Different Shades of Fungal Metabolites: An

Overview

Shaily Goyal, K. G. Ramawat, and J. M. Mérillon

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2 Brief Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3 Fungal Metabolites Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4 Metabolic Engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
5 Fungi as Functional Food and Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
6 Fungi in Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
7 Fungal Mycotoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
7.1 Aflatoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
7.2 Ochratoxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
7.3 Fumonisins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
7.4 Zearalenone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
7.5 Patulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
7.6 Trichothecene Toxin: Deoxynivalenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
8 Fungi as Producer of Colorants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
9 Fungal Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
10 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

S. Goyal
Erie, PA, USA
e-mail: goyalshaily@gmail.com
K.G. Ramawat (*)
Botany Department, M.L.Sukhadia University, Badgaon, Udaipur, India
e-mail: kg_ramawat@yahoo.com
J.M. Mérillon
Faculté des Sciences Pharmaceutiques, ISVV, Groupe d’Etude des Substances Végétales à Activité
Biologique-EA 3675, Université de Bordeaux, Villenave d’Ornon, France
e-mail: jean-michel.merillon@u-bordeaux.fr

# Springer International Publishing Switzerland 2016 1

J.-M. Mérillon, K.G. Ramawat (eds.), Fungal Metabolites,
DOI 10.1007/978-3-319-19456-1_34-1
2 S. Goyal et al.

Abstract
Fungi can be found in almost all types of habitats. Its several thousand species are
very diverse in morphological characters with plethora of secondary metabolites.
These secondary metabolites make some of the fungi our friend as well as foe.
Many of these secondary metabolites exhibit harmful effect being mycotoxins.
Fungi are notoriously known as food spoiler, causing damage to cooked food and
grains, and as plant pathogen, causing various severe diseases. However, fungi
are beneficial to mankind as producer of antibiotics, food colorant, enzymes, and
as a nutritious food. Today many industries are based on fungi or fungal products.
Fungi are believed to be the future microbial cell factories for the production of
food grade pigments, enzymes, and pharmaceuticals. Owing to the increasing
demand of these products, the large-scale production can be achieved by using
modern tools of biotechnology and appropriate use of fermentation physiology.
Heterologous expression of secondary metabolite production or even manipula-
tion of physical and chemical growth factors can enhance the desired product
yield with improved functionality. But still, there is a vast scope for improved
production and search for novel fungal metabolites which will render our safe
future against resistance-developing bacteria and other dreaded diseases. In this
brief review, we present a global scenario of fungal metabolites.

Keywords
Fungal classification • Antibiotics • Mycotoxins • Fungal bioactive molecules •
Enzymes • Fungal pigments

1 Introduction

Today we all are familiar with the importance of secondary metabolites in pharma-
ceuticals, agrochemicals, food additives, and as ingredients in cosmetics. Secondary
metabolites are believed to have no function in the life cycle of producer cells, unlike
primary metabolites. They are chemically heterogeneous group with molecular
weight less than 3000 Da [Dalton is the standard unit that is used for indicating
mass on an atomic or molecular scale (atomic mass)]. In the search of new bioactive
secondary metabolites, most of the scientists’ intense interest surrounds the plants.
But the fact is that until 2014 about 170,000 natural products have been described
[1, 2], out of which more than 22,500 bioactive metabolites are produced by
microorganisms, with about 45 % as products of actinomycetes fermentation and
about 38 % of fungal origin [3, 4].
Fungi can be found in almost all types of habitats. In their need to live and
reproduce, they compete with other organisms. They grow fast on the surface of
plant/nutrition to prevent other competitors from reaching their nutrient source.
Some live in symbiosis with the host and some off the dead organisms. In order to
survive, fungi have developed a number of strategies for protection and communi-
cation, one of which is production of different types of secondary metabolites. These
Different Shades of Fungal Metabolites: An Overview 3

Microbial enzymes
Fungi
Beneficial
Harmful
effects

Fig. 1 Beneficial and harmful effects of fungi

fungal or fungal-induced compounds in plants increase the ability of plant to resist

invasion of predators, parasites, and diseases and may be used for competition
between species or to facilitate reproductive processes [5].
Fungi are notoriously known as food spoiler, causing damage to cooked food and
grains, as plant pathogen, causing various severe diseases such as Potato late blight,
caused by Phytophthora infestans responsible for potato famine of Ireland
(1845–1849), and rice blast, which leads to infamous Bengal famine of 1943;
however, fungi are beneficial to humankind as producer of antibiotics (penicillin,
cephalosporin, cyclosporine etc) and statins. Poisoning of cattle by ergot (a fungal
body formed by mycelium of Claviceps species, especially C. purpurea) and
mycotoxins [produced by several species of Aspergillus in stored grains (aflatoxins,
ochratoxin A)] is common in several countries. Beneficial effects of fungi are of
relatively of recent origin (except applications in cheese making) such as producer of
several enzymes (cellulase, lipase, ligninolytic enzymes), alkaloids (ergot alkaloids
from Claviceps), pigments (anthraquinone, betalains), aroma and flavors, and in
biological control of nematodes, health benefits by edible fungi (source of selenium,
potassium, riboflavin, niacin, vitamin D, proteins) and in prevention of or treatment
for Parkinson, Alzheimer, hypertension, cancers, and high risk of stroke [6–11]. All
these drastically different activities of fungi (Fig. 1) are attributed to the plethora of
metabolites they have. These metabolites represent a large source of compounds
endowed with ingenious structures and potent biological activities. They comprises
of aliphatic and aromatic hydrocarbons, organic acids, esters, ketones, aldehydes,
alcohols, and mono-, sesqui-, and diterpenes [12]. The present article provides an
4 S. Goyal et al.

Table 1 Characteristics of various subdivisions of fungal kingdom

Sub-division Characteristics and remarks
Basidiomycota This division contains the mushrooms and toadstools. Divided into
3 subphyla: Agaricomycotina, Ustilaginomycotina, Pucciniomycotina
such as puffballs and stinkhorns, rusts and smuts, and gilled and pored
fungi. Spores are produced on a characteristic cell called a basidium
(plural basidia)
Ascomycota Three subphyla : Taphrinomycotina, Saccharomycotina,
Pezizomycotina. The largest number of species occurs in this group such
as the cup fungi and flask fungi. Spores are produced in a sack like
structure called an ascus (plural asci)
Zygomycota Mostly microscopic species, the pin molds with coenocytic hyphae
Oomycota The Oomycota includes the water molds and some important pathogens
such as potato blight. Many produce motile spores during their life cycle
which can swim. This group is now classified along with brown algae
Deuteromycota Species for which sexual reproduction is not known such as molds
=Fungi imperfecti (Alternaria, Aspergillus, Penicillium). Mainly basidiomycotina or
ascomycotina anamorph
Microsporidiomycota Spore forming unicellular parasites

overview of the current knowledge on fungal metabolites and gives prospects for the
future developments.

2 Brief Classification

About 1.5 million species of the fungi have been raised to a separate kingdom of
organisms, as complex and diverse as plants and animals, of which only about 10 %
have been named and described. Originally there were only two kingdoms – plants
and animals. If an organism did not move, it was usually placed in the plant
kingdom. In 1969, a scientist named Robert Whittaker published the first major
revision to Linnaeus’s proposed two kingdom classification – animals and plants
(which included fungi). In the revised version, Whittaker suggested that fungi should
be classified as a separate kingdom, and this has been accepted by scientists
[13]. Fungi are placed in a separate kingdom because they have many characteristics
which are different from plants and animals. Their cell walls are made of chitin and
mode of nutrition is absorption, contrasting to plants which have cell walls made of
cellulose and use photosynthesis to synthesize carbohydrates. Thus, bacteria includ-
ing actinobacteria (previously called as actinomyces), fungi, plants, protozoa, and
animals are recognized as separate kingdoms. Major characteristic and examples of
various subdivisions of fungal kingdom are given in Table 1. A comprehensive
phylogenetic classification of the kingdom Fungi has been developed in light of
recent molecular phylogenetic analyses and with input from diverse groups of the
fungal taxonomic. The readers primarily interested in classification can consult
reviews on this aspect [14, 15].
Different Shades of Fungal Metabolites: An Overview 5

Aflatoxin
Patulin
Polyketides
Zearalenone
Griseofulvin Fatty acids

Acetyl co enzyme
Sesquiterpenes

Diterpenes

Steroids

Sterols Building blocks Alkaloids

Gibberellins Siderophores

ß lactams

Cyclopeptides
Polypeptide hormones

Structural proteins
Enzymes Polypeptide hormones

Fig. 2 Biosynthesis of different metabolites by fungi using building blocks. Building blocks are
photosynthates; green fonts-primary metabolites, blue fonts-secondary metabolites

3 Fungal Metabolites Biosynthesis

Fungi produce diversified extent of metabolites ranging from antibiotics to myco-

toxins. The biosynthetic pathways involve in the synthesis of these molecules are also
diverse. However, it is surprising that these complex structures are synthesized by
relatively few building blocks. The pathways are usually named after enzymes or
intermediates involved and are also commonly used to classify secondary metabolites.
Three most common pathways studied are (1) the mevalonic acid pathway (synthesize
terpenoids, steroids, etc), (2) the shikimic acid pathway (synthesize aromatic amino
acids, alkaloids, etc), and (3) the acetate pathway (synthesize polyketides, fatty acids,
etc). The enzymes associated with these pathways are nonribosomal peptide synthe-
tases (NRPSs), polyketide synthases (PKSs), terpene cyclases (TCs), dimethylallyl
tryptophan synthetases (DMATs), and geranylgeranyl diphosphate synthases
(GGPPs), etc. These enzymes utilize building blocks like acetyl-coA, amino acids,
mevalonate, and their different counterparts for the production of different fungal
metabolites as shown in Fig. 2. In case of terpenes, steroids, gibberellins, the actual
fundamental building block is dimethylallyl diphosphate (DMAPP). DMAPP are
biosynthesized via the mevalonic acid (MVA) which is formed by combining three
acetyl-coenzyme A (acetyl-CoA) [16, 17]. In microorganisms, an alternative pathway
6 S. Goyal et al.

for terpenes biosynthesis was described where glyceraldehyde 3-phosphate

(or ultimately glyceraldehyde) and a C2 unit derived from pyruvate decarboxylation
were the only precursors of the C5 skeleton of isoprenic units in this nonmevalonate
pathway for isoprenoid biosynthesis [18]. Thus, many hybrid secondary metabolites
are derived from the tandem action of these enzymes, building blocks, and cofactors.

4 Metabolic Engineering

Metabolic engineering is an emerging field where using the modern biotechnological

tools and techniques, cell factories are generated. Now-a-days many genetically
well-characterized fungi are modified for the production of industrially relevant
enzymes, pharmaceuticals, and biofuels and are widely used by the research com-
munity to produce proteins that cannot be actively expressed in Escherichia coli or
require glycosylation for proper folding and biological activity. Most of the heterol-
ogous expressions are mainly performed in baker’s yeast Saccharomyces cerevisiae
[19]. There are over hundred proof-of-concept chemicals that have been made in
yeast [20]. One of the most important biopharmaceuticals produced by yeast is
insulin and insulin analogs. It is a continuous growing market as the global insulin
sale is expected to grow from USD 12 billion in 2011 to more than USD 32 billion
by 2018. Other important biopharmaceuticals produced by yeast are human serum
albumin, hepatitis vaccines, and human papilloma virus vaccine [21]. Besides yeast,
filamentous fungi that dominate the heterologous expression of useful metabolites
are Aspergillus niger, A. oryzae, Trichoderma reesei, and A. nidulans. Another
fungus with great potential is Chrysosporium lucknowense [22]. So far, the genome
has only been sequenced for a few species of filamentous fungi, and there is no
detailed metabolic reconstruction of any filamentous fungi.

5 Fungi as Functional Food and Health

Fungi, particularly mushrooms such as Cordyceps sinensis (Fig. 3), Ganoderma

lucidum, Hericium erinaceus, Lentinus edodes (Fig. 4), Sclerotinia sclerotiorum,
Tremella mesenterica, Trametes versicolor, are increasingly consumed as food for
their health benefits as nutraceuticals and functional foods [9, 23–27]. Besides
nutritional benefits, many fungi are associated with medicinal properties and
myths. These mushrooms are rich in some physiologically important components,
especially β-glucan polysaccharides, which are responsible for anticancer, immuno-
modulating, hypolipidemic, antioxidant, and neuro-protective activities. Shiitake
mushrooms have been used medicinally by the Chinese for more than 6,000 years.
Another fungus Ganoderma lucidum is a potent immune system regulator, promis-
ing anticancer agent, and stress reducer. This mushroom is frequently used in
traditional Chinese medicine [28]. All Cordyceps species (about 400 species
known) are endoparasitoids, parasitic mainly on insects and other arthropods.
Gordon Wasson believed that the Soma plant used in religious ceremonies, over
Different Shades of Fungal Metabolites: An Overview 7

Fig. 3 Cordyceps sinensis –

The caterpillar fungi emerging
from larvae

Fig. 4 Cultivation of Shiitake

mushroom (Lentinus edodes),
Courtesy of Sophie Mérillon
(Loches, France)

4000 years ago by Aryans, was a mushroom (the other plants considered are
Amanita, Ephedra sinica, Cannabis sativa, etc). The Vedic juice called “soma
rasa” is said to bestow divine qualities on the soul of the consumer, even immortality
[24, 25]. The fungus Cordyceps sinensis is also found in Tibetan medicine. Tradi-
tional healers in Sikkim recommend the fungus/mushroom Cordyceps sinensis to
improve energy, appetite, stamina, libido, endurance, and sleeping patterns
[25]. Main constituent of the extract derived from this fungus comprises a novel
biometabolite called as Cordycepin (3’deoxyadenosine), which has a very potent
anticancer, antioxidant, and anti-inflammatory activities [26] (see chapter on
Cordycepin in this book).
8 S. Goyal et al.

Cyclosporins
Penicillins Coumarins
Designed
Echinocandins statins
Cephalosporins Fingolimod
Ergot alkaloids
Grieseofulvin Fusidic acid Statins
Mycophenolic
acid

1900 1918 1928 1939 1941 1948 1962 1971 1974 1976 1995 2004

Fig. 5 Historical developments showing discovery of fungal metabolites

6 Fungi in Pharmaceuticals

The word antibiotic was used for the first time by Selman Waksman in 1941 to
describe any small molecule made by a microbe that antagonizes the growth of other
microbes [29]. On the morning of September 3, 1928, when Professor Alexander
Fleming was in process of cleaning up plates loaded with Staphyloccocus, he
observed a clean zone around the mold (Penicillium notatum) grown as contamina-
tion. Fleming concluded that the bacteria on the plate around the mold had been
killed off by some substance that had come from the mold. It was 10 years later that
Howard Florey and Ernst Chain, working at Oxford University, isolated the bacteria-
killing substance found in the mold – penicillin. (http://www.historylearningsite.co.
uk/a-history-of-medicine/antibiotics/).
This discovery and medicinal use of antibiotics in the 1950s revolutionized the
treatment and suffering and increased the life span. Antibiotics are useful in the
treatment of bacterial, fungal, and protozoal infections and some physiological
diseases (e.g., lowering cholesterol) [30]. Landmark discoveries of fungal metabo-
lites are shown in Fig. 5. With the increasing use of antibiotics, resistance to
antibiotics started developing, which leads to search for new antibiotics. The number
of new antibiotics, mainly analogs, increased almost exponentially. To eliminate
antibiotic resistance, the pharmaceutical industry developed thousands of new semi-
synthetic antibiotics, opening up a new area of antibiotic discovery [4].
More than 90 % of the studies performed by large pharmaceutical companies
between 1980 and 2003 resulted in decreasing profits due to increased research
expenses, the small number of new leads, and regulatory obstacles [31–33]. It is
difficult to assess the number of metabolites produced by fungi but currently total
entries for fungal metabolites on Google scholar is 466,000. Some of the selected
recently discovered (2013–2015) bioactive molecules with medicinal properties
are presented in Table 2. Some of these molecules can potentially be future
medicines. Antibiotics are major contribution of fungi towards human health and
alleviating suffering, for example, genus Streptomyces (in historical perspectives)
being principal producer (~80 % of total known) of large number of antibiotics and
Different Shades of Fungal Metabolites: An Overview 9

Table 2 Recent examples of bioactive molecules of fungi and their biological activities
Metabolites Source Bioactivity References
Ascomycone B and Biatriospora sp. CCF Cytotoxicity [37]
6-deoxyfusarubin 4378
Asperterpenoid A; Aspergillus sp. 16-5c Inhibitor of Mycobacterium [38, 39]
asperlones A and B, tuberculosis protein
mitorubrin tyrosine phosphatase B
Aspiketolactonol, Aspergillus sp. 6-02-1 Cytotoxic: human cancer [40]
aspyronol, cell lines K562, HL-60,
epiaspinonediol HeLa, and BGC-823
Apicidin F Fusarium fujikuroi Antimalarial [41]
Beauvericin Fusarium sp. Trypanocidal activity [42]
Citrinin Sponge associated Antibacterial and cytotoxic [43]
Penicillium sp.
Cladosin C Cladosporium Antiviral activity: influenza [44]
sphaerospermum A H1N1 virus
2005-01-E3
Cercosporenes F Cercospora sp. Cytotoxic: human cancer [45]
cell lines HeLa, A549,
MCF-7, HCT116, T24 and
induces autophagy in
HCT116 cells
1-(2,6-dihydroxyphenyl) Cryptosporiopsis sp. Antibacterial [46]
pentan-1-one
6,8-di-O-methylaverufin Aspergillus versicolor Antibacterial [47]
Dihydronaphthalenone 2 Nodulisporium sp. Antimycobacterial activity [48]
Dinapinone AB2 Talaromyces Inhibition of triacylglycerol [49]
pinophilus FKI-3864 synthesis in mammalian
cells
Fumiquinazoline Q and Penicillium expansum Mitigative effect on [50]
Protuboxepin E Y32 bradycardia and
vasculogenetic activity
Gliotoxin Aspergillus sp. YL-06 Cytotoxic: human cancer [51]
cell lines HeLa
Ganoleucoins A and C Ganoderma Inhibitory activity against [52]
leucocontextum HMG-CoA reductase
4-Hydroxymellein Phoma sp. Inhibitory activity against [53]
P388 murine leukemia cells
Herqueidiketal Penicillium sp. Significant activity against [54]
Staphylococcus aureus
sortase A.
Hispidin Phaeolus schweinitzii Antioxidant activity [55]
Isosclerone Aspergillus fumigatus Antiproliferative:MCF-7 [56]
human breast cancer cells
Nodulisporiviridin G Nodulisporium Amyloid β42 aggregation [57]
sp. (No. 65-17-2-1) inhibitory activities
Neoechinulin A Eurotium sp. SF-5989 Anti-inflammatory effect [58]
Pestalotiopsone A Pestalotiopsis sp. Antibacterial [59]
(continued)
10 S. Goyal et al.

Table 2 (continued)
Metabolites Source Bioactivity References
Polyporusterone B Polyporus umbellatus Antitumor activity: HepG2 [60]
cells
Phenylpyropenes Penicillium Cytotoxic: MGC-803 cell [61]
E and F concentricum line
ZLQ-69
Pinazaphilones B and Penicillium Inhibits α-glucosidase [62]
()-penifupyrone sp. HN29-3B
Reduced gliotoxin , Neosartorya Cytotoxic and antibacterial [63]
6-acetylbis(methylthio) pseudofischeri
gliotoxin
Solaninaphthoquione Fusarium solani Cytotoxic: MCF-7 human [64]
PSU-RSPG227 breast cancer cells
Sorbicatechols A and B Penicillium Antiviral:influenza virus A [65]
chrysogenum PJX-17 (H1N1)
Stemphyperylenol Botryosphaeria Antifungal and cytotoxicity [66]
dothidea KJ-1 against HCT116 cancer cell
line
Verrucosidin Penicillium Antimycobacterial activity. [67]
sp. TPU1271

secondary metabolites [34–36]. Besides antibiotics, cholesterol synthesis inhibitor

statin, ergot alkaloids, and lipase are important pharmaceutical products of fungal
origin.

7 Fungal Mycotoxins

Mycotoxins are low molecular weight (MW ~ 700) toxic secondary metabolites of
certain fungi. They are often very stable molecules and produced by several genera,
in particular Penicillium, Aspergillus, and Fusarium spp. [68, 69]. Besides these,
other genera exhibiting mycotoxin production includes Alternaria, Chaetomium,
Cladosporium, Claviceps, Diplodia, Myrothecium, Monascus, Phoma, Phomopsis,
Pithomyces, Trichoderma, and Stachybotrys spp. [70]. Mycotoxin contamination is a
global problem and occurs both in temperate and tropical regions of the world, based
on the species of fungi. Major food crops infected by fungi are cereals, cocoa, coffee,
oil seeds, spices, nuts, dried fruit, dried peas, beans, and fruits. The cereals are
usually invaded by fungi both in the field and after harvest, and as a consequence
they carry multitoxins. Generally, crops that are stored for more than a few days
Different Shades of Fungal Metabolites: An Overview 11

become vulnerable to mold growth and mycotoxin formation. The production of

mycotoxins is often inevitable and depends on environmental conditions during the
plant growth and the subsequent food storage.
These toxins have caused major epidemics in humans and animals during ancient
times. Ergotism [71] and Alimentary Toxic Alexia (ATA) [72] were some of the
dreaded mycotoxicosis instances which killed hundreds and thousands of people in
Europe and Russia, respectively. Mycotoxins cause four basic kinds of toxicity:
acute, chronic, mutagenic, and teratogenic. Different mycotoxins have different
modes of action in the body, while some deteriorate the liver or kidney function to
the extreme that may cause death or interfere with protein synthesis which produces
series of other problems including extreme immunodeficiency, some are neurotoxic
responsible for brain damage or death in higher doses. Due to the variety of
structures of these toxins, it is impossible to use one standard technique for analysis
and/or detection. The most studied mycotoxins are aflatoxins (AF), citrinin, tricho-
thecenes such as deoxynivalenol (DON), patulin, ochratoxin A (OTA), fumonisins
(FB), and zearalenone (ZEA) and some major toxins of endophytic fungi (ergot
toxins and ergotamine) (Fig. 6).

7.1 Aflatoxins

Aflatoxins (AF) are mycotoxins that are produced by fungi Aspergillus flavus and
Aspergillus parasiticus. Among them, A. flavus has been reported to be a common
contaminant of agricultural produce. However, A. bombycis, A. ochraceoroseus,
A. nomius, and A. pseudotamari are also less common, AF-producing species
[73–75]. Aflatoxins were discovered because of their devastating effect on turkey
poults (Turkey-X-disease) and other chicks in 1960 in England, when more than
100,000 turkey poults died [76]. Aflatoxin contamination is most common in
African, Asian, and South American countries with warm and humid climates, but
also occurs in temperate areas of North America and Europe. The habitat of
Aspergillus is in soil, decaying vegetation, hay, and grains, which are undergoing
microbiological deterioration. It can invade all types of organic substrates with
inadequate drying or improper storage conditions. They have a particular affinity
for nuts and oil seeds. Peanuts, maize, and cotton seed are the three most important
crops affected by Aspergillus.
AF are difuranocoumarin derivatives produced by a polyketide pathway. The
naturally occurring aflatoxins are AFB1, AFB2, AFG1, and AFG2, here “B” and
“G” refer to the blue and green fluorescent colors produced by these compounds
under UV light and relative chromatographic mobility during thin-layer chromatog-
raphy (TLC) [75] and the subscript numbers 1 and 2 indicate major and minor
compounds, respectively. Among these, AFB1 is the most abundant, toxic, and
carcinogenic [77]. Other aflatoxins AFM1 and AFM2 are the hydroxylation products
of AFB1 and AFB2, respectively, and are found in milk and milk products
[78]. After entering the body, aflatoxins may be metabolized by the liver to a reactive
epoxide intermediate or hydroxylated to become AFM1 and AFM2. AFM1 and
12 S. Goyal et al.

AFM2 are in lower toxicity than the parent molecules, but significant because of the
widespread consumption of cows’ milk by infants.
Aflatoxins are hepatocarcinogenic in humans, particularly in conjunction with
chronic hepatitis B virus infection; thus, the probability of people developing cancer
of the liver is much higher in areas where both aflatoxins and hepatitis B are
prevalent [79]. Aflatoxins are not only hepatocarcinogen, but they are also
genotoxins and immunotoxins, which can suppress both cellular and humoral
responses and also be responsible for growth retardation in animals [80, 81].

7.2 Ochratoxin

Ochratoxin A (OTA) was first discovered as a fungal metabolite that showed toxic
behavior towards animals, from a strain of Aspergillus ochraceus in 1965
[82]. Ochratoxin A is mainly produced by Aspergillus ochraceus, Aspergillus
carbonarius, and Penicillium verrucosum [83]. The natural occurrence of these
fungi is widespread, since all these species grow in a wide range of conditions
(substrate, pH, moisture, and temperature). A. ochraceus dominates in tropical
regions, while the P. verrucosum predominates in temperate regions such as eastern
and north eastern Europe, Canada, and parts of South America [84]. OTA commonly
contaminates grains such as corn, barley, oats, rye, and wheat and has also been
reported in other plant products including coffee beans, spices, nuts, olives, grapes,
beans, and figs [85, 86]. Mostly dried vine fruits, wines, and probably coffee are
contaminated with A. carbonarius [87] which can survive sun drying. Biosynthet-
ically, it is a pentaketide derived from the dihydrocoumarins family coupled with
β-phenylalanine. The biochemistry and molecular biology of ochratoxin A biosyn-
thesis have been comprehensively reviewed [88].OTA is a potential risk to human
health not only as a result of the intake of contaminated foods of vegetable origin, but
also through foods of animal origin. It is important to know that ochratoxin A is fat
soluble and stable molecule and is not readily excreted, which means that the intake
of OTA leads to its buildup in the circulatory system, liver, and other tissues of the
animals. This is due to the feeding of mold-contaminated fodder by animals.

7.3 Fumonisins

Fumonisins are a group of polyketide mycotoxins that are produced by Fusarium

verticillioides and Fusarium proliferatum, main pathogens of maize and sorghum
[89]. Fumonisins were discovered in the late 1980s as the result of many years of
study of the disease known as equine leucoencephalomalacia (LEM). Fumonisin B1
and fumonisin B2 were isolated for the first time by Gelderblom and coworkers [90]
from cultures of F. verticillioides MRC 826 by means of a bioassay based on the
cancer-promoting activity in rat liver. Fumonisins consist of a 20-carbon aliphatic
chain with two ester-linked hydrophilic side chains, resembling sphingosine, an
essential phospholipid in cell membranes. The toxic action of fumonisins appears
Different Shades of Fungal Metabolites: An Overview 13

to be a result from competition with sphingosine in sphingolipid metabolism [91]. It

is also important to mention that the main concern for human health in regard to
aflatoxins, ochratoxin A [92], and fumonisins in developed countries appeared to be
their carcinogenic or genotoxic and teratogenic effects rather than their acute
effects [93].

7.4 Zearalenone

Zearalenone (ZEA) is produced by different species of Fusarium fungi, for example,

F. graminearum, F. culmorum, F. cerealis, F. equiseti, F. crookwellense, and
F. semitectum. These common soil fungi are pathogenic to cereal crops worldwide
[75]. Zearalenone is heat-stable and is found in a number of cereal crops, such as
maize, barley, wheat, oats, rice, and sorghum [94]. Fusarium spp. infect cereals in
the field. Toxin production mainly takes place before harvesting, but may also occur
during or post harvest if the crop is not handled and dried properly [95]. Zearalenone
is a nonsteroidal mycotoxin biosynthesized through a polyketide pathway. ZEA is a
resorcylic acid lactone. Historically, Christensen and coworkers [96] isolated this
metabolite and called it F-2. Its isolation resulted from the observation of the disease
syndrome in two swine herds in Minnesota. Prior to the discovery and implemen-
tation of modern milling practices, Fusarium species have been implicated in several
human outbreaks of mycotoxicoses [97]. Unlike Ochratoxin, ZEA is rapidly
biotransformed and excreted after consumption; therefore, the dietary intake of
ZEA from meat is probably of less significance [98]. However, ZEA can be excreted
into milk after lactating cows are fed it in high doses. ZEA and its metabolites are
often referred to as a mycoestrogen because of its potent estrogenic activity. ZEA is
implicated in reproductive disorders of farm animals and occasionally in
hypoestrogenic syndromes in humans [99]. Studies have demonstrated the potential
for ZEA to stimulate growth of human breast cancer cells containing estrogen
response receptors [100]. Another recent study also established a potential role of
α-ZEA in the risk of developing breast cancer [101].

7.5 Patulin

Patulin (PAT) is a toxic metabolite produced by several species of Penicillium,

Aspergillus, and Byssochlamys [102, 103]. It is the most common mycotoxin in
apples and apple-derived products including juice, compotes, cider, and baby foods.
It also contaminates other fruits such as grapes, oranges, pears, and peaches [102,
104]. Patulin (4-hydroxy-4H-furo [3,2c] pyran-2[6H]-one) is a water-soluble lactone
isolated in 1940s. Initially PAT was isolated as a broad spectrum antifungal antibi-
otic. Due to co-discovery of the compound by various groups, it has historically been
known by names such as clavacin [105], expansine [106], claviformin [107],
clavatin [108], gigantic acid [109]. Patulin poses several biological activities and
induces toxicity in vitro and in vivo. It is considered as genotoxic, immunotoxic,
14 S. Goyal et al.

OH O CH3 OH

O O
O
HO O
patulin
zearalenone O O
O
O
O
H
HO

O
O
CH3
H O O
Aflatoxin B1
O COOH
HO HO
deoxynivalenol
COOH
O

NH2 OH O

OH OH
O O
fumonsin B1
COOH
O OH
O OH O

COOH
N O

H
ochratoxin A: R1 = Cl CH3
H
ochratoxin B: R1 = H R1

Fig. 6 Structures of selected mycotoxins

neurotoxic to rodents, and teratogenic to chicken [110]. Cellular effects of patulin

include the formation of reactive oxygen species (ROS), cell cycle arrest, cyto-
chrome C release from mitochondria, caspase-3 activation, PARP cleavage, ATF3
expression, and subsequent apoptosis. Patulin causes DNA damage and is muta-
genic, carcinogenic, and teratogenic [102, 104, 111, 112]. On the other hand, a recent
study suggests that PAT induces cytotoxicity through a ROS-dependent mechanism
involving endoplasmic reticulum stress and activation of mitochondrial apoptotic
pathway in human intestinal and kidney cells [113].
Different Shades of Fungal Metabolites: An Overview 15

7.6 Trichothecene Toxin: Deoxynivalenol

Mycotoxin deoxynivalenol (DON; also known as vomitoxin) is an epoxy-

sesquiterpenoid produced by fungi, Fusarium graminearum and F. culmorum.
They are the most potent eukaryotic protein-synthesis inhibitors known
[114]. Vomitoxin has been naturally occurring in cereal grains throughout the
world. It occurs mostly in grains such as wheat, barley, oats, rye, and maize, and
less often in rice, sorghum, and triticale [115]. Its capacity to induce vomiting
episodes in various species including humans explains its commonly used nickname
“vomitoxin.”

8 Fungi as Producer of Colorants

There is an increasing demand for pigments from natural sources which can be used
in foodstuff, cosmetics, and pharmaceuticals. Currently, the major sources of natural
colorants are of either plant or animal origin. The production of many currently
authorized natural food colorants has numerous disadvantages, like nonavailability
throughout the year, variations in pigment extraction, instability against light, heat or
adverse pH, and low water solubility. Even the present commercial natural food
colorants have several drawbacks, for instance the violet and purple colors of
anthocyanins (flavonoids) are sensitive to oxidation, bleaching by sulfur dioxide,
and vary with pH, limiting their application to acidic foods and beverages. Betanins,
carotenoids, and chlorophyll pigments are easily decolorized by oxidation, making
them sensitive to light, heat, and oxygen. Furthermore, there are also some weird
source of natural colorants like red colorant carmine; to produce 100 g carmine
colorant, approximately 14,000 female cochineal insects are required [116]. To
overcome these problems, alternative ways to produce natural colorants are highly
desired. In this regard, fungi have attracted special attention. Fungi-derived food
colorants are natural, which shows high chemical and light stability [117, 118], high
yield, and variety of colors. The authorization of fungal food colorant has expedited
research to explore the fungi for the biotechnological production of pigments.
However, these studies require a comprehensive knowledge of already recognized
fungal metabolites, pathogenic strains, and toxin producers.
Filamentous fungi produce an extraordinary range of pigments that include
several chemical classes such as carotenoids, melanins, flavins, phenazines, qui-
nones, and more specifically monascins, violacein, or indigo. These pigments show
diversity of chemical structures and a spectrum of colors (Figs. 7 and 8). In nature,
these pigments help fungi to serve different ecological functions, for example,
melanins protect them against environmental stress, caroteniods against lethal
photo-oxidations, and flavins act as cofactors in enzyme catalysis [119, 120].
Fungi are looked upon as future microbial cell factories for the production of food
grade pigments. However, there are discrepancies and controversial views over the
safety of these pigments. This is due to the co-production of mycotoxin along with
the target compound. For instance, Monascus spp. are often used for rice
16 S. Goyal et al.

Fig. 7 Chemical structures of

a few important fungal O
colorants
H

O
O
O
O Monascin

O OH O

OH

R1 OH
OH
O
R2
O Arpink Red Basic structure

O OH O

O O O
O OH
Bikaverin

fermentation to produce red yeast rice, a special product used either for food coloring
or as a food supplement in the South East Asia for more than thousands of years
[121] (see chapter on Pigments and Colorants from Filamentous Fungi, Monascus
Secondary Metabolites, Melanin Pigments of Fungi in this book). The colored
appearance (red, orange, or yellow) of Monascus fermented substrates is produced
by a mixture of oligoketide pigments that are synthesized by a combination of
polyketide and fatty acid synthases. The major pigments consist of pairs of yellow
(ankaflavin and monascin), orange (rubropunctatin and monascorubrin) [122], and
red (rubropunctamine and monascorubramine) compounds. Although these polyke-
tide pigments from the Monascus sp. have been commercially produced and legally
used as food colorants in the form of pigment extracts, European Union (EU) and
USA have not approved them as food colorant due to the risk of the possible
contamination by the nephrotoxic and hepatotoxic metabolite citrinin and a group
of monacolin substances [123]. Other examples of mycotoxin co-production are
fungal hydroxyanthraquinoid (HAQN) pigments like emodin (yellow), physcion
(yellow), questin (yellow to orange-brown), erythroglaucin (red), catenarin (red),
and rubrocristin (red), produced from some strains of Aspergillus sp. (A. glaucus,
A. cristatus, and A. repens) [124] and are contaminated with secalonic acid D,
 Different Shades of Fungal Metabolites: An Overview

Fig. 8 A representative photo of an array of pigments produced by fungi (Courtesy of Olivier Laurence, Mycosphere, Fumel, France)
17
18 S. Goyal et al.

oxaline, citrinin, tanzawaic acid A, cyclochlorotine, islanditoxin, luteoskyrin,

erythroskyrin rugulosin, or aspergiolide A. All these fungal secondary metabolites,
the yellow and the red HAQN pigments that show substitution on both aromatic
rings and the naphthoquinone type mycotoxins, are biosynthetically synthesized by
polyketide pathway. Likewise, species of Eurotium co-produce the mycotoxin
echinulin and two benzaldehyde coloring compounds: flavoglaucin (yellow) and
auroglaucin (red) along with the yellow pigment physcion and the red pigment
erythroglaucin [125]. This infers that these fungal strains are not safe, and there is
an urge to continue to explore new strains of fungi which do not produce myco-
toxins. Many of such strains are now known; for example, a strain of Dermocybe
sanguinea (Cortinarius sanguineus) produces red HAQN glycoside dermocybin-1-
b-D-glycopyranoside, together with the pigments emodin and physcion without
co-production of mycotoxins [126]. Another polyketide pigment orevactaene is
shown to be produced by nonmycotoxigenic fungi Epicoccum nigrum [127]. Another
useful discovery is the production of Monascus like polyketide azaphilone (MPA)
pigments without co-production of citrinin or any other known mycotoxins, by some
strains of Talaromyces species (formerly Penicillium sp.) viz. Talaromyces
aculeatus, T. funiculosus, T. pinophilus, and T. purpurogenus [127, 128]. Moreover,
even a patent has been granted for a submerged cultivation method, for some of the
nonmycotoxigenic strains of Talaromyces sp. [129].
Owing to the increasing demand of food colorant, an alternative route for the
large-scale production of natural food colorants can be achieved by using modern
tools of biotechnology and appropriate use of fermentation physiology. Heterolo-
gous expression of secondary metabolite production or even manipulation of culture
medium or precursor/inhibitor feeding can enhance the desired product yield with
improved functionality [130, 131]. Presently, we can find some fermentative food
grade pigments in the market. Arpink redTM (now Natural RedTM) manufactured by
the Czech company (Ascolor Biotech followed by Natural Red) has been claimed to
be produced by fermentation and bioprocess engineering using the fungal strain
Penicillium oxalicum. Furthermore, riboflavin from Ashbya gossypii, lycopene and
b-carotene from Blakeslea trispora, and bikaverin from Fusarium sp. are obtained
from fermentation process [132–134].

9 Fungal Enzymes

Enzymes are biological macromolecules (primary metabolites) used to catalyze the

chemical reactions. Human beings are using the enzymes since long back for the
processes like cheese making, brewing, baking, and the production of antibiotics. In
nature, fungi play a main role in degradation of plant biomass. They secrete a wide
range of active enzymes and then absorb these “predigested” foodstuffs back into
their cells. This natural phenomenon of fungi has lead researchers to identify and
utilize various enzymes and proteases that fungi produce for industrial use [135]. His-
torically, Taka-diastase was the first enzyme preparation to be patented for industrial
use by Dr. Jokichi Takamine in 1884. It was produced by the filamentous fungus
Different Shades of Fungal Metabolites: An Overview 19

Table 3 Functions and applications of fungal enzymes in diverse fields

Enzymes Functions Applications
Cellulases Improve paper quality and smooth fibers Paper production
Cellulases, Beta- Ethanol production Biofuels
glucosidase
Laccases Soften paper and improving bleaching as Paper
biotransformers to remove nonionic surfactants Bioremediation
Lactase Part of β-glucosidase family of enzymes and can Dairy industry
Pectinases break down lactose to glucose and galactose in
the manufacture of yogurt
Lignocellulolytic Breakdown of agrowaste in to ethanol Biofuels
enzymes
Lipase Fat removal, esterification, hydrolysis Dairy, detergent, pulp,
pharmaceuticals,
leather
Pectinases, To clarify fruit juices and form jams Fruit and jam
cellulases – manufacturing
Peroxidases Removal of pollutants by precipitation Waste water treatment
Proteases Protein to amino acids Baking, brewing,
detergent, leather
Yeast enzymes Beer production and malting Brewing industry
Tyrosinases Convert monophenols into diphenols Food additives,
pharmaceutical drugs

Aspergillus oryzae. Since then, there are continuous advancements in exploration

and extraction technology of fungal enzymes. Fungal enzymes are always preferred
over plant and animal enzymes owing to their wide varieties and exceptional
properties. They are active under mild conditions related to temperature and
pH. There production is cheaper and faster and the yield is higher. Moreover, fungal
systems are easily susceptible to genetic manipulation. According to a report, till
now about 200 fungal enzymes have been purified from fungal cultures with
biochemical and catalytic properties characterized [136, 137]. These enzymes have
significant uses in pharmaceutical, agricultural, food, paper, detergent, and textile-
based industries (Table 3). Some of the main enzymes that dominate the industrial
enzyme market are amylase, cellulase, chitinase, invertase, laccase, lipase, protease,
tyrosinase, and xylase.
Amylases are possibly the most important enzymes in present day biotechnology
because of their wide ranging application in food, fermentation, textiles, and paper
industries. These enzymes have even successfully replaced the chemical hydrolysis
of starch in starch-processing industries. Research on cellulases and related
polysaccharidases actively began in the early 1950s. These enzymes convert ligno-
cellulose to glucose and soluble sugars [138, 139]. Currently, cellulases are widely
used in pharmaceutical, baking, detergent, wine, and textile industries [140]. Another
enzyme of varied importance is chitinases. It hydrolyzes the linear polymer chitin.
Though bacteria are one of the major sources of chitinase, filamentous fungi too have
many different chitinases belonging to GH family 18 [141]. Over the past few years,
20 S. Goyal et al.

chitin and chitin derivatives have been used in cosmetics, food, nutrition, and
biotechnology. Chitinase gene from mycoparasitic Trichoderma spp. when
expressed in several agriculturally important plants, e.g., lemon, cotton, apple, and
carrot, rendered in them defense response against various fungal pathogens [142,
143]. Unlike chitinase production, fungi are the best producers of industrial inver-
tases. Yeast Saccharomyces cerevisiae is most extensively used for the purpose. This
enzyme is widely used in the processed food and confectionery industry. Other uses
of the enzyme include lactic acid production, fermentation of cane sugar molasses,
etc [144]. Another enzyme of immense industrial potential is laccases. Laccases are
copper-containing enzymes that catalyze the oxidation of a wide variety of organic
and inorganic substrates including mono-, di-, and polyphenols, amino phenols,
methoxy phenols, aromatic amines, and ascorbate [145]. Laccases have been found
in Ascomycetes, Deuteromycetes, and Basidiomycetes; being particularly abundant
in many white-rot fungi such as Coriolus versicolor and Pycnoporus sanguineus
[146]. Most potential industrial applications of laccase are the delignification and
pulp bleaching and the bioremediation of contaminating environmental pollutants
[147, 148]. Laccase production is an expensive process. In order to find the afford-
able and higher yielding sources of laccase, cloning of laccase gene followed by
heterologous expression is gaining impetus [149]. Similarly, lipase, an essential
catalyst that digests water-insoluble lipids, also has costly purification procedures.
In addition, it also exhibits extracellular instability. Therefore, in order to avoid
enzyme purification step, direct use of cells or biomass with endoactivity of lipases
within a porous biomass support could represent a very attractive process for lipase
production and applied to several processes as in case of bulk biodiesel production.
The fungi Penicillium sp. F2 and Rhizomucor sp. F18 showed great potential for
extra and intracellular lipase production, aiming at its future use in processes of
hydrolysis and transesterification of residual oils and greases of environmental
sanitation [150]. Lipases are also beneficial in different industries such as food,
pharmaceuticals, oleo chemicals, cosmetics, fuel, and detergents [151].
Among all these enzymes, one of the most important enzymes is proteases. It is
estimated that proteases account for about 60 % of the total global industrial enzyme
sales (>3 billion USD) [152]. Proteases hydrolyse the peptide bond (CO-NH) in a
protein molecule. Proteolytic enzymes occur naturally in all living organisms.
However, fungal proteases are active over a wide pH range (pH 4 to 11) and exhibit
broad substrate specificity [153, 154]. Filamentous fungal strains such as Aspergillus
have been widely used for industrial production of protease. Industrially they have
applications in food, leather, detergent, pharmaceutical, diagnostics, and waste
management. Tyrosinase and xylanases are enzymes gaining importance due to
their industrial and environmental applications. Tyrosinase can convert
monophenols into diphenols and thus helps in production of antioxidant ortho-
diphenols with beneficial properties as food additives or pharmaceutical drugs
[155], while xylanases have many commercial uses, such as in paper manufacturing,
animal feed, bread-making, juice and wine industries, xylitol production. Among
xylanases sources, filamentous fungi are especially preferred due to their ability to
secret enzyme into the medium and high xylanases production [156, 157].
Different Shades of Fungal Metabolites: An Overview 21

10 Conclusions

The enormous biodiversity within the Mycota and the eminent role played by the
fungi in the production of pharmaceuticals, chemicals, biofuels, enzymes, and food
colorants is fascinating more and more people to the fungal research. Nonetheless,
their studies also help in preventing the food and feed spoilage and pathogenicity
caused by mycotoxins in plants, animals, and humans of different levels and
intensity. Fungi as a group of microorganisms cause the most economical damage
on crops [158]. Besides these notorious activities, some fungi are the great source of
healthy food such as basidiomycetes. They are packed with useful vitamins, min-
erals, and secondary metabolites that have been found to inhibit the growth of
different kinds of tumors [9, 159] and have many other beneficial effects.
Today people are more intended towards natural sources. In this regard, various
fungal usage and high yields have always attracted the attention. For example, in
case of food colorant, in many countries still plants are the main source of natural
food colorant and fungi are feared of their co-mycotoxin production along with
desired product. Thus, more imperative measures are required to carry out the
necessary toxicology testing. In these ways, fungal pigments could be accepted by
the current consumer round the world. Similarly, another thing in high demand is
renewable sources of energy like biofuels. This can be met from agriculture waste or
underutilized agriculture products if we can breakdown the cell wall polysaccharide,
cellulose, hemicelluloses, and lignin into simple monomer molecules like glucose/
cellobiose. However, these polysaccharides are hard nut to crack, and microbial/
fungal enzymes are used to break the complex molecules in to glucose/cellobiose for
biofuel generation (see chapter on Lignocellulose Degrading Enzymes from Fungi
and Fungal Metabolism in this book). Production of biofuels/chemicals by microbial
fermentation can have several advantages like lower costs of production than
through traditional routes, use of renewable feed stocks, and production of chemicals
with properties that allow for synthesis of new advanced polymers. In the past few
years, rapid developments have occurred in the enzyme supply market. Present
evolution in protein engineering and heterologous expression has revolutionized
enzyme production and commercialization by extending the list of enzymes now
available. This increasing demand and production of enzymes also increased the
incidence of occupational exposure to high-molecular-weight allergens. Workers
that are in direct contact with fungal enzymes are at a great risk of IgE-mediated
disease and occupational asthma. Some of the majors which can be helpful in
alleviation of enzyme exposure are like use of safety equipments; protein encapsu-
lation and setting the threshold limit values [160].
Today fungi are one of the major parts of pharmaceutical industries, but still there
is a need to continue to explore new bioactive molecules from fungi. As we know
that now-a-days development of resistance in microbes and tumor cells has become a
major problem. This resistance increasingly limits the effectiveness of current
antibiotics. According to a report by Katz [161] in 2004, more than 70 % of
pathogenic bacteria were estimated to be resistant to at least one of the currently
available antibiotics. We believe that novel antibiotics and other bioactive secondary
22 S. Goyal et al.

metabolites can still be discovered from microbial sources knowing the fact that in
fully sequenced fungi, numbers of genes and gene clusters that potentially may lead
to production of secondary metabolites are very higher in accordance with the
number of secondary metabolites known [130, 162]. Fungi are easy to cultivate
and scale up as compared to plant cells and are grown at relatively very high
volumes. Genome, transcriptome, proteome, and metabolome analyses help us in
understanding fungal science as a whole. Now tools with advanced version for
metabolome analysis, such as mass spectroscopy, single crystal x-ray diffraction,
and nuclear magnetic resonance spectrometry with increasingly sophisticated
methods of chromatography, have made possible continuing discovery of novel
fungal metabolites and future wonder drugs.

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