© Benaki Phytopathological Institute
Venieraki
et al.
52
ural products, have been used to treat vari-
ous ailments and have been the foundation
for discovery and development of modern
therapeutics (Pan
et al.
, 2013). Up to 80 % of
people in developing countries are totally
dependent on herbal drugs for their prima-
ry healthcare. More than 51% of small mole-
cule drugs approved between 1981 and 2014
were based on natural products, the rest be-
ing synthetic (Chen
et al.
, 2016). With the in-
creasing demand for herbal drugs, natural
health products and secondary metabolites,
the use of medicinal plants is growing rapid-
ly throughout the world (Chen
et al
., 2016).
However, we are facing the accelerated loss
of wild medicinal plant species; one third
of the estimated 50.000-80.000 medicinal
plant species are threatened with extinction
from overharvesting and natural anthropo-
genic habitat destruction (Chen
et al
., 2016).
Furthermore, the feasibility of access to
plant bioactive compounds is challenged by
the low levels at which these products accu-
mulate in native medicinal plants, the long
growth periods required for plant matura-
tion, and the difficulty in their recovery from
other plant-derived metabolites (Staniek
et
al
., 2014). For example, the taxol concentra-
tion is about 0.001–0.05% in
Taxus brevifolia
,
which is the most productive species. Thus,
15 kg of Taxus bark, three trees, are required
for production of 1 g, while every cancer pa-
tient requires about 2.5 g (Malik
et al
., 2011).
Therefore, it is important to find alter-
native approaches to produce the medici-
nal plant-derived biologically active com-
pounds, in particularly those derived from
endangered or difficult-to-cultivate plant
species, to meet the medical demand. This
can be achieved by the application of plant
cell and tissue culture, heterologous pro-
duction, total chemical synthesis, semi-syn-
thesis, or by starting with a microbially - pro-
duced or plant-extracted natural product
occurring more abundantly in nature (Ata-
nasof
et al
., 2015; Rai
et al.
, 2016; Ramirez-Es-
trada
et al
., 2016) or by exploiting the abili-
ty of endophytic fungi residing in plants to
produce the same or similar bioactive com-
pounds as their hosts (Zhao
et al
., 2011). In
this review, we aim to show that the large
number of medicinal plants used for the
isolation of medically important bioactive
compounds harbor endophytic fungi capa-
ble of host-independent biosynthesis of the
same or similar bioactive secondary metab-
olites as their hosts. This review will also dis-
cuss the evolution and origin of pathways
involved in the biosynthesis of these bioac-
tive compounds and potential approaches
aiming to enhance their production.
Medicinal plants harbor endophytic
fungi capable of mimicking their host
plant secondary metabolite profile-
Case studies on medicinal plants
producing metabolites of known
medical importance
Since the first report of endophyte
Tax-
omyces andreanae
that produces the same
bioactive secondary metabolite taxol (pacli-
taxel) as its host
Taxus brevifolia
in 1993 (Sti-
erle
et al
., 1993), several studies have shown
that plant-derived secondary metabolites
are produced by endophytes (Zhao
et al
.,
2011). In this section, we will present a liter-
ature survey aiming to show that medicinal
plants used for isolation of medically impor-
tant secondary metabolites usually harbor
endophytic fungi which are capable of host-
independent biosynthesis of these metabo-
lites. In each one of the presented case stud-
ies, emphasis will be placed on the plant
species, the organ where the bioactive com-
pound is accumulated and the organ from
which the active compound-producing fun-
gi were isolated.
Salvia sp. (Lamiaceae)
Salvia
species have many important
medicinal properties with proven pharma-
cological potential. Some of these proper-
ties may be mediated by biologically active
polyphenols or terpenoids (Wu
et al
., 2012).
Two kinds of bioactive compounds, tanshi-
nones (tanshinone I, tanshinone IIA, tanshi-
none IIB, isotanshinone I, and cryptotanshi-
none) and salvianolic acids (salvianolic acid
