
us o
f top
ical
app
licat
ion
in tr
oops
[11]
Page 33 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 7
Seco
ndar
y m
etab
olit
e of
oth
er e
ndop
hyti
cs in
Gin
kgo
bilo
ba
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
12-
(Hyd
roxy
met
hylth
io)e
than
ol87
6503
-58-
1Co
lleto
tric
hum
sp.
NTB
-2Pl
atel
et a
ggre
gatio
n in
hibi
tor,
an a
lpha
-glu
-co
sida
se in
hibi
tor,
an a
ntin
eopl
astic
age
nt[6
3]
2A
pige
nin-
8-C
-β-d
-gl
ucop
yran
osid
e36
81-9
3-4
Colle
totr
ichu
m s
p.[6
3, 6
4]
36-
Etho
xyl-2
,4-a
mid
e la
cton
eBa
cillu
s am
ylol
ique
faci
ens
CGM
CC 5
569
[64]
46-
Hyd
roxy
lbut
yl-2
,4-a
mid
e la
cton
eBa
cillu
s am
ylol
ique
faci
ens
CGM
CC 5
569
[64]
56-
Hyd
roxy
prop
yl-2
,4-a
mid
e la
cton
eBa
cillu
s am
ylol
ique
faci
ens
CGM
CC 5
569
[64]
6Bi
uret
108-
19-0
Baci
llus a
myl
oliq
uefa
cien
s CG
MCC
556
9U
sed
for p
reve
ntin
g, d
estr
oyin
g or
miti
gat-
ing
pest
s[6
4]
7G
inkg
olid
e B
1529
1-77
-7O
ospo
ra w
allr.
G10
Fibr
inol
ytic
age
nts
[65]
82′
-Deo
xyur
idin
e/ur
acil
deox
y-rib
osid
e95
1-78
-0U
nide
ntifi
edA
ntim
etab
olite
s[6
5]
93-
Met
hylp
iper
azin
e-2,
5-di
one
6062
-46-
0U
nide
ntifi
ed[6
5]
10A
deni
ne73
-24-
5U
nide
ntifi
ed[6
5]
11A
deni
ne d
eoxy
ribos
ide
Uni
dent
ified
[65]
12A
deno
sine
58-6
1-7
Uni
dent
ified
Use
d as
an
initi
al tr
eatm
ent f
or th
e te
rmin
a-tio
n of
par
oxys
mal
Sup
rave
ntric
ular
ta
chyc
ardi
a
[65]
Page 34 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 7
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
13Q
uerc
etin
117-
39-5
Stem
phyl
ium
sp.
Act
inom
yces
Ant
ioxi
dant
s[3
7, 6
6]
Nod
ulisp
oriu
m h
yalo
spor
umSc
hizo
phyl
lum
com
mun
e Fr
.[6
7]
Fuse
lla S
acc
Alte
rnar
ia s
pSp
hace
lia s
p.An
pelo
myc
es h
umul
i
[37]
Phom
a gl
omer
ate
[30,
61]
Tric
hoth
eciu
m[5
3]
Muc
or c
ircin
ello
ides
[40]
Spha
erop
sis s
p. B
301
[68]
14Ka
empf
erol
520-
18-3
Fuse
lla S
acc
Alte
rnar
ia s
p.G
ibbe
rella
sp.
Spha
celia
sp.
Dem
atiu
m P
ers
As
a se
lect
ive
estr
ogen
rece
ptor
mod
ulat
or[6
6]
Tric
hoth
eciu
m[5
3]
Spha
erop
sis s
p.[6
8]
15Ce
rebr
osid
e B
8864
2-46
-0Ph
yllo
stic
ta s
p. T
P78,
(Gen
Bank
ID
: KC
4457
36)
An
antim
icro
bial
com
poun
d[2
0, 2
1]
16Ce
rebr
osid
e C
9867
7-33
-9Ph
yllo
stic
ta s
p. T
P78
(Gen
Bank
ID
: KC
4457
36)
Incr
ease
s to
lera
nce
to c
hilli
ng in
jury
and
al
ters
lipi
d co
mpo
sitio
n in
whe
at ro
ots
[20,
21]
17En
niat
in B
119
914-
20-6
Tube
rcul
aria
ceae
F1-
3Fu
sariu
m m
ycot
oxin
s[6
9]
18En
niat
in D
1989
3-21
-1Tu
berc
ular
iace
ae s
p. F
1-3
Inhi
bitio
n of
Bot
rytis
cin
erea
spo
re g
erm
ina-
tion
[69]
19Be
nzen
eeth
anol
/Phe
nyle
thyl
al
coho
l60
-12-
8M
usco
dor a
lbus
str
ain
GBA
Ant
i-bac
teria
l age
nts
and
antio
xida
nts.
Ant
i-In
fect
ive
Age
nts
[69]
Page 35 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 7
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
20G
inkg
olid
e C
1529
1-76
-6G
loeo
spor
ium
; Tol
ura;
Pha
co-
dium
Redu
ced
lipid
acc
umul
atio
n an
d su
ppre
sses
ad
ipog
enes
is[3
2]
21Ka
empf
erid
e49
1-54
-3Ph
oma
glom
erat
aRe
vers
e ba
cter
ial r
esis
tanc
e to
am
oxic
illin
in
ARE
C[6
1]
Anpe
lom
yces
hum
uli
[61]
22Ru
tin15
3-18
-4M
ucor
circ
inel
loid
es G
F521
Use
d th
erap
eutic
ally
to d
ecre
ase
capi
llary
fra
gilit
y[6
1]
Nod
ulisp
oriu
m h
yalo
spor
um[6
7]
23Sp
orot
hrio
lide
1547
99-9
2-5
Nod
ulisp
oriu
m s
p. A
21U
sed
to tr
eat t
he in
fect
ion
caus
ed b
y ca
ndid
a al
bica
ns a
nd c
rypt
ococ
cus
neof
orm
ans
[55]
24Is
orha
mne
tin48
0-19
-3St
emph
yliu
m s
p.Al
tern
aria
sp
Gib
bere
lla s
p.Tr
icho
thec
ium
prev
ents
end
othe
lial d
ysfu
nctio
n, s
uper
-ox
ide
prod
uctio
n, Is
orha
mne
tin a
ppea
rs
to b
e a
pote
nt d
rug
agai
nst e
soph
agea
l ca
ncer
[62]
spha
erop
sis[6
8]
Plan
tact
inos
pora
sp.
NEA
U-g
xj3
[20,
21]
25A
ntib
iotic
U-6
2162
8251
6-67
-4Pl
anta
ctin
ospo
ra s
p. N
EAU
-gxj
3In
hibi
ted
the
grow
th o
f Gra
m-p
ositi
ve
bact
eria
[20,
21]
26Sa
ltern
amid
e C
1662
688-
81-4
spha
erop
sis[6
8]
27A
bsci
sic
acid
2129
3-29
-8Ph
oma
beta
ePl
ant G
row
th R
egul
ator
[69]
28Ta
xol
3306
9-62
-4Ph
omop
sis s
p. 2
str
ain
BKH
30
(BSL
No.
72)
An
antin
eopl
astic
age
nt, t
ubul
in m
odul
ator
s[7
0]
Mus
codo
r alb
us s
trai
n G
BA[6
9]
29A
cetic
aci
d, m
ethy
l est
er79
-20-
9M
usco
dor a
lbus
str
ain
GBA
[69]
Page 36 of 40Yuan et al. Chin Med (2019) 14:51
Tabl
e 7
(con
tinu
ed)
No.
Met
abol
ites
CAS
num
ber
Mol
ecul
ar s
truc
ture
Endo
phyt
esA
pplic
atio
nRe
fere
nces
302-
Buta
none
78-9
3-3
Mus
codo
r alb
us s
trai
n G
BAPo
lar a
prot
ic s
olve
nt[6
9]
31A
cetic
aci
d, 2
-met
hylp
ropy
l es
ter
110-
19-0
Mus
codo
r alb
us s
trai
n G
BAA
n an
tifun
gal a
gent
[71]
321-
Prop
anol
, 2-m
ethy
l78
-83-
1M
usco
dor a
lbus
str
ain
GBA
Poss
esse
s ni
cotin
e-lik
e sy
napt
otro
pic
actio
ns
on th
e ne
rvou
s sy
stem
s[7
1]
331-
Buta
nol,
3-m
ethy
l-,ac
etat
e12
3-92
-2M
usco
dor a
lbus
str
ain
GBA
[71]
34Cy
cloh
exan
e,1-
met
hyl-4
-met
h-yl
ene
2808
-80-
2M
usco
dor a
lbus
str
ain
GBA
[69]
352,
3-D
imet
hyl-3
-isop
ropy
l-cy
clop
ente
ne73
331-
73-4
Mus
codo
r alb
us s
trai
n G
BA[6
9]
361-
Buta
nol,
3-m
ethy
l12
3-51
-3M
usco
dor a
lbus
str
ain
GBA
[69]
37Py
rrol
idin
e12
3-75
-1M
usco
dor a
lbus
str
ain
GBA
[72]
38G
erm
acre
ne B
1542
3-57
-1M
usco
dor a
lbus
str
ain
GBA
[72]
39α-
Sine
nsal
1790
9-77
-2M
usco
dor a
lbus
str
ain
GBA
[69]
40Pr
opan
oic
acid
, 2-m
ethy
l79
-31-
2M
usco
dor a
lbus
str
ain
GBA
[73]
41Tr
ans-
cary
ophy
llene
87-4
4-5
Mus
codo
r alb
us s
trai
n G
BAA
nti-i
nflam
mat
ory
agen
ts[7
3]
424-
Pipe
ridin
one,
1-m
ethy
l14
45-7
3-4
Mus
codo
r alb
us s
trai
n G
BA[7
3]
43A
cetic
aci
d, 2
-phe
nyle
thyl
est
er10
3-45
-7M
usco
dor a
lbus
str
ain
GBA
[73]
44(+
)-Vitr
ene
9025
0-82
-1M
usco
dor a
lbus
str
ain
GBA
[73]
Page 37 of 40Yuan et al. Chin Med (2019) 14:51
This strain displayed the strongest antibacterial activity [35].
Secondary metabolites of Xylaria43 kinds of compounds were isolated from the fermen-tation products of Xylaria in Ginkgo biloba (Table 5), in which the compound 7-amino-4-methylcoumarin was isolated from the fermentation product of Xylaria sp. YX-28 [36]. It has antibacterial activity and also has strong inhibitory activity against 13 kinds of human sus-ceptible pathogens, which is significantly higher than the positive controls ampicillin, gentamicin and tetracycline.
Secondary metabolites of FusariumFusarium is one of the dominant bacteria, which can be isolated from different parts of Ginkgo cultivated in vari-ous areas. According to the literatures, 25 kinds of com-pounds were isolated from the fermentation products of Fusarium (Table 6). Since Fusarium of G. biloba can produce ginkgolides B, it can be used as a new source of ginkgolides B [37]. Some studies have shown that Fusar-ium oxysporum GF521 can produce rutin and kaemp-ferol, and the total flavonoids production of endophytic fungi is 21.10 ± 1.30 mg/L, which indicates that Fusarium genus also have a high ability of producing flavonoids [37].
Secondary metabolites of other genus53 compounds were isolated from the fermentation products of other genus in G. biloba (Table 7), some of which can also produce other valuable compounds. From the endophytic Muscodor albus GBA, 19 kinds of volatile components can be separated [24], which normally have a strong ecological effect. Some vola-tile components can inhibit the pathogenic microor-ganisms and enhance the disease resistance of plants. Bacillus amyloliquefaciens can produce 8 kinds of compounds [35, 37] which have some biological activi-ties. Two compounds, apigenin-8-C-glucoside and 2-(Hydroxymethylthio) ethanol, were isolated from Colletotrichum sp. NTB-2., in which apigenin-8-C-glucoside has strong inhibitory activity against Bacil-lus subtilis, Salmonella typhimurium and Pseudomonas cepacia [38]. Moreover, Colletotrichum sp. could pro-duce flavones which exhibited potent anti-cancer, anti-HIV [39] and antioxidant activities [40].
In recent years, some new ginkgo endophytes and sec-ondary metabolites have been discovered. Guo et al. [20, 21] discovered a new amide compound from Plantacti-nospora sp. NEAU-gxj3, Cao et al. [22] found the metab-olite sporothriolide from the Nodulisporium of G. biloba, which has anti-phytopathogenic activity.
Application of secondary metabolites from Ginkgo bilobaFollowing the discovery by Schwabe of Germany that Ginkgo biloba contains active ingredients—ginkgo flavo-noids and ginkgolides for the prevention and treatment of cardiovascular, cerebrovascular and neurological dis-eases, the researches about ginkgo has become more popular. Germany and France were the first countries in the world to develop ginkgo leaf products. In the mid-1970s, they first developed Ginkgo biloba leaves for the treatment of cardiovascular diseases. Since then, there are more than 50 kinds of ginkgo products on the market.
In the application, Ginkgo can be used with the extracts. Some examples, a substance EGb 761 extracted from Ginkgo biloba has shown to be effective against Noise-induced hearing loss (NIHL) in an animal model. This substance is assumed to protect the cochlea from hair cell loss after intensive noise exposure by reducing reactive oxygen species (ROS). Further effects of EGb 761 on the cellular and systemic levels of the nervous system make it a promising candidate not only for protection against NIHL but also for its secondary comorbidities like tinnitus [41]; One Ginkgo biloba extract (GbE) was used as a nontoxic natural reducing and stabilizing agent for preparing cytocompatible graphene. The as-prepared GbE-reduced graphene oxide (Gb-rGO) showed sig-nificant biocompatibility with cancer cells. Addition of GbE makes rGO producing procedure cost-effective and green. This method could be used for various biomedi-cal applications, such as tissue engineering, drug delivery, biosensing, and molecular imaging [42].
Some application has been using a part of the plant. Another example, Ginkgo tea is a kind of health food pro-duced from Ginkgo biloba leaves. Two kinds of glycosi-dase were used to improve the flavor of Ginkgo tea, and three kinds of bioactivities were selected to investigate the health care function of the tea infusion [43].
The Ginkgo preparation mainly includes capsules, tablets, granules, tea bags. Capsules and tablets are most popular in the formulation of the product. Recently, new prepara-tion like shampoo, facial cleanser and hair moisturizer have been introduced in cosmetics applications. Most of the ginkgo products on the market are registered as health foods and a few are registered as over-the-counter drugs.
In many existing products, especially in the medi-cines, 24% of total flavonoids and 6% of ginkgolides are the basic quality requirements for Ginkgo biloba extracts. Some famous manufacturers proposed higher standards. They appended ginkgolides A, B, C, J and biloba lactone as the quality indicators and generally required the con-tent of ginkgolides A, B, C, J greater than 2.5%, the con-tent of biloba lactone greater than 2.6%.
Page 38 of 40Yuan et al. Chin Med (2019) 14:51
On the basis of data about the endophytes and sec-ondary metabolites in G. biloba, the catalogue is diverse in terms of structural complexity and lots of them have promising biological activities, which have the poten-tial to be a source of new pharmaceutical agents which have a constant, critical need to combat cancers, viral infections, infectious diseases, and autoimmune disor-ders. There is also a growing need to fight insect-borne diseases of both animals and plants as climatological changes provide conditions conducive to more intensive outbreaks of these events. The fight against any disease is a dynamic equilibrium between advances in chemother-apy and natural selection in infectious or invasive agents. If the scientific community is to maintain parity in this never-ending struggle, then new sources of novel, bioac-tive chemotherapeutic agents must be found.
It appears that the mechanism by which endophytes produce secondary metabolites that mimic those pro-duced by their host plants is far from clear. Even though efforts to unravel the pathway genes in the endophytes, it has failed to detect critical genes corresponding to those existing in plants, our understanding of the mecha-nisms associated with the development of different dis-eases increases, our ability to use this knowledge to select for ever more potent and selective compounds should
increase commensurately. Endophytes of G. biloba will continue to provide a fertile arena for these quests.
ProspectsWith human aging process is accelerating, it has been common pursuit for a healthy and high-quality living. Since Ginkgo biloba preparations have a worldwide repu-tation as natural medicines and healthy products, Ginkgo development and the prospects are attractive. In the United States, Ginkgo biloba extracts have been on the list of imported drugs. Ginkgo products on the market are almost all products of American companies, and few products have been seen in Europe. At present, the Euro-pean market is basically occupied by French and German products. Most of the Ginkgo extracts on the US market are produced by Japan and South Korea, a small portion is purchased from China.
Although comparing with the developed countries, China market is not competitive and too weak to take the risks, the potential of China’s Ginkgo development is still worth looking forward to. China is the birthplace and main producing area of the world’s Ginkgo. Many excellent Ginkgo germplasm resources are valuable treasures for China. With the sharp increase in Ginkgo resources and products output in China, the market has become more concerned at present (Fig. 7). At present, the Ginkgo products in China have low added-value and quality. In the development of ginkgo industry in China, it is necessary to increase the quality standardization and to improve the scientific research efforts and the produc-tion technology of Ginkgo preparations. It deserves to initiate new and technological products on flavonoids, bilobalide, polyisoprene, etc. Especially some new appli-cation in other industries should be explored, such as supplying in cytocompatible graphene preparation.
Chinese people have a tradition to have Ginkgo prepa-ration as healthy products. China’s population accounts for about a quarter of the world’s total population. There-fore, the Ginkgo products in China should have more concerns on the domestic market and at the same time expand the international market with high-quality and featured products.
AbbreviationsG. biloba: Ginkgo biloba; CD: electronic circular dichroism; Gb-rGO: gbE-reduced graphene oxide; NIHL: noise-induced hearing loss; ROS: reactive oxygen species.
AcknowledgementsNot applicable.
Authors’ contributionsZY and YT drafted the manuscript and prepared tables and figures. FH and HZ contributed to revisions of the manuscript. All authors read and approved the final manuscript.
503.5568.2
610.1664.1
712.5
Ging
o ex
trac
t pro
duc�
on/t
year
2014 2015 2016 2017 2018
prop
or�o
n of
Gin
kgo
prod
uc�o
n/%
year
a
b
Fig. 7 The production of Ginkgo extracts in China and its proportion in the world market. a The production of Ginkgo extracts in China from 2015 to 2019; b the proportion of China Ginkgo products in the world market from 2014 to 2018
Page 39 of 40Yuan et al. Chin Med (2019) 14:51
FundingThe work reported in the paper has been supported by the National Natural Science Foundation of China (No. 31741109), the Hunan Provincial Natural Science Foundation of China (Nos. 2018JJ2145, 2018JJ2146) and the Scientific Research Project of Hunan University of Science and Technology (17XKY002, 17XKY011, 17XKY012).
Availability of data and materialsNot applicable.
Ethics approval and consent to participateNot applicable.
Consent for publicationNot applicable.
Competing interestsThe authors declare that they have no competing interests.
Author details1 College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China. 2 Hunan Provincial Engineering Research Center for Ginkgo Biloba, Yongzhou 425199, China. 3 College of Chemistry and Bio-engineering, Hunan University of Science and Engineering, Yongzhou 425199, China.
Received: 14 July 2019 Accepted: 23 October 2019
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