Fungal Secondary Metabolites in Food and Pharmaceuticals in The Era of Multi Omics

Applied Microbiology and Biotechnology (2022) 106:3465–3488
https://doi.org/10.1007/s00253-022-11945-8
MINI-REVIEW
Fungal secondary metabolites in food and pharmaceuticals in the era

of multi‑omics
Akshay Shankar1 · Krishna Kant Sharma1
Received: 1 February 2022 / Revised: 12 April 2022 / Accepted: 24 April 2022 / Published online: 12 May 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022
Abstract
Fungi produce several bioactive metabolites, pigments, dyes, antioxidants, polysaccharides, and industrial enzymes. Fungal
products are also the primary sources of functional food and nutrition, and their pharmacological products are used for
healthy aging. Their molecular properties are validated through the use of recent high-throughput genomic, transcriptomic,
and metabolomic tools and techniques. Together, these updated multi-omic tools have been used to study fungal metabolites
structure and their mode of action on biological and cellular processes. Diverse groups of fungi produce different proteins
and secondary metabolites, which possess tremendous biotechnological and pharmaceutical applications. Furthermore, its
use and acceptability can be accelerated by adopting multi-omics, bioinformatics, and machine learning tools that generate
a huge amount of molecular data. The integration of artificial intelligence and machine learning tools in the era of omics
and big data has opened up a new outlook in both basic and applied researches in the area of nutraceuticals and functional
food and nutrition.
Key Points
• Multi-omic tool helps in the identification of novel fungal metabolites
• Intra-omic data from genomics to bioinformatics
• Novel metabolites and application in human health
Keywords Fungal metabolites · Multi-omics · Transcriptomic · Metabolomic · Machine learning
Introduction SMs are differentially structured organic compounds mainly

extracted from plants, fungi, and bacteria. These metabolites
The evolution in multi-omic tools, like genomics, meta- not only are essential for the growth of the organism, but
genomics, transcriptomics, proteomics, and metabolomics, it has also been used in pharmacological as well as in the
have explored many avenues in analyzing complex biologi- development of functional food. To date, ~35% of the natu-
cal data (big data) to reveal the structure and function of rally derived product contribute to drug discovery and are
fungal secondary metabolites. Nowadays, a researcher can approved by the US Food and Drug Administration (FDA).
sequence and study the whole genome (using next-genera- Among the approved SMs, ~ 15% belongs to microbial ori-
tion sequencing approaches), proteome for both the extra and gin, 25% plants, and approx 5% is extracted from animal
intracellular proteins study, and metabolome for secondary source (Calixto 2019). In microbial groups of fungi and their
metabolite (SM) study from basidiomycetous fungi which products, for example, enzymes, fermented foods, animal
has tremendous commercial potential (Jain et al. 2020). feed, antibiotics, pharmacy products, and pigments have
contributed significantly to humans and many biotechnologi-
cal industries (Sahu et al. 2021). Furthermore, many flavor-
* Krishna Kant Sharma ing compounds, flavored coffee, and cosmeceutical products
kekulsharma@gmail.com;
kksharma.microbiology@mdurohtak.ac.in
have also been produced from a basidiomycetous fungus,
for example, Ganoderma lucidum and Trametes versicolor
1
Laboratory of Enzymology and Recombinant DNA (Sahu et al. 2021). Multi-omic tool refers to many advanced
Technology, Department of Microbiology, Maharshi technologies which are used to collect the data of biological
Dayanand University, Rohtak 124001, Haryana, India
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3466 Applied Microbiology and Biotechnology (2022) 106:3465–3488
molecules for their functions as well as an action mechanism needed to screen newer fungi and increase the pool of novel
on the differentially affected cells (Bogale 2020). Multi-omic metabolites with their molecular interaction and exploit the
research is not new; it has been updated chronologically in fungal cultures with their metabolic capacity.
the research field and accelerated its popularity in the sci- Initially, the whole-genome sequencing was used to pro-
entific universe in the past few years. Prior to the advent of vide limited data related to genomic features like annotated
multi-omics, the scientists were unable to suggest or predict genome and enzymatic pathways (Sharma 2016). After com-
the structure, function, 3-D model, and mode of action of paring from the earlier estimation-based procedure, whole-
the fungal SMs. Earlier, single genomic or proteomic data genome sequencing tools were found to predict more SM
were used to provide inconclusive results due to the absence production from fungal strains than plant or bacterial species
of single pipeline for metabolite study. After the genesis of (Kumar et al. 2019). Furthermore, the genetic makeup of a
high-throughput omic technology, there is a quest for the fungus provides useful information to improve the enzyme
accurate information about single-gene analysis and complex production from a culture through different culture condi-
global investigation of the whole (fungal) organism like fun- tions or media engineering. The data generated by the multi-
gal metabolites and their evolution, fungal interaction with omic sciences (such as comparative genomics, transcriptom-
their substrates, fungal role in pharmaceutics, and their SM ics and deep sequencing, proteomics, and metabolomics)
study. It also provides the functional information of genes and bioinformatics (massive data analysis) can majorly con-
and compare the genes with other organism’s genome (func- tribute to improving the production methods and the use
tional genomics and comparative genomics), the expression of metabolites (Amer and Baidoo 2021). In system biology
profile of mRNA of the metabolites producing fungi (tran- research, data collected from the multi-omic tools are ana-
scriptomics), protein profiling (proteomics) and complete lyzed through statistical, mathematical, and computational
study of metabolites like the weight of compound, and func- models. Furthermore, the results obtained through these
tional properties in the cell (metabolomics) that assist in the techniques explain the actual behavior of the fungal cells
rapid identification of novel SMs (Fig. 1) (Amer and Baidoo by providing data on the biological, cellular, and molecular
2021). According to an old estimate, 1.5 million fungal spe- functions, which help in the better understanding of inter-
cies are present on the Earth, and only 10% have been inves- actions between environmental factors, genetic variants,
tigated for their secretory products (Palazzotto and Weber genetic expression patterns, and changes in the concentra-
2018). Therefore, new and advanced omic approaches are tion of metabolites (Fig. 2).
Fig. 1 Flow chart depicts multi-omic tool with data integration and artificial intelligence modeling used for fungal metabolite studies
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Applied Microbiology and Biotechnology (2022) 106:3465–3488 3467
Fig. 2 Scheme to screen and isolate novel fungal secondary metabolites
Finally, there is an urgent need to update the knowledge in chemical entities which may be beneficial or harmful (Hyde
the area of artificial intelligence (AI) and machine learning et al. 2019). Furthermore, most filamentous fungi synthesize
and its integration with multi-omic technologies to predict SMs that have rich sources of compounds for the biotech-
microbial metabolites for abovementioned applications. In nological and pharmaceutical industries, such as antibiotics,
this review, we had tried to explain multi-omic technologies medicinal products, organic acids, food processing enzymes,
used to facilitate the analysis of data on metabolites from and many other metabolites used in feed and food industry.
basidiomycetous fungi and also updated their application in Furthermore, lignocellulose degrading and polysaccharide
many biotechnology-based industries involved in the pro- secreting white and brown-rot fungi have greater diversity
duction of customized food, nutraceuticals, and functional for lignin-degrading peroxidases, multi-copper oxidases, and
foods. glycoside hydrolase. In sequential pattern, these enzymes
help in the progressive decay of lignin-rich substrates (Jain
et al. 2020; Saini et al. 2020).
White‑rot basidiomycete fungi and their Due to biological demand of the SM-based products,
metabolites milti-omic tool becomes an integral part in the detec-
tion and characterization of novel metabolites. After the
White-rot basidiomycetes are lignocellulose degrading genome sequencing, advance techniques such as transcrip-
filamentous fungi that can grow in a lignin-rich environ- tomics, DNA microarrays, proteomics, and metablomics
ment with high humidity. They have an enormous role in were explored in differential induction and production of
lignin, cellulose, and hemicellulose degradation, which SMs from fungi (Palazzotto and Weber 2018; Shankar
reflect a significant function in the carbon cycle. Fungi are et al. 2019). Basidiomycete fungi have the prime ability to
one of the most important sources of many biological and degrade complex lignin structure and xenobiotic compound
13
by sensing their environment and regulating the secretome regions (Baby et al. 2015). G. lucidum belongs to a fam-
and proteome profile (Téllez-Téllez and Diaz-Godinez ily of medicinal mushroom, and it is non-edible due to its
2019). From the past few years, SM studies are done by thick, corky, and tough fruiting bodies; also, they do not
using the omic tools to find out the novel compounds and have the fleshy texture as well as good taste. Till now, 431
their important biological effects which can be used for secondary metabolites have been isolated particularly from
human health, such as anticancer activity, antidiabetic effect, the species G. lucidum (Baby et al. 2015); few of the exam-
antimicrobial effect, and cytotoxicity studies (Fig. 3) (Ball ples are triterpenoids polysaccharides, steroids, ganoderic
et al. 2020). Many industrial products composing of fun- acid, alkaloids, ganomycins, fornicins, and ganocins. Among
gal metabolites from basidiomycete source are directly or all, triterpenoids are important metabolites of G. lucidum,
indirectly benefited to the human health (Table 1). People and it has beneficial biological effects. These major groups
have been using many types of mushroom in their diet since of SMs are extracted from many Ganoderma species like
long time, but their functions were not known. Nowadays, G. lucidum, G. applanatum, G. lipsense, G. colossum, G.
due to the upgraded and integrated multi-omic technology, orbiform, G. sinense, G. cochlear, G. amboinense, G. res-
their detection process and properties of SMs are known to inaceum, G. hainanense, G. pfeifferi, G. austral, G. tsugae,
us. Hence, the demand of fungal mushroom and their SMs G. carnosum, G. capense, G. fornicatum, G. neo-japonicum,
has significantly increased (Table 1). Furthermore, most of G. theaecolum, G. boninense, G. annulare, G. concinna, G.
the white-rot basidiomycetes produce different types of SMs sinense, and G. mastoporum (Baby et al. 2015). The triter-
with different structures and functions (Table 2). penoids are comprised from six isoprene units (C30) which
are found in a cyclic form like mono-, di-, tri-, tetra-, or
Ganoderma lucidum: Polyporales group of medicinal pentacyclic carbon subunit, where the pentacyclic triterpe-
mushroom noids are well known group (Noji et al. 2021). Many volatile
oils are also extracted from Ganoderma species. Baby et al.
Ganoderma is a filamentous wood-decaying fungus that (2015) described the essential volatile oil from the fruiting
belongs to the phyla Basidiomycota and has the unique material of G. lucidum by hydro-distillation, followed by GC
ability to degrade the xylem cell wall components such with flame ionization detector (GC-FID) and GC-MS that
as cellulose hemicelluloses and lignin. According to tax- analyzed their functional properties.
onomic reports, the genus Ganoderma consists of more
than 300 species, and most of them are spread in tropical
Fig. 3 Action mechanism of fungal secondary metabolites and their effect on human health
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Table 1 Multi-omic tools used to study basidiomycetous SMs and their products in food and pharmaceutical industries
Product name/fungal sources Key component of SMs Mode of action and applications Omic tool References
SM of Pleurotus ostreatus Resveratrol Antioxidant Genomics and metabolomics Takahashi et al. (2020)
Nutrient of Dictyophora indusiata Vitamin C Antioxidant activity Nuclear magnetic resonance spectros- Liu et al. (2019)
copy
Bitter tea powder from G. lucidum & Lentinan Antitumor properties or immunostim- 2-DE coupled with mass spectrometry Chuang et al. (2009)
L. edodes ulants
Low-density lipoprotein (LDL) drug Lovastatin Lowers cholesterol level RP-HPLC Kała et al. (2020)
from A. bisporus, C. cibarius, I.
abadia, and L. edodes

MycoNutri Cordyceps Organic from Cordycepin Reducing the LDL level, total choles- Genomics and NMR Ashraf et al. (2020)
C. militaris terol, triglycerides, and hyperlipi-
demia
Sun mushroom from A. subrufescens Polyphenols and polysaccharides Decrease oxidative stress and prevent HPLC-MS Navegantes-Lima et al. (2020)
non-transmissible chronic diseases
(NTCD)
Niu-Chang-Chih from A. cinnamomeaAntcins Treat various diseases such as diar- NMR, electron ionization mass spec- Kumar et al. (2020)
rhea, abdominal pain, hypertension, trometry (EI-MS)
and reduced prostate cancer
Caterpillar as a H. sinensis Polysaccharides Prebiotic and diabetic control Next-generation sequencing technol- Takahashi et al. (2020)
ogy
Edible mushroom V. volvacea, P. Ergosterol class, ergosterol peroxide Immunoregulation and antitumor NMR-based metabolomics Chen et al. (2020); Takahashi et al.
geesteranum, H. erinaceus, and P. effect (2020)
sapidus in China, East and Southeast
Asia
Fusarium venenatum by Quorn™ Food supplements Immunological action, antioxidant Fermentation and transcriptomics Meyer et al. (2020)
industry
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3469
Phanerochaete chrysosporium: model in white‑rot Pleurotus ostreatus: oyster mushroom of order

fungus of order Polyporales Agaricales
Phanerochaete chrysosporium is a white-rot filamentous Pleurotus is a white-rot basidiomycete group of fungi,

basidiomycete with ability to decompose lignin-rich plant which belongs to the family Pleurotaceae and order Aga-
material composing of lignocelluloses and other hemicel- ricales group, formed as an oyster type of fruiting bodies.
luloses. It produces two important SM compounds, i.e., This edible mushroom has high nutritional value; also, its
veratryl glycerol and veratryl alcohol, in their extracellular compounds are highly used in tumor treatment, antibacte-
culture fraction (Rodarte-Morales et al. 2011). Furthermore, rial effect, and diabetes patients (Younis et al. 2015). These
P. chrysosporium has been considered as a model wood- edible fungi secrete many SMs that have diverse structure
decaying basidiomycete that has been used since long time of polysaccharides and terpenoids. These complex struc-
in SM pathway studies. Additionally, it has also been used tures of polysaccharides activate many essential pathways
to study lignin metabolism through the omic tool of the which help in the defense mechanism of an organism. Ber-
whole-genome sequencing (WGS) (Ozsolak and Milos ovic and Podgornik (2019) worked on a submerged culture
2011), proteomic secretome analyses (Shankar et al. 2019), of P. ostreatus and identified important SMs, for example,
transcriptome studies (Ozsolak and Milos 2011), and gene oleic acid, palmitic acid, linoleic acid, stearic acid, and
transformation studies (Sharma et al. 2006). The first whole- their methyl esters. Many other species of Pleurotus con-
genome sequencing of this model organism was published tain various compounds like polysaccharides FII, eryngi-
for wood decay and lignin metabolism to establish the signif- olide A, β-glucan, ubiquinone-9, and some terpenoids like
icant enzymatic pathway and their role in degradation. The eryngiolide A, pleuroton A and B, and pleuroton B. These
32.5-Mb genome was sequenced and a total of 10,048 genes compounds have an essential role in disease treatment due
were screened, which is online available on public domain to its antioxidant, antiviral, and antimicrobial properties, and
(Martinez-Gomez et al. 2012). Furthermore, in silico tool it also boosts host immune system (Wisbeck et al. 2017).
confirms the presence of genes for lignin peroxidases (LiP)
and manganese peroxidases (MnP) in P. chrysosporium Pycnoporus cinnabarinus: a cinnabar Polyporales
that has role in secondary metabolite production (Martinez-
Gomez et al. 2012). White-rot basidiomycete, Pycnoporus, is an edible mush-
room that belongs to the Polyporaceae family member.
Trametes: a Polyporales These groups of fungi degrade cellulose, hemicelluloses,
and lignin by secreting enzymes (redox and CAZy family)
Trametes versicolor (also known as Coriolus versicolor) is and pigments. P. sanguineus releases very effective metab-
a medicinal mushroom that refers to the family Polyporales olites like cinnabarinic acid which inhibits the growth of
and class Agaricomycetes of the white-rot basidiomycetes Gram-positive and Gram-negative bacteria and antimi-
and grows on the dead decaying wood and deciduous trees. crobial agents of many food products with other common
The pigment forming T. versicolor secretes a high amount pathogens (Evana et al. 2021). Many species of Pycnopo-
of laccase enzyme, and also, its genomic as well as WGS rus release flavoring compounds like methyl anthranilate
updates confirm the lignin peroxidases (LiPs), dye-decolor- and phenoxazinone-type compounds like cinnabarinic acid
izing peroxidases (DyPs), manganese peroxidases (MnPs), and tramesanguin. Recent studies suggest that the molecule
and versatile peroxidases (VPs) (Wang et al. 2015). Leliebre- of cinnabarinic acid could play a beneficial role in neuro-
Lara et al. (2015) extracted different types of metabolites like inflammation disease, improve immune system, and have
flavonoids, alkaloids, triterpenes, a small amount of card- beneficial role in the disease of the central nervous system
enolides, and steroids through the ethanol extraction proce- (Fukushima-Sakuno 2020).
dure. Xu et al. (2017) worked on the co-cultural fungal inter-
action of T. versicolor and G. applanatum, which confirm the
series of carboxylic acid and novel xylosides with medicinal Different fungal products and their health
and industrial applications. In different countries like Japan benefits
and Europe, a chemical derivative of polysaccharide-K from
T. versicolor has been approved for cancer treatment; also, Fungi secrete different types of enzymes and metabolites
different strains were screened for polysaccharide production for their survival in both favorable and unfavorable environ-
having different structures and properties. Many other com- mental conditions. The products of all fungal enzymes and
pounds were isolated from Trametes sp., namely spiroaxane metabolites are beneficial for human health due to its immu-
sesquiterpenes, rosenonolactone, tramspiroins, and funatrol nomodulatory (Fukushima-Sakuno 2020), anticancer (Ball
D with beneficial role in human health (Wang et al. 2015). et al. 2020), anti-inflammatory (Xu et al. 2017), antiviral
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Table 2 Different basidiomycete fungi and secondary metabolite with their application in human health
Fungal Secondary metabolite Structure Description Therapeutic role Reference
Culture
G. lucidum Polysaccharides- (β-D- Total 71 Anti-tumor effects, (Baby et
glucans, Galactose, proteins were immunomodulator al. 2015;

Β –D- Glucans Galactose Mannose
Mannose, Arabinose, identified and y, anti-angiogenic, Xu et al.
Rhamnose, Fructose) classified and cytotoxic 2017)
Triterpenoids Arabinose Rhamnose Fructose functionally, effects
(Ganoderic acids- A, B, 430 SMs were
cerevisterol, lucidenic extracted;

Ganoderic acids Cerevisterol Lucidenic lactone
lactone, lanostane terpenoids
triterpenes, methyl (380), steroids
ganoderate A acetonide Methyl ganoderate (30),

A acetonide n-butyl Lanostane
Ganoderate triterpenes
and n-butyl Ganoderate)
Pleurotus Linoleic acid, oleic Total 87
eryngii acid, trans 3,4-dihydro- proteins were

Antibiotic, (Wisbeck
3,4,8- identified, 107
antitumor, et al. 2017)
trihydroxynapthalen- Linoleic acid trans 3,4-dihydro-3,4,8- metabolites
Oleic acid
trihydroxynapthalen- antiviral, and
1(2H)-one
1(2H)-one, 4- including
anticholesterolic
hydroxybenzaldehyde, alkane (27),
4- indolo-3-
activities
hydroxyben carboxylic
indolo-3-carboxylic zaldehyde
esters (27),
acid Uracil
acid, uracil terpenoids (4),
fatty acid (8)
and phenols (2)
Total 181 Antimicrobial
proteins were effect, Antitumor

Lentinula Lentionine, 1,2,4,6- (Takahashi
identified, ~24 property,
edodes Tetrathiepane, Dimethyl et al. 2020;
SMs extracted Antidiabetic,
disulfide, Ergosterol, Fukushima
including antiviral,
Demethylincisterol A3, -Sakuno
phenolic Immunomodulator
(Wisbeck et al. 2017), antiatherosclerosis (Hyde et al. 2019), the extraction of the metabolites and their products that are
antidiabetic (Zhou et al. 2021), antioxidant (Kumar et al. beneficial for human health and fitness. These fungi are
2015), and antiaging properties (Jue et al. 2017) (Table 1). exploited for pharmaceutical and other medicinal products
Mushroom-producing white-rot fungi are mostly used for used for human health purposes.
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Table 2 (continued)
Lovastatin, Eritadenine components y effect 2020)
1,2,4,6- Dimethyl
Lentionine
Tetrathiepane disulfide
Ergosterol
Lovastatin Eritadenine
Total 123 Anti-inflammatory
protein and effect, Antifungal

P. veratryl alcohol (Rodarte-
SMs including property,
chrysospor Morales et
auxin, abscisic Enzymatic al. 2011)
ium
Veratryl acid, zeatin, degradation of
alcohol
IAA were xenobiotic
identified compounds
Schizophyl Carotenoids, indole Total 229 Antimicrobial (Tel-
lum derivatives, flavonoids, proteins, 16 activity, Çayan

Carotinoids
commune saponins Indole
polysaccharide Antitumor, 2019)
lyases were Antiviral, Anti-
Flavonoids identified inflammatory

Saponins
effect
Gloeophyll Sesquiterpenoids, Total 109 Antioxidant
um trabeum (3Z,6Z,8E)- proteins and activity, Anticholin

(Singh et
Sesquiterpenoids
dodecatrien-1-ol SMs including esterase effect
al. 2021;
(cryptosporin,
Umezawa
coryoctalacton
Dodecatrien et al. 2020)
e, quinones and
catechol) were
identified
All the studies were done using LC-MS/MS and GC-MS studies
There are six important classes of SM compounds Terpenoids

secreted from white-rot fungi that are identified by using
different multi-omic tools (Ijoma et al. 2021): Terpenes are a major class of bioactive metabolites that
are produced from a higher class of Polyporales group of
13
basidiomycetes, such as Pycnoporus sanguineus (Gauna These groups of metabolites include antibiotics, statins (low-
et al. 2021), Pleurotus spp. (Wisbeck et al 2017), Gano- ers the cholesterol levels), and antidepressant drugs (Ijoma
derma spp. (Baby et al. 2015), and Agaricus blazei (Shimizu et al. 2021).
et al. 2016), and other fungi from class ascomycetes, like
Fusarium spp. (Nazari et al. 2016) and Trichoderma virens Phenylpropanoids and aromatic amino acids
(Xu et al. 2017). These compounds are structural constitu-
ents of another group of metabolites that are formed through Secondary metabolites consist of phenolic compounds and
the linkage of isoprene units (hemiterpenes C5, monoterte- are secreted from the fungal and plant metabolic path-
penes C10, diterpenes C20, sesterterpenes C25, triterpenes ways called the shikimate pathway. Metabolite of this
C30, tetraterpenes C40). Different NMR and other omic tool group includes compounds like folic acid and salicylic
confirm the member of the terpenoid class of compounds acid, which help in reducing inflammation and pain; it
such as steroids, menthol, and taxol, which have key compo- is also used in antioxidant drug resveratrol (Singh et al.
nents for anticancer drugs and β-carotene properties. These 2021). Phenolic compounds have many functions in plant,
bioactive compounds possess anti-infection, anti-inflam- in which some have defense role against herbivores and
matory, anticancer, antiproliferative, and antiangiogenic other insects. Due to the high antioxidant effect and free
medicinal properties (Ijoma et al. 2021). radical scavenging property, phenylpropanoid compound
has major attention in the area of human health, and nowa-
Polyketides and fatty acids days, their functions are updated by the use of multi-omic
tool (Singh et al. 2021).
Fatty acid and fungal polyketides are common metabolites
present in large groups of ascomycete and basidiomycete
fungi. These SMs are present in different species of mush- Alkaloids
room-like Agaricus bisporus, Lentinus edodes, beefsteak
fungus (Fistulina hepatica), and many other molds of asco- Alkaloids are nitrogen-containing compounds that have an
mycetes like Aspergillus oryzae (Shimizu et al. 2016). All important class of SMs, such as caffeine, cocaine, nicotine,
groups of microbial polyketides are synthesized by multi- morphine, and strychnine. These compounds were originated
domain polyketide synthases (PKSs), which are structur- from one or many linked amino acids that can be synthesized
ally diverse. It ranges from pharmaceutically modified drugs from many biosynthetic pathways (Krause et al. 2020). It
like lovastatin and griseofulvin to the most potent carcino- can regulate sodium ion channels and other microbial activ-
genic compound “aflatoxin B1” (Cox et al. 2018). PKSs are ity, which enhances their property to induce the immune
broadly categorized into three classes: system, causing cell death. The alkaloid products have been
used to treat human diseases like cancer, lung disease, and
1. Type I polyketide synthases: They are large, multi- acquired immune deficiency syndrome (AIDS) (Dey et al.
modular, and different functional proteins consisting 2020). Secondary metabolites of many endophytic fungi are
of enzymatic domains that perform a direct reaction in composed of alkaloids, which have diverse biological and
polyketide chain assembly. clinical properties like antifungal, antiviral, and antibacterial
2. Type II PKSs are an assembly of regular proteins that properties (Zhang et al. 2012). Fusarium chlamydosporum
catalyze the formation of aromatic polyketides like anti- isolated from the root nodule, having indole alkaloids, shows
biotic actinorhodin. phytotoxic activity against the bacterial species. Many other
3. Type III PKSs are a group of small aromatic compounds fungi, such as Mucor sp., A. terreus, and P. janthinellum,
that produce different structures of SMs with many bio- have been isolated from plant material. They are known
logical activities and antimicrobial properties (Navarro- to secrete different antimicrobial alkaloids like terezine E,
Muñoz and Collemare 2020). Genomic study of A. ory- indole derivative CC50, asperimides A–D, brasiliamide, and
zae has revealed the presence of four type III PKS genes, peniciolidone, respectively, that are proportionally beneficial
namely CsyA, CsyB, CsyC, and CsyD. Similar kind of to human health (Deshmukh et al. 2022; Nazari et al. 2016).
genes has also been reported in the basidiomycete group
of fungi (Navarro-Muñoz and Collemare 2020).
Proteins, peptides, and derivatives of amino acids
These secondary metabolites are formed through the ace-
tate pathway within the cell by coupling of acetate group. In Peptides and proteins are significant component of SMs,
the fatty acid group, crude fat is considered under all catego- where the products of metabolites have similarity between
ries of lipid compounds, including fatty acids, monoglycer- the compounds secreted from a large number of organisms.
ides, diglycerides, triglycerides, sterols, and phospholipids. The protein contents are 20–30% by dry weight in most of
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Fig. 4 Integration and prediction of SM from gene to metabolite level using multi-omic tool
the edible mushrooms (Pleurotus spp., Agaricus bisporus, Multi‑omic tools in basidiomycete
Volvariella volvacea, and Lentinus edodes), which helps the metabolite regulation studies
vegetarians to maintain the protein content, vitamins, and
fiber in their diet (Du et al. 2021). Multi-omics composes of the most advance tools and tech-
niques of the system biology. Many big pharma companies
Specialized carbohydrates are using multi-omic tools for their basic research, finding
natural products and novel molecules from the basidiomy-
All fungal organisms are the primary source of carbohy- cetous fungi (Zhou et al. 2021; Amer and Baidoo 2021). In
drates, which can be described as primary metabolites. the past few years, many researchers have explored multi-
Those fungal metabolites have tremendous applications in omic technologies for clinical trials and biotechnological
the pharmaceutical industry. The polysaccharide of Pholiota industries for screening and characterization of novel fungal
microspora has a significant property to decrease low-den- SMs (Fig. 2). During COVID-19 pandemic condition, the
sity lipoprotein and increase high-density cholesterol. After researcher also worked in the area of SMs from endophytic
comparison between different basidiomycete fungi, varying fungi and predicted their inhibitory effect against single
amounts of polysaccharide may be found, for example, poly- RNA-dependent RNA polymerase of coronavirus using
saccharides present in Pleurotus species range from 46.6 to molecular docking and simulation tools. The whole-genome
81.8%, whereas A. bisporus has 60% on a dry weight basis data of the viruses and the plants helped in the prediction of
(Berovic and Podgornik 2019). Nowadays, upgradation of two metabolites (namely dankasterone B and pyrrocidine A),
many extractions and characterization tools help to discover which cause inhibition of viral RdRp (mutation associated
novel carbohydrates and other metabolites that are key com- in SARS-COV-2 genome) (Ebrahimi et al. 2021). Apply-
ponents of food and feed industry. ing these high-throughput tools, researchers get access to
13
the structure of the metabolite. Therefore, their functions 2020), for comparative genomics and transcriptomics
can be predicted; furthermore, they can improve the produc- study (Pavlopoulos et al. 2015). By the advancement
tion of the specific metabolite to confirm their role. In the in system biology approach in the genomic era, gene
recent past, the bioinformatic tools including transcriptomics clusters and the conserved sequence of a SM-producing
and proteomics have assisted in gene ontology (GO) stud- gene have been predicted. Furthermore, it can be edited
ies, pathway predictions, structure prediction, and genetic through the molecular approach, whereas comparative
expression, and they have also been instrumental in the genome analyses were used to know the SM biosynthetic
protein-protein interaction (PPI) studies (Jain et al. 2020). pathway (Cairns and Meyer 2017). Proteomic timescale
Multi-omics can be used to study the complex process has provided an updated tool to estimate the production
of life that learned through the various protocols and time- capability, quality of fungal enzyme, structure of SM, and
line for all sets of data and standards. Earlier, a single omic their biosynthetic pathway at whole proteomic scale using
tool (genomics) was used for the analysis of the research LC-MS/MS technique (Jain et al. 2020).
query with many sets of samples. Due to the limitations in
validating the data using genomics, like low computational Genomic tools for fungal metabolite study
power, less data storage capacity, and scarcity of data anal-
ysis software, lots of effort were needed to standardize Genomics is one of the initial omic tools that have been
the data, pipeline development, and report preparation for applied in high-throughput research field, which cover from
single data analysis (Brazma et al. 2001). comparative genetics to biotechnological and pharmaceuti-
Nowadays, the research background has a suite of omic cal industry like diagnostic, pharmacogenomics, and evo-
tools (multi-omics) which are in demand due to their lutionary genetic measurement (Sharma 2016). Earlier in
technological advancement. The use of multi-omics has genomics, SNP-ChIP was used to measure up to 5 million
improved the ease of doing research due to the result clar- single nucleotide polymorphisms (SNPs), which were time-
ity, cost-effectiveness, and high-throughput result analysis taking and costly, but next-generation sequencing (NGS) has
of biological entities (Subramanian et al. 2020). It offers come in limelight and has replaced the chip technology with
a comprehensive, structured, and interactive overview of reduced cost of sequencing by $0.10 per million bp. The
a biological mechanism and provides better opportunities NGS technologies like Roche 454, Illumina Solexa GA, and
with some challenges to the biologists, bioinformaticians, SOLiD (MacLean et al. 2009) and NextSeq 2000 (www.
biostatisticians, and biomathematicians (Pavlopoulos et al. illumina.com) have many suitable platforms for recovering
2015). The major multi-omic tools and technologies are hundreds of millions of genomic sequences, single-cell gene
metagenomics, transcriptomics, proteomics, secretom- expression, shotgun metagenomics of environmental sam-
ics, and metabolomics. These new omic tools are high ple, and discovering major novel genes of fungi at low cost.
throughput and rapid in identifying the fungal genomes Nowadays, the cost of genome sequencing is estimated to
and their metabolites. Many other specialized fields which be $600–$1000/genome when performed at a commercial
are included under the line of omic tools are epigenomics, scale using third-generation Oxford Nanopore PromethION
ionomics (total elemental composition of an organism), (https://nanoporetech.com/products). Therefore, reducing
lipidomics, fluxomics (analysis metabolic profiling), toxi- costs has expanded the reach of the technology into the iden-
cogenomics (study change in the global gene expression tification of microbial (fungal) metabolites.
profile and toxicological endpoints), nutrigenomics (study The abovementioned NGS tools are explored in new com-
the relationship between human genome, nutrition, and mercial products and many metabolic pathways by the use of
health), and foodomics (omic approach to food science) biological pathway analysis database and software (KEGG
(Capozzi and Bordoni 2012; Özdemir et al. 2017). By pathway, PANTHER, Ingenuity Pathway (IPA)) (Garber
integration of these multi-omic techniques, production of et al. 2011). Fungal SM identification and characterization
targeted SM can be achieved and verified at various levels have been done by using advanced technologies of NGS
(Fig. 4). Furthermore, it can be helpful for the industries to through mass spectrometry which rely on the freely avail-
identify the new commercial products and also to improve able fungal genomes that accelerate the fungal proteome
their metabolic fluxes. analysis (Jain et al. 2020). Genome mining tools have also
Many recent reviewers had enlisted the omic tech- been used to identify the uncharacterized natural product
niques as genome-based molecular biology tools and by estimating the genetic potential of strain through scan-
envisaged their applications in sequence alignment ning the gene of interest (Ziemert et al. 2012). In genome
(Cairns and Meyer 2017), nucleotide assembly (Keller sequencing of Aspergillus niger, a total of 200 new proteases
2019), RNA sequence analysis, metabolic pathway con- have been checked during annotation; among them, two have
struction (Pavlopoulos et al. 2015), microarray analy- been commercialized as prevention of haze in beer produc-
sis (Cary et al. 2018), and network analysis (Jain et al. tion and others applied for the production of sports drinks
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Table 3 Genomics and transcriptomic tool with their uses in SM study of white rot fungi
Tool and techniques Mechanism Application References
Genomic techniques
DNA microarray Hybridization based genomic technology identified gene Prediction of specific protein and metabolite sequences Özdemir et al. (2017)
from gene clusters by comparing with another genome
Genome mining Locate the genes into the genome Search the location of genes that helps in metabolite Narayanan et al. (2010)
formation
Screening of unknown genes from whole-genome To know the biosynthetic potential of fungal SM BGC Palazzotto and Weber (2018)
sequence
Global Natural Product Social Added with MS/MS spectrum coupled with GC/LC to Perform MS searches using MS/MS spectrum as a query Mao et al. (2021)
Molecular Networking (GNPS) know the natural products search, help in the quantification of metabolites or other
drug components into the sample
CRISPR/Cas9 Based on genome editing technology Highly efficient genetic manipulation technique with Hadjithomas et al. (2017)
enabled the taking advantage and discovery of new
bioactive compounds
Transcriptomic approach
cDNA-AFLP Sequence needed for cluster and alignment Discover novel genes for metabolite production Garber et al. (2011)
Shotgun sequencing RNA identification by forming cDNA fragments Detect, quantify, and annotate the coding/non-coding Fondi and Liò (2015)
RNA
Probe-based arrays mRNA analysis with labeled sample and connect with Explore gene expression at global level, screening of SM Hasin et al. (2017)
cap analysis of gene expression tool (CAGE) BGC cluster using Southern blots
Deep-sequencing technologies RNA-sequencing for SM gene prediction in fungi Determine RNA expression level, capture transcriptome Ozsolak and Milos (2011)
dynamics
Next-generation sequence (NGS) RNA sequence identification by alter the DNA sequenc- Biomarker, therapeutic targets, SM gene cluster verifica- Liu et al. (2021); Hasin et al. (2017)
ing tion
(van Schaick et al. 2021). The application of whole-genome the accumulation of pneumocandin B0 from Glarea lozoy-
sequencing technology in the SM secreting fungi or its gene ensis. Thus, by predicting the SM gene clusters and its path-
clusters bypasses the need of DNA hybridization, library way from genomic analysis, researcher can find their gene
construction, screening, and chromosome editing techniques of interest in a wild fungal strain and modify the pathway
(Cacho et al. 2015). using CRISPR/Cas9 tool for enhanced SM production. The
Evidently, the connecting link between secondary metab- said pathway modifications can be verified by transcriptomic
olite and genes of organism is contributing majorly (a) in the and proteomic tools.
exact prediction of secondary metabolite structure based on
the DNA sequences and (b) in the designing of biosynthetic Transcriptomics
pathways for the synthesis of valuable products. Overall,
the connecting gap between the genes and molecules using Arguably, transcriptomics is the most advanced tool to
comparative genomics and transcriptomic tools helps in study the metabolic update of molecular changes (like tran-
understanding of the natural function in SM study (Table 3) scription, translation, and post-translation modifications),
(Cacho et al. 2015). Many other established in silico tools natural metabolite biosynthesis, and gene regulation and to
like antiSMASH (Antibiotics and Secondary Metabolite validate the results of gene modification (CRISPR/Cas9) in
Analysis Shell) (Blin et al. 2013) and PRISM 3 (Skinnider wild genes at the transcriptional level (Palazzotto and Weber
et al. 2017) have been upgraded with many features to know 2018). Compared to the traditional protein-coding transcrip-
the function of enzymes found in the biosynthesis of SMs tome, modern non-coding RNA methods have shown high
as well as to build the connection between biosynthetic research output due to less complexity. Several RNA-based
gene clusters (BGCs) with their consistent natural prod- tools are used from the past few years (Table 3), where three
ucts. Fungal genome sequencing had revealed that SMs main strategies have played a key role in the advancement
represents <3% BGC, where the most common enzymes of transcriptomic studies: (a) knowledge of microarray, (b)
which are backbone for their gene cluster includes polyke- serial analysis of gene expression (SAGE) and suppression
tide synthases (PKSs), non-ribosomal peptide synthetases subtractive hybridization (SSH) (Brazma et al. 2001), and
(NRPSs), dimethylallyl transferases (DMATs), and terpene (c) de novo transcript sequence assembly (Jain et al. 2020).
synthases (Li et al. 2016). BGC prediction in fungal gene These instrumental techniques of the transcriptomic tool
cluster was explored by doing fungal genome sequencing can increase the sequencing quality with their quantitative
of ~ 1037 species by antiSMASH (including Ascomycota, results at the average cost increment.
Basidiomycota, and other fungal taxa), and 36,399 BGCs The transcriptomic study is deeply involved to detect the
were found to be organized in 12,067 network of gene clus- differentially expressed gene sets and their pathways, which
ter families (Robey et al. 2021). Thousands of identified or are majorly responsible for the production of the metabolites
predicted fungal BGC data were uploaded and stored on using statistical tools, such as limma (Ritchie et al. 2015),
public domain, like antiSMASH, MIBiG (Minimum Infor- DESeq2 (Love et al. 2014), Gene Set Enrichment Analysis
mation about a Biosynthetic Gene Cluster), ClusterFinder, (GSEA) (Zito et al. 2021), and DAVID (Ziemert et al. 2012).
and IMG-ABC Database. Researchers have developed pipelines such as GenePattern
Similarly, hexaricins are a family of natural polyketide and UTAP (User-friendly Transcriptome Analysis Pipeline)
products identified through the genomic tool, and the pres- for the transcriptomic data analysis and their evaluations.
ence of gene clusters was predicted in the rare marine actino- Among these models, probabilistic graphical models are
mycete Streptosporangium sp. (Tian et al. 2016). Also, some most popular, which explains the distribution of transcripts
of the natural metabolites, like bikaverin, immunomodulator data that is the key of transcriptomic tools (Palazzotto and
endocrocin, and antibacterial compounds, were identified Weber 2018; Hasin et al. 2017).
from the BGC group of Fusarium spp. (Keller 2019). Novel Earlier, transcriptomic studies suggest that ~ 3% of the
metabolite cyclic tetrapeptide, viz., cyclo-(l-leucyl-trans- genes code for the translational products, whereas up to
4-hydroxy-l-prolyl-d-leucyl-trans-4-hydroxy-l-proline), 80% of the genome is transcribed into RNA transcripts (The
was identified through co-culturing of Phomopsis sp. K38 ENCODE Project Consortium: An integrated encyclopedia
and Alternaria sp. E33 (Rashmi and Venkateswara 2019). of DNA elements in the human genome 2012). Additionally,
In recent times, unique secondary metabolites like lovas- this technique is helpful to reveal the link between the genes
tatin and swainsonine have been identified from filamen- and pathways for the production of SMs. A differential gene
tous fungi. However, an integration of clustered regularly regulation study by Jain and co-workers reveals that G. luci-
interspaced short palindromic repeats-Cas9 (CRISPR/Cas9) dum MDU-7, a white-rot basidiomycete has several up- and
technique in omic tool has improved the production of bio- downregulated transcripts which eventually trigger the SM
synthesized SMs (Jiang et al. 2021). With the help of the pathway like terpenoids and polyketides. These polyketide
CRISPR/Cas9 tool, Wei et al. (2020) significantly enhanced synthase transcripts elongate polyketide products, which
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Table 4 Proteomic and secretomic tools used in secondary metabolite study
Tool and techniques Mechanism Applications References
2-D PAGE and Isoelectric focusing (IEF) Separation and identification of proteins by their Helps in the identification of posttranslational modi- Shankar et al. (2019)
charge-to-mass ratio fied natural protein and SM
MALDI-ToF/ToF Ionize biological molecule to identify their mass and Ionized biological sample gives all about the Shankar et al. (2019)
sequences molecular weight, protein sequence, and three-
dimensional structure of metabolites
Electrospray ionization-mass spectrometry (ESI- Elucidation of biological mass, amino acid Ionized biological sample gives all about the mass, Tsuchiya et al. (2020)
MS) sequences, and modified structure of peptides and sequence and three-dimensional structure
proteins
Systematic Evolution of Ligands by Exponential Isolate aptamers from different microbial targets, Deciphering the protein-DNA sequence specificity Liu et al. (2020)
Enrichment (SELEX) toxins, and chemical compound to address the fundamental biological query
Microchip Identification and separation of metabolites and their Highly applicable due to the requirement of less Shankar et al. (2019)
Capillary profiling sample, short analysis time, high-throughput capa-
Electrophoresis bility, low waste generation, and portability
2-D fluorescence difference gel electrophoresis Labeling and separation of one or more proteins by Done with comparative proteomics study by sepa- Vilasi et al. (2013)
(2D-DIGE) isoelectric focusing rating complex protein into simple component
Exponentially modified protein abundance index Comparative proteomic analysis performed to esti- Easy to applied in multi-dimensional proteomic Shinoda et al. (2010)
(emPAI) mate protein abundance separation-MS/MS
iTRAQ/LC-MS/MS Identify total protein with their differential regula- Widely used for quantitative proteomics, prediction Martinez-Gomez et al. (2012)
tion of SM production
Nano-flow liquid chromatography tandem mass Proteolytically digested proteins isolated by 2-D gel Robust tool in the qualitative and quantitative pro- Laatsch (2011)
spectrometry (nano-flow LC-MS/MS) electrophoresis tein identification
Stable isotope labeling by amino acids in cell cul- Identify targeted labeled protein from a large set of Applied for targeted protein quantification in vari- Wang et al. (2016)
ture (Absolute SILAC) samples ous biomedical research and clinical practices
LTQ-Orbitrap Identify and structurally characterize peptides in a More sensitive with higher accuracy then other Narayanan et al. (2010)
LC MS/MS highly complex sample mixture proteomic tools
Label-free LCMS/MS Total protein profiling in a single run with their Fast, low-cost, rigorous, powerful tools for analyz- Jain et al. (2020)
quantification ing protein changes in large-scale proteomics
studies
include secondary metabolites (Jain et al. 2020). Using Fungal secretomic study reveals many novel and func-
similar transcriptomic techniques, CRISPR-modified SM- tional SMs that help in the better understanding of their
producing pathway can be analyzed for required change in mechanism and enzymatic pathways. Due to the advances
expression at transcript level. in these proteomic and secretomic tools, the research out-
put of metabolic processes gives significant knowledge and
Proteomic and secretomic tools beneficial product in biotechnological and pharmaceutical
industries. The protein fractions of G. lucidum at devel-
The proteomic tools play a pivotal role in functional analy- opmental (16 days of mycelial grown stage) and fruiting
sis, as they give the knowledge at the peptide and protein bodies stages (60 and 90 days of mycelial stage) revealed
level, which is not indeed equivalent to the transcriptomic 803 proteins after LC-MS/MS analysis and explore against
information. Over a decade, proteomic tools have emerged genome database (Yu et al. 2015). Furthermore, proteomic
because of the huge transcriptome and proteome cloud data and sequence alignment studies suggested a unique immu-
availability (Jain et al. 2020). Also, bioinformatic advances nomodulatory protein (GL18769) with significantly high
have access to the detailed analysis of fungal biochemistry bioactivity. The proteomic and secretomic tools are impor-
(Kumar et al. 2021). Proteomic studies are required for the tant nowadays in the study of secondary metabolites due
analytical process of some techniques such as mass spec- to regular up-gradation in mass spectrometry data on the
trometry (MS), 2-D mass spectrometry, and matrix-assisted cloud is going on. Implementation of shotgun proteomic
laser desorption ionization-time of flight mass spectrometry approach in Aspergillus fumigatus detected 414 mycelial
(MALDI-TOF MS) that are involved in the SM identification proteins which were represented in 2-D protein interaction
and their analysis (Téllez-Téllez and Diaz-Godinez 2019). maps (Owens et al. 2014). Quantitative proteomic analy-
The proteomic study of P. chrysosporium revealed more than sis of different filamentous groups of Aspergillus spp. was
1100 intracellular and 300 mitochondrial proteins which checked and analyzed for various purposes, i.e., better pro-
concluded in the 2-D gel electrophoresis method, and their duction level of SMs, comparison to the metabolic process,
metabolic flux shift was checked by comparative proteomic and to know the involvement of the protein in SM production
tool (Rodarte-Morales et al. 2011). (Ma et al. 2021). However, recent secretome profiling of
Recently, the experimental methods have been updated G. lucidum by Jain and co-workers revealed 83 proteins in
from 2-D gel electrophoresis, mass spectrometry (MS), control and 142 proteins in the copper-induced supernatant.
MALDI to high-throughput tools like LC-MS/MS and They used the transcriptomic data as a referenced database
iTRAQ to study fungal metabolites, with improvement in for the unknown/ unreviewed peptide data in the protein
their analysis software and tools (Table 4) (Kumar et al. identification. Thus, the function of unknown peptides can
2017; Shankar et al. 2019; Jain et al. 2020). Till date, more be predicted (Jain et al. 2020). In secretome analysis, differ-
than hundreds of fungal genomes are publicly available ent white-rot fungi and other ascomycetes are analyzed as
(http://genome.jgi.doe.gov/programs/fungi/index; http:// well as their secretory protein and SMs; also, their functions
jgi.doe.gov/our-science/science-programs/fungal-genom were checked through gene ontology. They produce differ-
ics/r ecent-f ungal-g enome-e lease s/) by 1000 Fungal Genome ent lignin-, cellulose-, and hemicellulose-degrading enzymes
(1KFG) project (Sharma 2016). The LC-MS/MS tool pro- like laccases, cellulases, peroxidases, LiP, MnP, and other
vides data in spectral format, from which peptides and pro- related enzymes used by different biotechnologists and in
teins can be identified using tools such as Andromeda and pharmaceutical industries (Jain et al. 2020; Amer and Bai-
X!Tandem by utilizing referenced databases, i.e., 1KFG doo 2021; Kumar et al. 2021). In comparison to transcrip-
(Sharma 2016), UniProt (Apweiler et al. 2004), and Inte- tomics, better validation can be obtained from proteomics by
grated Microbial Genomes (IMG) (Hadjithomas et al. 2017). upregulation of required proteins in SM pathway.
Andromeda comes as a stand-alone tool or integrated into
MaxQuant open source software; it can handle many labe- Metabolomic tool
ling strategies and label-free quantification and 3D graphic
visualization. The resulted peptides can be used for gene Metabolomics analyzes metabolites, like small molecules
ontology (GO) analysis by Blast2Go and GOnet that provide of cells, tissues or organisms, and biofluids. This tiny frac-
profile of present proteins, enzymes, and pathways (Conesa tion of molecules and their interaction with the biological
et al. 2005; Pomaznoy et al. 2018). Differential expression system is called the metabolome. This tool is becoming
and pathway enrichment analysis can be performed on pep- very important for the researcher to collect information
tide data using limma (Ritchie et al. 2015), DESeq2 (Love regarding fungal SM characterization and their production.
et al. 2014), GSEA (Zito et al. 2021), and DAVID (Ziemert Moreover, it also provides opportunities to explore the new
et al. 2012). fungal ecological niches with many unknown SM diversi-
ties and their functional, as well as production properties.
13
Table 5 Bioinformatic tools and databases for SM study
3480
S. no. Name Functions URL References
13
1. Secondary Metabolite Bioinformatics Portal Database catalog and links of bioinformatic tool http://www.secondarymetabolites.org Palazzotto and Weber (2018)
(SMBP) for the secondary metabolite study
2. Antibiotics and Secondary Metabolite Analysis Web application and autonomous tool (LINUX, http://antismash.secondarymetabolites.org. Blin et al. (2013)
SHell (antiSMASH) MacOS and MS Windows) to mine and analyze
BGCs; include genomic tools and a homology-
based metabolic modeling pipeline
3. Natural Product Domain Seeker (NaPDoS) Tool for the rapid detection and analysis of second- http://napdos.ucsd.edu/run_analysis.html Ziemert et al. (2012)
ary metabolite genes to detect and classify KS
and C domains
4. NP.searcher Web application search tool (LINUX) to mine for http://dna.sherman.lsi.umich.edu/ Chavali and Rhee (2018)
PKS/NRPS BGCs
5. Genes to natural products/prediction informatics Cluster mining tool and analyze the pathway for http://magarveylab.ca/gnp/#!/genome Skinnider et al. (2017)
for secondary metabolomes (GNP/PRISM) PKS and NRPS http://magarveylab.ca/prism
6. Secondary Metabolite Unknown Region Finder Tool to mine PKS/NRPS/terpenoid gene clusters in www.jcvi.org/smurf/ Wang et al. (2016)
(SMURF) fungal genome
7. Cluster Finder Stand-alone tool (LINUX and MacOS) to detect https://github.com/petercim/ClusterFinder Chavali and Rhee (2018)
BGCs with secondary metabolite gene clusters in
genomic and metagenomic data
8. HMMER web server Identify ketosynthase domain and condensation http://hmmer.org/ Potter et al. (2018)
domain encoding genes in genomic and metagen-
omic datasets
9. XCMS Metabolomic data processing algorithm tool to https://xcmsonline.scripps.edu. Domingo-Almenara et al. (2018)
extract metabolic features from raw MS data and
perform statistical analysis.
10. iSNAP Web tool which automatically identify metabolites http://snap.cifr.ncsu.edu Baptista et al. (2022)
in MS/MS data based on genomic data
11. CLUsterSEquenceANalyzer (CLUSEAN) Web accessible database of PKS/NRPS BGCs and http://bioserv.pbf.hr/ Chavali and Rhee (2018)
annotation pipeline for secondary metabolite http://csdb.bioserv.pbf.hr/
biosynthetic gene clusters.
12. Minimum Information about a Biosynthetic Gene Web tool for annotations and metadata on biosyn- https://mibig.secondarymetabolites.org/ Bian et al. (2020)
cluster (MIBiG) thetic gene clusters and their molecular products.
13. EvoMining approach Stand-alone tool for phylogenomic approach of (https://github.com/nselem/evomining/wiki) Sélem-Mojica et al. (2019)
cluster identification
14. Integrative meta-analysis of expression data Web-based tool to support meta-analysis of multi- http://www.inmex.ca Xia et al. (2013)
(INMEX) ple gene expression datasets
15. Metscape 2 Web tool for the analysis and visualization of http://metscape.ncibi.org Rosato et al. (2018)
metabolomics and gene expression data and visu-
alize changes in the gene/metabolite data.
16. Crux MS analysis toolkit that combine computational, https://crux.ms/ McIlwain et al. (2014)
machine learning and statistical methods for
proteomics analysis
The metabolomics makes an ideal tool for the biotechno- more than 18,000 natural products from the Mass Bank
logical industry, agricultural industries, and pharmaceuti- (Horai et al. 2010), ReSpect (Sawada et al. 2012), and
cal and healthcare products; therefore, biomarker products NIST (http://www.nist.gov/srd/nist1a.cfm) databases that
and drug safety issues are two examples where metabo- also provide tools for metabolite identification, quantifica-
lomics has started making products and other testing kits. tion, and analysis.
In the metabolome study, two complementary processes As mentioned earlier, genes of SM pathway identified in
are mainly used for SM profiling, i.e., (a) targeted and (b) wild strain through genomic study and edited using CRISPR/
untargeted approaches. In targeted approaches, a fixed set Cas9 technology can be further verified at transcriptome
of known metabolite compound is analyzed which mainly level for successful transcription of pathway genes (i.e.,
confirms the absolute quantification and, in untargeted pro- no random splicing) and at proteomic level for scrupulous
filing, it detects all the compounds and shows the potential translation into peptides (i.e., no silencing at translational
of total metabolic profile, including unknown substance. level). Finally, successful production of targeted SM can be
Therefore, untargeted approaches are mainly preferred to identified using LC/QqQ/MS, and structure validation can
detect the change in metabolome, and it is leading in the be done by NMR (Fig. 4).
scientific field. The MS/MS-based tools are used under
the untargeted approaches where GC-MS and LC-HRMS Bioinformatic tools: integration of artificial
are the best techniques for the analysis of complex SMs intelligence and machine learning
produced by filamentous fungi (Klitgaard et al. 2014).
Many technologies like high-resolution mass spectrom- In the past, many analytical and chemical processes gave
etry, liquid chromatography with tandem mass spectrom- access to natural products; nowadays, genomics, proteomics,
etry (LC-MS/MS), nuclear magnetic resonance (NMR), and metabolomic tools provide a complementary approach
and metabolite mass spectrometry imaging (MSI) have to identify and characterize the molecules. These compli-
increased the scope of metabolomic tool to detect many mentary tools come alone with several computational tools
unknown compounds. Liquid chromatography-ultraviolet that together form system biology. Several important com-
(LC-UV), ultra-high performance liquid chromatography putational challenges have appeared after the emergence of
(UHPLC), LC-MS/MS, and GC-MS are highly sensitive next-generation sequencing tools including 454, Illumina,
detector machines with tremendous selectivity (like physi- SOLiD, and ion semiconductor. Upgrading of this tool for
cal compound separation by chromatographic technique secondary metabolite and the natural product study has gen-
and co-eluting separation of analytes through m/z ratio of erated large datasets with hundreds and thousands of MS and
an ionized molecule), which determine hundreds of meta- MS/MS spectra (Table 5). In practice, online data bank has
bolic compounds in a single run (Klitgaard et al. 2014; El- been updated with microbial data that are related to metabo-
Elimat et al. 2021). For targeted metabolite analysis, tool lite studies like MIBiG, a BGC repository that has a database
such as liquid chromatography triple quadrupole tandem for 206 fungi and 1196 bacteria BGCs (Kautsar et al. 2020),
mass spectrometry (LC/QqQ/MS) gives result by applying and ClusterMine 360 is a peptide database that contains gene
triple-stage quadrupole mass spectrometers (QqQ/MS) by cluster domains for microbial polyketide synthase (PKS)
operating in selected or multiple reaction monitoring (S/ and non-ribosomal peptide synthetase (NRPS) biosynthe-
MRM) mode (Thadhani et al. 2021). ses (http://www.clustermine360.ca/) (Cruz-Morales et al.
Earlier, the most accessed and frequently used tech- 2016). Furthermore, many web accesses portal and database
nique for untargeted metabolomics was liquid chromatog- search engines have played a key role in the bioinformatic
raphy with high-resolution mass spectrometer (LC-HRMS) tool (Table 5). Bioinformaticians have designed tools using
which annotates the compound and confirms the function biological data, data mining approaches, mathematics, sta-
with similarly structured compound data from the respec- tistics, and machine learning. Many machine learning algo-
tive database. Furthermore, it also predicts the molecu- rithms are designed to run the online database of bacterial,
lar formula by comparing accurately measured masses fungal, and other human genome data to predict the results
with the well-known databases like Chemical Entities of used in the biotechnological and pharma fields (Fig. 1). The
Biological Interest (ChEBI) (Degtyarenkoet al. 2009), most frequently used machine learning algorithms applied
PubChem (Kim et al. 2016), and AntiBase 2014, which for biological data analysis include artificial neural networks
have comprehensive database of more than 40,000 natural (ANNs) (Almeida et al. 2019), Naive Bayes (Quinlan 1993),
compounds from bacteria and fungi (Laatsch 2011). In support vector machine (SVM) (Huang et al. 2018), C4.5
silico software, Global Natural Products Social Molecular decision tree (Quinlan 1993), k-nearest neighbors (KNN)
Networking (GNPS) system, is a general web-based mass (McKinney et al. 2013), and regression (Zeng and Lumley
spectrometry ecosystem that has an open access library 2018). Majorly, two different strategies are used in the in
which shares approx. 220,000 MS/MS spectra that confirm silico tool, where best approaches are used to identify the
13
biosynthetic gene clusters (BGCs), in which the data mining using this bioinformatic tools (Chavali and Rhee 2018). Cur-
process identifies genes with their conserved enzymes that rently, in metabolite prediction study, data reflected with
are linked with secondary metabolism, whereas the second high false-positive results with low reliability while studying
strategy is used for the identified hits with different classes specific enzyme system. To overcome this issue, a method
of natural product confirmation. was designed by Wang and their co-workers that established
Comparative interactomic outlook is a robust alterna- a broad coverage of the SMARTS-coded metabolic reac-
tive approach for discovering modules and their pathways tion rule database. This intelligence tool could suggest the
across all cellular and metabolomic networks using SVM optimal metabolic reaction with accuracy rate of 70% (Wang
and ANN. Genomic and proteomic sequences of fungal spe- et al. 2016). The use of metabolomics and AI learning tool
cies are used to integrate protein annotation into network in the mycotoxins study proposed the best linkage of afla-
analysis, potential signals, and different metabolic regulatory toxins and their biomarkers which is an example of poten-
pathways. These sequences are modeled as complex network tially emerging mycotoxins. Recently, Xie and co-worker
patterns that help in metabolite production and their applica- introduced the XGBoost algorithm tool into the global food
tion in many medical as well as industrial areas. Probabilistic safety risk management. It will be used in the prevention and
models have integrated network and expression data from control of mycotoxins by analyzing novel biomarkers associ-
gene knockout expression studies to predict cell-signaling ated with aflatoxigenic Aspergillus species using population
cascades (Palazzotto and Weber 2018). Many pipelines metabolomics and machine learning tools (Xie et al. 2022).
have been developed earlier for the study of the microbial
products like Antibiotic Resistance Target Seeker (ARTS)
using deep learning and Fungal Resistance Gene-directed Future prospects and conclusions
Genome mining (FRIGG), and Crux (https://www.cruxi
nforma tics.c om/) is a mass spectrometry analysis toolkit that The multi-omic concept is still rooting in the area of fungal
provides multiple machine learning based tool for tandem biology. The beauty of the fungal omic tools is to clarify
mass spectra analysis, statistics, and visualization (McIlwain the cellular, molecular, and biological processes and give
et al. 2014; Stahlecker et al. 2021). These tools represent a response at different levels of Crick’s central dogma of
recent progress in many microbial aspects, including RNA molecular biology (DNA, RNA, and protein). The appli-
sequencing analysis, comparative proteomics, metagenom- cation of modern highly sophisticated tools mentioned in
ics, and developments of new computational workflows in this review highlights deep analysis, and many other essen-
fungal physiology and biology (Xiao et al. 2017). Capec- tial metabolic engineering approaches help to enhance the
chi and Reymond (2021) classified the natural product as a knowledge in the improvement of industrial as well as phar-
resource of new drug discovery where they reported the Col- maceutical bioproducts. Multi-omic research tool gives a
lection of Open Natural Products (COCONUT) database, a better way for self-accepting and validating the results
database assigned for bacteria, fungi, and plant SM products, through the use of combined or parallel tools that acceler-
and trained machine learning tool (MAP4 SVM -https://np- ate the understanding of complex raw data and help in the
svm-map4.gdb.tools/) that predicts the presence of plant, development of engineered metabolites of biotechnological
bacterial, or fungal SMs. importance.
Artificial intelligence is a complex network and layer Bioinformatic-assisted fusion of different omic tools
of multiple machine learning algorithms resembling brain which make a pipeline to form machine learning program
neurons. The deep neural network (DNN) implements in a needs to accept the challenges posed from different datasets
machine learning tool. It is a robust approach for the omic of sample size, sample quality, small sample analysis pipe-
tool’s classification, regression, and other statistical dis- lines, and data formats for many fungal or other selected
ciplines. Another emerging concept, meta-learning, i.e., raw data. The recent trend is followed by an updated multi-
“one’s learning and learning processes,” is fundamental in omic tool which forms a bridge between wet-lab work and
the transfer of learning from one situation to another. Meta- computational tools in the basic and applied research area.
learning enables an automated way to optimize the DNN In this review, many web servers are mentioned, which can
and save incredible human effort and time. A significant explore diverse tools and databases in one stop for SM study.
number of machine learning methodologies and system Overall, the development of multi-omics and big data, and
biology prediction tools are used in novel pharmaceutical many other integrated tools such as CRISPR/Cas9, artificial
product development. AlphaFold software, using artificial intelligence, and machine learning tools, are involved in the
intelligence, predicts 3D protein structure only based on its genomic, transcriptional, as well as translational study of
genetic sequence; provided whole genome as input, it can fungal primary and secondary metabolomes, which will lead
predict all the proteins in genome (Jumper et al. 2021). Fur- to the advancement in the understanding of fungal biology
thermore, definite metabolism site has also been reported and its products. In the era of multi-omics, it is time to shift
13
our focus on the precise prediction of fungal metabolites; nutraceutical and therapeutic potential. Molecules 25:2735.
therefore, the structural spectral fingerprints are collected https://doi.org/10.3390/molecules25122735
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ture and cloud computing resources to efficiently analyze advanced and diverse technologies to explore emerging fungal
pathogens and define mechanisms of antifungal resistance. MBio
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achieve coherence with multiple organizations, like univer- Baptista RP, Li Y, Sateriale A, Sanders MJ, Brooks KL, Tracey A,
sities, pharmaceutical industries, data resource centers, and Ansell Brendan R.E., Jex AR, Cooper GW, Smith ED, Xiao R,
government-funded research institutes. Dumaine JE, Georgeson P, Pope BJ, Berriman M, Striepen B,
Cotton JA, Kissinger JC (2022) Long-read assembly and com-
parative evidence-based reanalysis of Cryptosporidium genome
Acknowledgements The authors acknowledge the Maharshi Dayanand sequences reveal expanded transporter repertoire and duplica-
University, Rohtak, Haryana, India, for infrastructural support. They tion of entire chromosome ends including subtelomeric regions.
also acknowledge Biorender.com for the figure presentation. AS also Genome Res 32(1):203–213. https://doi.org/10.1101/2021.01.
acknowledges Maharshi Dayanand University, Rohtak, Haryana, for 29.428682
University Research Fellowship. Berovic M, Podgornik BB (2019) Engineering aspects in production
of various medicinal mushrooms biomass in submerged bioreac-
Author contribution KKS conceived and designed the manuscript. tors. Int J Med Mushrooms 21(8) https://doi.org/10.3390/molec
AS wrote and formatted the manuscript. KKS read and approved the ules17032714
manuscript. Bian Y, Zheng R, Bayer FP, Wong C, Chang YC, Meng C, Zolg DP,
Reinecke M, Zecha J, Wiechmann S, Heinzlmeir S, Scherr J,
Funding This work was supported by DST-FIST grant, Government Hemmer B, Baynham M, Gingras AC, Boychenko O, Kuster B
of India. (2020) Robust, reproducible and quantitative analysis of thou-
sands of proteomes by micro-flow LC–MS/MS. Nat Commun
Data availability No data is associated with the manuscript. 11(1):1–12. https://doi.org/10.1038/s41467-019-13973-x
Blin K, Medema MH, Kazempour D, Fischbach MA, Breitling R,
Takanoet E (2013) antiSMASH 2.0–a versatile platform for
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Acids Res 41:W204-12. https://doi.org/10.1093/NAR/GKT449
Declarations Bogale TT (2020) Biotechnological applications of white rot fungi: a
review. GSC Adv Res Rev 52:097–103. https://d oi.o rg/1 0.3 0574/
Ethics approval Not applicable. gscarr.2020.5.2.0043
Brazma A, Hingamp P, Quackenbush J, Sherlock G, Spellman P,
Consent to participate Not applicable. Stoeckert C, Aach J, Ansorge W, Ball CA, Causton HC, Gaas-
terland T, Glenisson P, Holstege FCP, Kim IF, Markowitz V,
Consent for publication Not applicable. Matese JC, Parkinson H, Robinson A, Sarkans U, Schulze-Kre-
mer S, Stewart J, Taylor R, Vilo J, Vingron M (2001) Minimum
Competing interests The authors declare no competing interests. information about a microarray experiment (MIAME)-toward
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Fungal Secondary Metabolites in Food and Pharmaceuticals in The Era of Multi Omics

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Applied Microbiology and Biotechnology (2022) 106:3465–3488

Fungal secondary metabolites in food and pharmaceuticals in the era

Keywords Fungal metabolites · Multi-omics · Transcriptomic · Metabolomic · Machine learning

Introduction SMs are differentially structured organic compounds mainly

Fig. 2 Scheme to screen and isolate novel fungal secondary metabolites

abadia, and L. edodes

Phanerochaete chrysosporium: model in white‑rot Pleurotus ostreatus: oyster mushroom of order

Phanerochaete chrysosporium is a white-rot filamentous Pleurotus is a white-rot basidiomycete group of fungi,

G. lucidum Polysaccharides- (β-D- Total 71 Anti-tumor effects, (Baby et

glucans, Galactose, proteins were immunomodulator al. 2015;

Mannose, Arabinose, identified and y, anti-angiogenic, Xu et al.

Rhamnose, Fructose) classified and cytotoxic 2017)

Triterpenoids Arabinose Rhamnose Fructose functionally, effects

(Ganoderic acids- A, B, 430 SMs were

cerevisterol, lucidenic extracted;

triterpenes, methyl (380), steroids

ganoderate A acetonide Methyl ganoderate (30),

Pleurotus Linoleic acid, oleic Total 87

eryngii acid, trans 3,4-dihydro- proteins were

acid, uracil terpenoids (4),

fatty acid (8)

and phenols (2)

Total 181 Antimicrobial

proteins were effect, Antitumor

Total 123 Anti-inflammatory

protein and effect, Antifungal

Schizophyl Carotenoids, indole Total 229 Antimicrobial (Tel-

lum derivatives, flavonoids, proteins, 16 activity, Çayan

lyases were Antiviral, Anti-

Flavonoids identified inflammatory

Gloeophyll Sesquiterpenoids, Total 109 Antioxidant

um trabeum (3Z,6Z,8E)- proteins and activity, Anticholin

There are six important classes of SM compounds Terpenoids

S. no. Name Functions URL References

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