Kozlovsky A. G., Zhelifonova V. P., and Antipova T. V. (2013) Signpost Open Access J. Org. Biomol. Chem. 1, 11-21.
Volume 01, Article ID 010302, 11 pages. ISSN: 2321-4163
http://signpostejournals.com
MINI REVIEW Open Access Biologically active metabolites of Penicillium fungi
A.G. Kozlovsky*, V.P. Zhelifonova, T.V. Antipova
G.K. Skryabin Institute of Biochemistry and Physiology of Microorganisms, Russian Academy of
Sciences, 5 Pr. Nauki, Pushchino, Moscow Region, 142290 Russia
E-mail: [email protected]
*Corresponding author
Copyright: Prof. A.G. Kozlovsky
Received: February 20, 2013
Accepted: March 12, 2013
Abstract
The present overview highlights potential biomolecules produced by microscopic fungi
Penicillium. These fungi are a large part of microbial diversity and open up exciting prospects
in the search of various biologically active natural scaffolds. In connection with the observed
signs of global warming (a decrease of the Arctic Ocean ice cover), the most topical are the
results obtained for fungi isolated from permafrost. The strategy for the search of secondary
metabolites was successfully implemented as evidenced from the isolation of novel
compounds and important metabolites. Studies of the toxigenic potential of the fungi grown on
artificial media and natural substrates, the observed correlation between them, confirm the
importance of the obtained data and are of ecotoxicological significance.
Keywords
Fungi Penicillium, Secondary metabolites, Mycotoxins, Ergot alkaloids, Global warming,
Permafrost
1. Introduction
share the tetracyclic ergoline nucleus. Clavine
alkaloids can be divided into three groups. The
first includes 6-N-methylergoline derivatives
such
as
festuclavine,
epicostaclavine,
fumigaclavines and isofumigaclavines A and B
with a completely saturated ring D. Ergolenes
having a double bond in position 8,9, such as
agroclavine, agroclavine-1, epoxyagroclavine-1
are assigned to the second group. The third group
Penicillia are some of the most widespread
hyphomycetes among microscopic fungi. Their
natural habitats are soils of northern latitudes.
They are known as producers of various types of
biologically active compounds such as ergot
alkaloids,
diketopiperazines,
quinolines,
quinazolines and polyketides [1].
Penicillium fungi synthesize clavine ergot
alkaloids whose structural specificity is that they
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Kozlovsky A. G., Zhelifonova V. P., and Antipova T. V. (2013) Signpost Open Access J. Org. Biomol. Chem. 1, 11-21.
Volume 01, Article ID 010302, 11 pages. ISSN: 2321-4163
http://signpostejournals.com
consists of clavine alkaloids with the modified
rings C and D; rugulovasines A and B,
aurantioclavine, and α-cyclopiazonic acid (CPA)
are some of the members of this group of
compounds.
Ergot alkaloids possess various kinds of
biological activity. They can act peripherally
leading to uterine vasoconstriction and
contraction; neurohormonally, by blocking the
action of adrenaline and serotonin; and can also
affect the central nervous system, by reducing the
activity of the vasomotor centre and stimulating
the sympathetic structures in the midbrain,
thereby causing a hallucinogenic effect, and also
inhibiting the secretion of prolactin, hyperthermia
and vomiting [2,3].
The pharmacology of ergot alkaloids finds its
origins in numerous Middle-Age accounts of
ergot toxicity in man and animals. This toxicity
called ergotism was due to the ingestion of (a
product from) rye grain infected with the ergot
fungus Claviceps purpurea [4,5]. Ergotism had
been well known from the Middle Ages to the
19th century as “Holy Fire” or ”St. Antony’s
Fire”. Convulsive ergotism is connected with
poisoning with clavine alkaloids, and gangrenous
ergotism is caused by peptide alkaloids produced
by Claviceps [3]. Earlier research into the
pharmacological activity of epoxyagroclavine-1
has shown this compound to possess a neurotropic
activity, to have a mild hypotensive effect, to slow
down the heart rate, to lower the reactivity of the
vascular system to noradrenaline [6]. Some ergot
alkaloids were found to have antibiotic and
cytostatic activities as well [7]. Thus, agroclavine,
festuclavine, and their alkyl derivatives exhibit
bacteriostatic effects with respect to Escherichia
coli, Staphylococcus aureus, Pseudomonas
aeruginosa, and other bacterial strains [8,9].
Festuclavine
derivatives,
by
suppressing
nucleoside transport in some tumor cells, inhibit
DNA and RNA syntheses [10].
Another group of biologically active
compounds synthesized by penicillia are cyclic
peptides diketopiperazines consisting of residues
of two amino acids and mevalonic acid. The
precursors of roquefortine and related alkaloids
such as 3,12-dihydroroquefortine, glandicolines
A and B, meleagrine, oxalin are tryptophan,
histidine and mevalonic acid [11]. Tryptophan
and mevalonic acid are also the precursors of
diketopiperazine alkaloids fellutanines and
isofellutanines [12]. Brevianamides A and B and
the new alkaloids piscarinines A and B are
formed from tryptophan, proline and from one or
more mevalonic acid molecules via the same
pathway [13]. Diketopiperazine alkaloids whose
precursors are tryptophan and leucine include
leucyl tryptophanyl diketopiperazine and
verrucosine [11]. Compounds formed from the
residues of tryptophan and phenylalanine are
represented by such alkaloids as rugulosuvine,
isorugulosuvine, puberulin (= rugulosuvine A),
puberulin A (= rugulosuvine B) [14].
Roquefortine is the most widespread and well
studied mycotoxin from the point of view of
biological activity. It is known as a neurotoxic
substance [1]. Under certain conditions, it
inhibits enzymes of the digestive tract [15] and
activities of cytochrome P 450 [16]. Some
diketopiperazines, e.g. rugulosuvines and
brevianamides, were shown to have antibiotic
and antitumor activities [14,17].
If anthranilic acid begins the biosynthetic
chain, the result of the metabolic processes are
benzodiazepine
compounds
(cyclopeptin,
cyclopenin and cyclopenol), quinoline compounds
(viridicatin, viridicatol, quinocitrinines A and B)
and quinazoline compounds (fumiquinazolines F
and G). Quinocitrinines A and B exhibit various
types of biological activity [18]. They are efficient
against a range of Gram-positive and Gramnegative bacteria, yeasts and fungi, and were
found to possess a moderate antiproliferative
activity with respect to L-929 cells and HeLa
cells. Thus, the inhibitory concentrations (LC50,
µg/mL) of quinocitrinines A and B for L-929
murine fibroblast cells are 33.1 and 18.6,
respectively; for K-562 human leukemic cells,
19.5 and 7.8; and HeLa >50, >50, respectively. In
turn, fumiquinazolines F and G exhibit moderate
cytotoxicities in the P388 lymphocytic leukaemia
test system in cell culture [19].
Interest in these metabolites increases
owing to their valuable pharmacological and
therapeutic properties (Table-1). The most
12
Kozlovsky A. G., Zhelifonova V. P., and Antipova T. V. (2013) Signpost Open Access J. Org. Biomol. Chem. 1, 11-21.
Volume 01, Article ID 010302, 11 pages. ISSN: 2321-4163
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numerous group of mycotoxins produced by
penicillia are polyketides. The most well
investigated mycotoxins among them are patulin,
citrinin, as well as ochratoxins A and B [4].
Ochratoxin A is a nephrotoxin and has been
entered into the list of five main mycotoxins the
levels of which in food and feed are strictly
controlled [20].
Table 1. Biological activity of secondary metabolites from Penicillium fungi
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Kozlovsky A. G., Zhelifonova V. P., and Antipova T. V. (2013) Signpost Open Access J. Org. Biomol. Chem. 1, 11-21.
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it was important to assess the toxigenic potential
of fungal microflora in sites, e.g. such as in the
Mir orbital space station. In view of the observed
climate changes and global warming predictions,
it is of undoubted interest to study the toxigenic
potential of the fungi isolated from permafrost.
2. Strategy of the search for new mycotoxin
producers and strains synthesizing earlier
unknown biologically active compounds
Various approaches have been used to search
for new biologically active molecules that pose a
hazard as mycotoxins. This study used strains
from microbial culture collections of a certain
official status, which are maintained under
controlled conditions. Strains were cultured
under conditions optimal for the synthesis of
secondary metabolites. Ordinarily, we used a
simple synthetic modified Abe’ s medium,
containing mannitol and succinic acid as a carbon
source and mineral salts, which is favourable and
optimal for secondary metabolite biosynthesis.
The strains were cultured under optimal
conditions on a rotary shaker for submerged
cultivation at 24°C and 220-240 rpm. The fungi
were grown in 750 mL flasks with 150 ml of the
media. The secondary metabolites were isolated
from the culture liquid by extraction. Chloroform
was used to recover substances from culture
liquid filtrate and a mixture of chloroform and
methanol (3:1) for extraction from mycelium.
Extracts
were
analyzed
by
thin-layer
chromatography using Ehrlich’s, Dragendorf’s
and similar reagents for functional groups and
groups of compounds. These data enabled a
preliminary identification of the metabolites by
using the mycotoxin samples available at the
laboratory. At this stage, we also selected
promising strains taking into account the
synthesis of new, earlier unknown metabolites.
The selected strains were cultured to produce the
required amounts of secondary metabolites. The
produced samples of the secondary metabolites
were used for further isolation and purification of
required individual substances. The last stage
was to elucidate the structures of the isolates.
Biological tests are an integral part of work.
The strains belonging to species creative with
respect to their ability to produce new
biomolecules were screened. Metabolome
components in the producers isolated from the
regions subjected to anthropogenic stress and
from other unusual habitats were studied.
Considering the specific features of the habitats,
2.1. Search for biologically active compound
producers among representatives of species
creative with respect to secondary metabolite
biosynthesis
An earlier study established an ability of the
fungus P. fellutanum (=P. sizovae) to produce
ergot alkaloids of unusual stereochemistry in
carbon atoms 5 and 10 of the ergoline nucleus.
These are agroclavine-1 and epoxiagroclavine-1,
as well as ergot alkaloids of a dimeric structure
with the N-N bond of the indolic ring — dimer of
agroclavine-1, dimer of epoxyagroclavine-1 and
mixed
dimers
of
agroclavine-1
and
epoxyagroclavine-1 (Figure 1) [21, 22].
Screening of five P. fellutanum strains found one
of them – VKM-3020 – to be able to produce a
group of evidently biogenetically related
diketopiperazine alkaloids in which tryptophan
was the precursor [12]. These metabolites were
named fellutanine A, fellutanine B, isofellutanine
B, fellutanine C, isofellutanine C, fellutanine D
and fellutanine E. Fellutanine D was cytotoxic
for L-969, K-562 and HeLa cells (Figure 2) [23].
P. piscarium fungi are well known as
producers of indole-containing tremorgenic
mycotoxins – jantitrem B, fumitremorgin B,
verruculogen and penitrems [24]. Information on
P. piscarium synthesis of alkaloids not belonging
to the tremorgenic group is scarce. The
metabolome studies of three P. piscarium strains
have found that they can produce various
diketopiperazine alkaloids [21]. Verrucosine,
prolyl tryptophanyl diketopiperazine, puberulin
A, isorugulosuvine and fellutanine A were found
in the VKM F-325 strain. The fungus F-1823
produced only isorugulosuvine and fellutanine A.
The strain VKM F-691 synthesized prolyl
tryptophanyl diketopiperazine. Two new
metabolites were isolated and purified from the
culture liquid of this strain, their structures were
elucidated [13]. These compounds belong to the
14
Kozlovsky A. G., Zhelifonova V. P., and Antipova T. V. (2013) Signpost Open Access J. Org. Biomol. Chem. 1, 11-21.
Volume 01, Article ID 010302, 11 pages. ISSN: 2321-4163
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H3C
N
CH3
H
H3C
O
N
CH3
H
H3C
O
H
H
N
H
N
N
Epoxyagroclavine-I
Dimer epoxyagroclavine-I
O
O
H
HO
N
CH3
H3C
H
NH
N
CH3
H3C
HO
CH2
H
Quinocitrinine A
CH3
O
H
N
H
N
H
Agroclavine-I
CH3 H3C
N
H
H
NH
CH2
H
Quinocitrinine B
Figure 1. Examples of few ergot alkaloids and quinocitrinins
Figure 2. Fellutanines A-D
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Kozlovsky A. G., Zhelifonova V. P., and Antipova T. V. (2013) Signpost Open Access J. Org. Biomol. Chem. 1, 11-21.
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Figure 3. Piscarinines A-B
diketopiperazine family of unusual structure of
the dihydropyranyl-substituted indole nucleus.
The metabolites were named piscarinine A and
piscarinine B (Figure 3). The substances
exhibited an average antimicrobial activity
against bacteria and fungi and an average
cytotoxicity. The metabolites are active against
the prostate cancer cell line LNCAP with IC50
values of 2.195 μg/mL for piscarinine A and
1.914 μg/mL for piscarinine B [13].
and light serozems (Gray Desert Soils)
(Turkmenistan). Besides, fungal isolates from the
snow of urban areas and domestic dust in blocks
of flats (Moscow) were investigated. All species
were chosen based on the preliminary analysis of
the general set of the filamentous fungi in a
location and were typical of them.
The culture conditions have a significant
effect on the quantity of fungal secondary
metabolites produced, and the relationship
between them [30]. The qualitative composition
of the metabolites is, however, constant as a rule
[30,31]. Therefore, in most cases submerged
cultivation of a producer in Abe’s medium with
mannitol and succinate as carbon and energy
sources, favourable for production of secondary
metabolites, makes it possible to reveal major
part of the mycotoxins produced by strains
examined.
The highest productivity was observed in
fungi of those species whose strains are known in
the literature to have a high toxin-forming
capability: P. chrysogenum, P. granulatum, P.
spinulosum, P. vulpinum. It should be noted that
several strains including P. aurantiogriseum №
3, P. chrysogenum № 4, P. spinulosum № 15
and P. vulpinum № 113 isolated from urban soils
and those polluted with nitrogen fertilizers were
able to produce biologically active substances
earlier unknown for these species.
Thus, P. chrysogenum is known as a producer
of penicillin, rugulovasine and diketopiperazine
alkaloids of the roquefortine group [32]. One of
the strains of this species – № 105 – isolated
2.2 Strains of fungi isolated from habitats
submerged to anthropogenic stress
It is known that anthropogenic factors cause
changes in soil micromycete communities and
fungal successions [26]. It has also been found
that the composition and amount of mycotoxins
synthesized by a producing strain depend on
various external factors [27]. However,
information on the toxigenic potential of the
strains isolated from habitats subjected to
anthropogenic stress is scarce [28].
This work investigated mycotoxins in 19
strains of 12 species of the Penicillium genus
[29]. The examined species were isolated from
areas with various environmental conditions at
various times. Major part of the strains were
isolated from plots exposed to high levels of
anthropogenic impact – urban soils, soils polluted
by lead, acid rain, oil fuel and pesticide
fundazole. Some strains were isolated from
extreme natural conditions – primitive arctic soils
(Kola Peninsula), primitive alpine soils (Pamir)
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from primitive alpine Pamir soils also
synthesized alkaloids of the roquefortine group.
Another – strain № 4 – isolated from domestic
dust produced a considerable quantity (up to 10
mg/L) of clavine alkaloids (fumigaclavine A,
fumigaclavine B and pyroclavine) unknown
before for representatives of this species.
P. vulpinum № 113 (P. claviforme) isolated
from an urban environment showed a high
production of α-CPA and its imine. Roquefortine,
oxaline, viridicatin, cyclopenin and patulin
described for this species [32] were not detected
in this strain. On the other hand, strain № 16
isolated from Moscow downtown snow produced
roquefortine, which is characteristic of the typical
strains of this species. P. granulatum is known as
a producer of such mycotoxins as patulin,
viridicatin and roquefortine [32]. Strain № 128
was characterized by a high production (up to 10
mg/L of culture broth) of alkaloids of the
roquefortine group – meleagrine, roquefortine,
3,12-dihydroroquefortine. New producers of
tryptophanyl
tryptophanyl
diketopiperazine
(fellutanine A) – P. spinulosum № 15 and P.
aurantiogriseum № 3 – were found. Both strains
were isolated from an urban environment. Fungi
of the species P. janczewskii are widely known as
producers of grisefulvin [32]. The strain P.
janczewskii № 2 isolated from soddy-podzolic
soils polluted by acid rains also synthesized this
metabolite.
In strains of the fungi assigned to such
species as P. glabrum, P. dangeardii, P. sp., P.
funiculosum the ability to synthesize noticeable
amounts of secondary metabolites was not found.
It should be noted that strains of these species do
not belong to pronounced producers of
mycotoxins.
The examined strains of P. aurantiogriseum,
P. chrysogenum, P. granulatum, P. griseofulvum,
P. spinulosum and P. vulpinum were found to
have other secondary metabolite profiles than
those described in the literature. Among them are
such mycotoxins as α-CPA and clavine alkaloids
extremely hazardous to man and animals. The
highest toxigenic potential was characteristic of
the isolates of P. vulpinum N113 (content of α-
CPA, up to 100 mg/l) and P. chrysogenum N4
(content of clavine alkaloids, up to 10 mg/L).
These results are of ecotoxicological
significance inasmuch as the fungal producers of
mycotoxins are becoming typical of and
dominant in microfungal communities in
ecosystems experiencing human impact [33].
2.3 Search for new producers among fungal
strains isolated in unusual, little investigated
habitats
2.3.1 Mir orbital space station as a habitat for
mycotoxin-producing fungi
Such an ecological system as Mir orbital
space station, which for many years underwent a
persistent influence of various factors, is
considered as a unique material for in-depth
studies [22]. Space flights, both manned and
unmanned, are accompanied with setting out a
great variety of microorganisms on onboard
equipment outside the limits of their natural
conditions. Investigations carried out onboard
Mir space station have shown that its microflora
includes more than 100 species of filamentous
fungi [34]. Some of them were capable of
resident long-term population of structural
materials of the interior, equipment and devices
of the station. The strains were reliably diagnosed
in the microflora tests in 1997-1998 and assigned
to the species P. expansum and P. chrysogenum –
remote descendants of the cultures isolated in the
living compartments of the station more than
eight years ago. Strains of penicillia isolated in
Mir station were studied for their ability to
produce
nitrogen-containing
secondary
metabolites such as alkaloids, antibiotics and
mycotoxins. Four strains of P. chrysogenum and
six strains of P. expansum were found to be able
to
synthesize
roquefortine,
3,12dihydroroquefortine,
meleagrin,
viridicatin,
viridicatol, isorugulosuvine, rugulosuvine B and
N-acetyltryptamin [23]. It was also shown that
the resident strains of P. expansum IMBP 2-7,
which had become dominant by the end of the
long-term flight, and P. chrysogenum IMBP
strains 1-5 and 1-6 were able to produce
biologically active compounds such as
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Kozlovsky A. G., Zhelifonova V. P., and Antipova T. V. (2013) Signpost Open Access J. Org. Biomol. Chem. 1, 11-21.
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xanthocillin X and questiomycin A ― the
antibiotics of a broad range of action [24].
number of transformations. Thus, meleagrine
produced by P. chrysogenum (3 strains) was the
result of roquefortine modification. Glandicolines
A and B isolated from a strain of P. chrysogenum
were intermediates in biosynthesis from
roquefortine to meleagrine.
P. solitum species (6 strains) produced
benzodiazepine compounds cyclopenin and
cyclopenol [43]. Two of them were found to
synthesize viridicatin. All of these metabolites
are linked by a common biosynthetic chain. The
first metabolite in this pathway was cyclopeptin,
from which cyclopenin and cyclopenol are
formed, which are further transformed into
quinoline alkaloids viridicatin and viridicatol.
Quinazoline compounds fumiquinazolines F and
G and polyketide metabolite PC-2 were identified
in two strains of P. thymicola. Fumiquinazolines
exhibited an activity against tumor cells [19].
P. rugulosum (3 strains) and P.
brevicompactum
(2
strains)
produced
mycophenolic acid. This mycotoxin was first
found in P. rugulosum. Mycophenolic acid
possesses antibiotic and immunodepressive
activities.
P. griseofulvum synthesized griseofulvin.
This metabolite is known as an antibiotic of
fungicide action little used at present due to its
high toxicity.
Thus, it has investigated the secondary
metabolites, including mycotoxins, in penicillia,
which are components of ancient microbial
communities in perennially frozen permafrost
deposits of various geneses and ages. It has been
shown that the strains that have existed under
long-time cryopreservation conditions possess a
high biosynthetic potential. The fungi produce
various biologically active compounds secondary metabolites – ergot alkaloids,
diketopiperazines, benzodiazepines, quinolines,
quinazolines and polyketides.
2.3.2 Fungal strains isolated from permafrost as new
producers of biologically active compounds
The profiles of the secondary metabolites
(mycotoxins) were investigated in 91 fungal
strains isolated from various permafrost regions –
North America, North-East Asia and Kamchatka
[37-43]. Cultures were isolated from soils,
cryopegs and volcanic ash of various geological
ages [44]. Different secondary metabolites were
identified in half of the cultures. By their ability
to produce secondary metabolites, the strains can
be divided into several groups.
The most numerous group includes strains,
which can produce ergot alkaloids. Fungi of P.
commune (10 strains) and P. palitans (2 strains)
synthesize a well known mycotoxin, α-CPA
[42,43]. Seven strains of P. palitans can also
produce clavine alkaloids such as fumigaclavine
A, fumigaclavine B and festuclavine. Five strains
of P. variabile were first found to produce
rugulovasines A and B. Two strains belonging to
P. waksmanii and P. citrinum were found to
synthesize clavine alkaloids of unusual
stereochemistry such as agroclavine-1 and
epoxyagroclavine-1 [38, 42]. These strains are
also producers of new, previously unknown
quinoline compounds quinocitrinine A and
quinocitrinine B [39].
Well known mycotoxins ochratoxin A and
ochratoxin B were produced by six strains of P.
verrucosum
[41].
Biosynthesis
of
the
roquefortine-group diketopiperazine compounds
was observed in P. chrysogenum (5 strains) and
P. aurantiogriseum (3 strains) [37, 40].
Tryptophanyldehydrohistidinyl-diketopiperazine
identified in P. chrysogenum (2 strains) was the
first intermediate of the biosynthetic pathway
leading to the formation of roquefortine. It is
assumed that 3,12-dihydroroquefortine found in
all strains of P. aurantiogriseum and in one strain
of P. chrysogenum is the next link in the pathway
of roquefortine biosynthesis. In several strains,
roquefortine was the final metabolite of the
biosynthetic pathway, for others, it undergoes a
3. Studies of fungal toxigenic potential using
artificial media and natural substrates
As is known, production of secondury
metabolites depends on many factors, first and
foremost, on the composition of culture liquid,
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Kozlovsky A. G., Zhelifonova V. P., and Antipova T. V. (2013) Signpost Open Access J. Org. Biomol. Chem. 1, 11-21.
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temperature and pH [45]. For this reason, it was
important to establish a correlation between the
data on the biosynthetic potentional fungi grown
on artificial media and on natural substrates.
The validity of the approaches used to assess
the fungal toxigenic potential was studied in [47].
Penicillium fungi of the species P. palitans, P.
expansum and P. farinosum species were grown
by means of surface and submerged cultivation in
simple and complex media, such as summer
wheat and apple juice. These species are well
known as contaminants of food and producers of
mycotoxins – ergot alkaloids including α-CPA,
benzodiazepines, diketopiperazines [24]. It was
established that biologically active compounds
detected in submerged cultivation in Abe’s
medium were synthesized under surface growth
conditions, including on dense media. The
spectra of alkaloids were the same as in
submerged culture on a simple Abe’s medium,
but in the case of natural substrates the relation
between particular components could vary. Thus,
the ability of fungal species to synthesize
biologically ative metabolites under laboratory
cоnditions correlated with that in nature.
These data are in conformity with current
views that secondary metabolism enzymes are in
many cases constitutive and that genes
controlling their synthesis arranged in
corresponding clusters [24].
importance of the obtained data and are of
ecotoxicological significance.
References
[1]
[2]
[3]
[4]
[5]
[6]
[7]
4. Conclusions
Penicillium fungi are a large part of microbial
diversity and offer exciting prospects in the
search of biomolecules with various biological
and pharmacological potentials and other related
properties. In connection with the observed signs
of global warming (a decrease of the Arctic
Ocean ice cover), the most topical are the results
obtained for fungi isolated from permafrost. The
strategy of the search for secondary metabolites
was successfully implemented, which is
confirmed by earlier unknown novel compounds
and important metabolites. Studies of the
toxigenic potential of the fungi grown on
artificial media and natural substrates, the
observed correlation between them, confirm the
[8]
[9]
[10]
[11]
[12]
19
Сole R. J., and Cox R. H. Наndbook of
toxin fungal metabolites. New York:
Acad. Press, 1981.
Fluckiger E., in Ergot compounds and
Brain function: neuroendocrine and
neuropsychiatric aspects, Goldstein M.,
Ed., New York: Raven Press, 1980.
Rehachek Z., and Sajdl P., Ergot
alkaloids. Chemistry, Biological Effect,
Biotechnology. Praha: Academia, 1990.
Tutel’yan V. A., Kravchenko L. V., and
Sergeev A. Yu. Mycotoxins. In:
Mikologiya segodnya (Mycology Today).
vol.1, D’yakov Yu. T., and Sergeev Yu.
V., Eds., Moscow: Nats. Akad. Mikol.,
2007, pp. 283-304.
Hofmann A. Die Grupper der ClavinAlkaloids, die Mutter Kornalkaloide.
Stuttgart: Ferdinand Enke Verglad, 1964.
Kozlovsky A. G., Zhelifonova V. P.,
Antipova T. V., Ozerskaya S. M.,
Kochkina G. A., and Ivanushkina N. E. А
method
of
producing
tartate
epoxiagroclavine-I and quinocitrinines,
RF Patent No. 2386692,
August 22,
2010.
Shcwartz G., and Eich E. (1983) Planta
Med. 47, 212-214.
Glatt H., Pertz H., Kasper R., and Eich E.
(1992) Anticancer Drugs 3, 609-614.
Eich E., Eichberg D., Schwarz G., Clas
F.,
and
Loos
M.
(1985)
Arzneimittelforschung 35, 1760-1762.
Hibasami H., Nakashima K., Pertz H.,
Kasper R., and Eich E. (1990) Cancer
Lett. 50, 161-164.
Kozlovskii A. G., Vinokurova N. G.,
Solov’eva T. F., and Buzilova I. G. (1996)
Prikl Biokhim Mikrobiol. 32, 43-52 [Appl.
Biochem. Microbiol. (Engl. Transl.),
1996, 32, 39-48].
Kozlovskii A. G., Vinokurova N. G.,
Adanin V. M., and Sedmera P. (1997)
Kozlovsky A. G., Zhelifonova V. P., and Antipova T. V. (2013) Signpost Open Access J. Org. Biomol. Chem. 1, 11-21.
Volume 01, Article ID 010302, 11 pages. ISSN: 2321-4163
http://signpostejournals.com
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
Prikl. Biokhim. Mikrobiol. 33, 408-414
[Appl. Biochem. Microbiol. (Engl.
Transl.), 1997, 33, 364-369].
Kozlovsky A. G., Vinokurova N. G.,
Adanin V. M., and Grafe U. (2000) Nat.
Prod. Lett. 14, 333-340.
Kozlovsky A. G., Adanin V. M., Daze
Kh. M., and Grefe U. (2001) Prikl.
Biokhim. Mikrobiol. 37, 292-296. [Appl.
Biochem. Microbiol. (Engl. Transl.),
2001, 37, 253-256].
Krupyanko V. I., and Reshetilova T. A.
The effect of roquefortine on some
enzymes of the gastroenteric tract. In: IX
International IUPAC Symposium on
Mycotoxins and Phycotoxins, Italy.
Rome, 1996, pp. 27–31.
Aninat C., Hayashi Y., Andre F., and
Delaforge M. (2001) Chem. Res. Toxicol.
14, 1259-1265.
Thomas G. R., Giles S., Flemming J.,
Miller J. D., and Puniani E. (2005)
Toxicol. Sci. 87, 213-222.
Kozlovsky A. G., Zhelifonova V. P.,
Antipova T. V., Adanin V. M., Ozerskaya
S. M., Kochkina G. A., Schlegel B.,
Dahse H. M., Gollmick F. A., and Grafe
U. (2003) J. Antibiot. 56, 488-491.
Takahashi C., Matsushita T., Doi M.,
Minoura K., Shingu T., Kumeda Y., and
Numata A. (1995) J. Chem. Soc. Perkin
Trans. 1. 18, 2345-2353.
Betina V. Mycotoxins. Production,
Isolation, Separation and Purification,
Amsterdam: Elsevier, 1984.
Kozlovskii A. G., Vepritskaya I. G., and
Gayazova N. B. (1986) Prikl. Biokhim.
Mikrobiol. 22, 205-210.
Kozlovsky A. G., Zelenkova N. F.,
Adanin V. M., Sakharovskii V. G., and
Arinbasarov M. U. (1995) Prikl Biokhim
Mikrobiol. 31, 540–544.
Kozlovsky A. G., Vinokurova N. G.,
Adanin V. M., Burkhard G. H., Dahse M.,
and Graefe U. (2000) J. Nat. Prod. 63,
698-700.
Frisvad J. C., Filtenborg O. Revision of
Penicillium subgenus Furcatum based on
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
20
secondary metabolites and conventional
characters. In: Samson RA., Pitt JI,
editors. Modern Concepts in Penicillium
and Aspergillus Classification N.-Y.:
Plenum Press, 1990, pp. 159-170.
Kozlovskii A. G., Vinokurova N. G., and
Adanin V. M. (2000) Prikl. Biokhim.
Mikrobiol. 36, 317-321 [Appl. Biochem.
Microbiol. (Engl. Transl.), 2000, 36, 271275].
Мarfenina O. E. (1994) Pochvovedenie,
1, 75-80.
Kozlovskii A. G. (1990) Proc. Jpn.
Assoc. Mycotoxicol. 32, 31-34.
Kozlovskii A. G., Solovґeva T. F.,
Bukhtiyarov Yu. E., Shurukhin Yu. V.,
Sakharovskii V. G., Adanin V. M.,
Nefedova M. Yu., Persova R. N., Tokarev
V. G., and Golovleva L. A. (1990)
Mikrobiol. 59, 601-608.
Kozlovskii A. G., Мarfenina O. E.,
Vinokurova N. G., Zhelifonova V. P.,
Adanin V. M. (1997) Mikrobiol. 66, 206210. [Microbiol. (Engl. Transl.), 1997, 66,
169-172].
Vinokurova N. G., Reshetilova T. A.,
Yarchuk N. I., Adanin V. M., and
Kozlovskii A. G. (1993) Prikl Biokhim
Mikrobiol. 29, 559-566.
Reshetilova T. A., Solovieva T. F.,
Baskunov B. P., Kozlovskii A. G. (1992)
Mikrobiol. 61, 873-879.
Samson R. A., and Frisvad J. C. (2004)
Studies in Mycology 49, 1-174.
Marfenina O. E., Karavaiko N. M.,
Ivanova A. E. (1996) Mikrobiol. 65, 119124.
Shnyreva A. V., Sizova T. P., Bragina M.
P., Viktorov A. N., and D'yakov Yu. T.
(2001) Mikol. Fitopatol. 35, 37-42.
Kozlovskii A. G., Zhelifonova V. P.,
Adanin V. M., Antipova T. V., Shnyreva
A. V., Viktorov A. I. (2002) Mikrobiol.
71, 773-777 [Microbiol. (Engl. Transl.),
71, 666-669].
Kozlovskii A. G., Zhelifonova V. P.,
Antipova T. V., Adanin V. M., Novikova
N. D., Deshevaya E. A., Shlegel’ B., Daze
Kozlovsky A. G., Zhelifonova V. P., and Antipova T. V. (2013) Signpost Open Access J. Org. Biomol. Chem. 1, 11-21.
Volume 01, Article ID 010302, 11 pages. ISSN: 2321-4163
http://signpostejournals.com
[37]
[38]
[39]
[40]
[41]
Kh. M., Gollmik F., and Grefe U. (2004)
Prikl Biokhim Mikrobiol. 40, 344-349
[Appl. Biochem. Microbiol. (Engl.
Transl.), 40, 291-397].
Kozlovskii A. G., Zhelifonova V. P.,
Adanin V. M., Antipova T. V., Ozepskaya
S. M., Kochkina G. A., and Grefe U.
(2003) Prikl. Biokhim. Mikrobiol. 39,
393-397. [Appl. Biochem. Microbiol.
(Engl. Transl.), 2003, 39, 393-397].
Kozlovsky A. G., Zhelifonova V. P.,
Adanin V. M., Antipova T. V., Ozerskaya
S. M., Kochkina G. A., and Grefe U.
(2003) Mikrobiol.
72, 816-821
[Microbiol. (Engl. Transl.), 2003, 72,
723-727].
Kozlovsky A. G., Zhelifonova V. P.,
Antipova T. V., Adanin V. M., Ozerskaya
S. M., Kochkina G. A., Schlegel B.,
Dahse H. M., Gollmick F. A., and Grafe
U. (2003) J. Antibiot. 56, 488-91.
Antipova T. V., Zhelifonova V. P.,
Kochkina G. A., and Kozlovskii A. G.
(2008)
Microbiol.
77,
502-507
[Microbiol. (Engl. Transl.), 2008, 77,
446-450].
Zhelifonova V. P., Antipova T. V.,
Ozerskaya S. M., Kochkina G. A., and
Kozlovskii A. G. (2009) Mikrobiol. 78,
393-398. [Microbiol. (Engl. Transl.),
2009, 78, 350-354].
[42]
[43]
[44]
[45]
[46]
[47]
21
Antipova T. V., Zhelifonova V. P.,
Baskunov B. P., Ozerskaya S. M.,
Ivanushkina N. E., and Kozlovsky A.
G. (2011) Prikl Biokhim Mikrobiol. 47,
288-292 [Appl. Biochem. Microbiol.
(Engl. Transl.), 2011, 47, 288-292].
Kozlovsky A. G., Zhelifonova V. P.,
Antipova T. V., Baskunov B. P.,
Kochkina G. A., and Ozerskaya S. M.
(2012)
Mikrobiol.
81, 332-338
[Microbiol. (Engl. Transl.), 2012, 81,
306-311]..
Ozerskaya,
S.,
Kochkina,
G.,
Ivanushkina, N., and Gilichinsky, D.,
in Permafrost Soils, Margesin, R., Ed.,
Berlin: Springer Verlag, 2009, pp. 85–95.
Reshetilova T. A., and Kozlovsky A. G.
(1990) Prikl Biokhim Mikrobiol. 26, 291306.
Vinokurova N. G., Reshetilova T. A.,
Adanin V. M., and Kozlovsky A. G.
(1991) Prikl Biokhim Mikrobiol. 27, 850855.
Kozlovsky A. G., Reshetilova T. A.,
Vinokurova N. G., and Lґvova L. S.
(1995) Mycotoxins, 41, 35-40.