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10.2 Classification of PSMs 191
the most abundant and structurally diverse natural compounds identified in plants, naturally occurring PSMs present in plant and flower essential oils. Terpenoids are found
primarily in plants and flowers, and essential oils containing terpenoids are used in perfumery and traditional medicine. Terpenoids can be present in varied plants and
flowers, including eucalyptus, cinnamon, cloves, ginger,
sunflowers, and tomatoes. Salvia divinorum, cannabis, and
Ginkgo biloba are examples of plants rich in terpenoids.
Terpenoids present a diverse range of complexity and biological functions. They occur naturally in plants and play a
protective role in them [10, 12].
Terpene synthases are cloistered from a diverse range of
plant species, including gymnosperms and angiosperms.
Thapsia laciniata has eight monoterpene and five sesquiterpene synthases, somewhat more than Arabidopsis thali-
ana and Artemisia annua. In addition, multiple
sesquiterpene synthases from maize have been cloned and
studied. Finally, plants and flowers are the primary natural
sources of terpenoids, and essential oils containing these
compounds are used in a range of industries. Terpenoids
are a sizable class of natural chemicals with varied chemical properties and applications. They are formed from isoprene and its derivatives and are classified into seven types
based on their carbon skeleton: hemiterpenes, monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, triterpenes, and tetraterpenes (carotenoids). Terpenes have the
same underlying five-carbon isoprene unit. Terpenoids are
terpene derivatives that contain oxygen molecules, resulting in different chemical properties and bioactivities. They
neutralized free radicals, prohibiting inflammation and
ulcers. Terpenoids, on the basis of special properties (antiinflammatory and antioxidant), can reduce reactive oxygen
species (ROS) and malondialdehyde (MDA) production
while enhancing superoxide dismutase (SOD) activity in
radical scavenging [10, 13].
Terpene synthases are responsible for the creation of terpenoids, and small changes in their design can result in
unique catalytic properties. The traditional route mostly
produces sterols, sesquiterpenes, and ubiquinones, whereas
the nonmevalonic acid pathway produces hemi-, mono-,
sesquiterpenes, and diterpenes, as well as carotenoids and
chlorophyll’s phytol tail. Many terpenoids have biological
characteristics and are used in medicine. Artemisinin, vincristine, and taxol, for example, are used to treat malaria
and cancer, whereas triterpenoids discovered in Momordica
charantia and Elephantopus scaber have antidiabetic properties. Cortistatin from the sea has significant antiangiogenic properties and may be useful in cancer and macular
degeneration treatment. Terpenoids are frequently utilized
in industrial applications, such as flavors, fragrances, and
spices, as well as perfumery and cosmetics. They are commercially available and synthesized in the pharmaceutical
and chemical industries, and their applications range from
increasing titers of value-added terpenoids to providing a
platform for overproduction and broadening the chemical
diversity of terpenoids [13].
10.2.3 Phenolic Compounds
PSMs containing a phenol moiety are chemically categorized
as (a) phenolic acids, (b) flavonoids, (c) tannins, (d) coumarins, (e) lignans, (f) quinones, (g) stilbenes, and (h) curcuminoids. The majority of soluble phenolic compounds
(PCs) are produced in plants’ endoplasmic reticulum and further stored in vacuoles. Phenolic chemicals differ from one
another by having at least one phenol unit, which is a benzene
ring with a hydroxyl group. Plant PC may be soluble or bound.
The transport of soluble PC to the cell wall causes the formation of bound PC, which are then conjugated with cell wall
macromolecules, such as cellulose and protein via ester and
glycosidic bonds, assisting in cell wall construction. PC are
present in all plant-based foods, beverages, fruits, and byproducts. Plant materials include phenolics, which are antibacterial, anti-inflammatory, and antimutagenic, among other
things. They demonstrate antioxidant and antimicrobial
activities [14, 15, 16]. Furthermore, highly oxidized phenolic
molecules can act as inhibitors, whereas pyrogallol and catechol, hydroxylated PC, are toxic to microorganisms.
Examples with unusual names are vanillin, hydroquinone,
salicylic acid, hydroquinone, pyrocatechol, resorcinol, cresol,
and eugenol [17]. PC are a broad category of phytochemicals
that may be classified into subgroups based on their chemical
structures. Flavonoids, phenolic acids, and polyphenols are
the three most significant types of dietary phenolics, with flavonoids being the biggest and most well studied category of
plant phenols. Phenolic acids, on the other hand, constitute
60% of total dietary PC and are classified into many groups,
including hydroxybenzoic and hydroxycinnamic acids [15,
18]. There are five major groups of PC found in fruits, which
include:
1. Flavonoids: flavonoids account for 30% of total die-
tary PC [15].
2. Tannins: phenolic polymers, often known as tannins,
are high-molecular weight molecules that may be
divided into two types: (a) hydrolyzable tannins and
(b) condensed tannins [14, 18]. Tannins have the
capacity to bind proteins and are extensively dispersed
throughout the plant world.
3. Phenolic Acids: the phrase refers to PC with one car-
boxylic acid group. The most frequent plant PCs are
phenolic or phenol carboxylic acids (also known as
polyphenols). Plant-based foods contain them in high
quantities, with seeds, fruit skins, and vegetable leaves
being the most abundant [19].
192 10 Classification and Therapeutic Applications of Plant Secondary Metabolites
4. Stilbenes: stilbenes are phenolic chemicals found in
plant groups, such as Vitaceae, Leguminaceae, Gnetaceae,
and Dipterocarpaceae. They have a C6-C2-C6 backbone
and normally have two isomeric variants [20].
5. Lignans: lignans are phenolic dimers having the
structure 2, 3-dibenzylbutane. These compounds are
known to appear as minor constituents in many plants,
where they act as the basis for lignin formation in the
plant cell wall. The compounds are often present in
glycosidic form [18].
These compounds exhibited a variety of positive health
impacts, which consist of antibacterial, anti-inflammatory,
and antimutagenic activity. In conclusion, PC are a vast
and varied category of phytochemicals that may be classified into subgroups according to their chemical structures,
with flavonoids and phenolic acids being the most frequent
PC consumed [15].
PCs are organic molecules with a phenol functional group,
giving them distinct physical and chemical properties.
Because of their polar properties, phenols have higher boiling points than alcohols. Because the phenol group can form
hydrogen bonds with water molecules, it is more soluble than
alcohol, uncolored liquids, or white solids at room temperature that can be highly toxic and corrosive. These compounds
have a wide variety of industrial applications. Wood preservatives contain PCs mixes known as cresols, whereas substituted PCs are utilized in dye sector to produce colored dyes
(azo). PCs also make plastics, explosives, pharmaceuticals,
and colors. Hydroquinone, a phenolic chemical, is employed
in the photographic developing process [16]. When PCs mix
with alcohols, they can undergo etherification reactions,
yielding the appropriate phenolic ether. This reaction can be
utilized to produce unique molecules with specific properties. PC can also undergo etherification reactions with
alkylating agents to form ether. These reactions are significant in organic synthesis and commercial applications
because they enable the incorporation of additional functional groups into a molecule [14].
10.2.4 Glycosides
Glycosides are naturally occurring chemicals found in varied plant groups that play critical roles in living organisms.
A glycoside is a chemical with a sugar linked to another
functional group by a glycosidic bond. They are also known
for antioxidant, antibacterial, antifungal, anti-inflammatory, antiviral, and anticancer effects. Plants are capable to
store chemicals as inactive glycosides, which can be activated via enzyme hydrolysis and also used as medications.
Glycosides are naturally occurring molecules made up
of a carbohydrate and a hydroxy component, containing
carbohydrates, such as cellulose, glycogen, or starch.
The carbohydrate component is commonly composed of
one or more sugars or uric acid, whereas the hydroxy component is composed of a non-sugar substance or another
carbohydrate. There are more than 11 distinct kinds of glycosides that include anthraquinone, cardiac, chromone,
coumarin, cyanogenic, flavonoid, saponin, steroidal, and
steviol glycosides. Glycosynthases are enzymes capable of
forming vast numbers of glycosidic linkages. Hydrolysis of
glycosides in the presence of acid or alkali can separate
them into glycone and aglycone components. The most
prominent enzymes involved in glycoside cleavage are glycoside hydrolyses, while the most significant enzymes
involved in glycoside synthesis are glycosyltransferases
(GTs). Glycosides may be O-, N-, or S-linked, as well as glycosidic [22, 23, 24]. Glycoside hydrolysis produces a sugar
hemiacetal or hemiketal as well as a free aglycon. Some
enzymes can hydrolyze – linkages, whereas others can
affect them. The orientation of the glycosidic bond determines whether glycosides are – glycosides or – glycosides
[22, 25]. Anthocyanins, for example, are glycosides that are
frequently found in flowers and fruits. Senna, rhubarb, and
aloe all contain glycosides. Glycosides are predominantly
found in dicot plants, with the exception of the monocot
family Liliaceae. They also possess laxative effects. The kind
of glycoside, such as glucoside, fructoside, and glucuronide,
is determined by the class of glycone, with biosides being a
type of glycoside with a disaccharide glycine [22, 24].
Glycosides can be categorized in a variety of ways, depending on the context. Glycoside hydrolyses, which break down
glycosides, are classified into more than 100 classes based
on sequence similarities. Carbohydrate-active enzymes
(CAZy) database includes over 160 GH families, each with
proteins connected by sequence and fold. In the CAZy database, the bulk of plant-glucosidases are classed as glycoside
hydrolase family 1 (GH1), with a few classified as GH families 5 and 30. All of them are members of GH Clan A. The
catalytic apparatus and molecular mechanism are substantially constant throughout most glycosidase families, with
the mechanism used remaining consistent within a GH
family. In addition to classification based on exo- or endoenzymes, they can be classified as inverting or retaining
enzymes based on how they respond. Categorized ones
employ a NAD-dependent hydrolysis mechanism, whereas
the GH97 family includes both retaining and inverting
enzymes. The glycoside classification is always available via
the CAZy database [25, 26]. Glycosides are substances that
have a sugar molecule bonded to another molecule, which
is often not sugar. Natural plant-derived glycosides have
been utilized in several medical applications, but further
study into their biological effects, bioavailability, and
metabolism is needed before they may be used clinically
to prevent or cure disorders. The N-glycan content of
10.2 Classification of PSMs 193
plant-produced recombinant enzymes may be precisely
regulated with genetically modified plants, demonstrating
glycosides’ promise in biotechnology applications [27].
Dietary glycosylated anthocyanins are absorbed intact and
can penetrate the blood-brain barrier to reach multiple
brain regions. In the small intestine, the enzyme SGLT1
absorbs quercetin glycosides. Understanding glycosides’
chemical and physical properties is crucial for maximizing
their therapeutic value [26, 28].
10.2.5 Tannins
Tannins are naturally occurring polyphenolic chemicals
classified as PC in many plant species, including flowering plant groups and coniferous trees. They are insoluble
and resistant to disintegration, which makes them longlasting. Tannins can be detected by texture and maturity
characteristics, and they can seep out of plants, creating
tannin-rich soil water with a dark color and a tea-like
appearance. Tannins are large molecules that easily
interact with proteins, cellulose, carbohydrates, minerals, and saliva. They are complex chemical compounds
derived from phenolic acids that have been investigated
and examined [29, 30, 31]. However, current research
suggests that tannins substantially impact the efficiency
with which nutrients are transformed into new body
components. Tannins, which are water-soluble polyphenols found in a variety of plant foods like grape skins,
stems, and seeds, contribute to the flavor and structure of
the wine, as well as its bitterness and astringency [30, 31,
32, 33]. Tannin-rich foods are thought to have little nutritional value while associating with some ailments, such
as esophageal cancer, when ingested in tannin-rich foods
like betel nuts and herbal teas. Tannins may be found in
many places, including plants, meals, and drinks [31,
33]. Tannins come from grape skins, seeds, stems, wood,
and winemaking additives [30]. Tannins from wood are
absorbed by wines aged in oak barrels [5, 34]. Clay-rich
soils add to the tannins in wine grapes, which causes
astringency. Tannin can also be present in coffee and
chocolate. The majority of human tannins are derived
from tea and coffee [33, 34]. Tannins may be present in a
variety of fruits, including apple, grape, and berry juices,
as well as beer and legumes [29, 34]. The tannin content
of legumes varies; red beans have the most tannin, while
white beans have the least. Peanuts without shells have
very low tannin levels. Tannins are generated during fermentation when juice, skin, and pips macerate together
in oak barrels which are used to age red wine [29, 31, 34].
The longer the maceration period during and after fermentation, the more tannic the finished wine. Wooden
fermentation and aging containers can be a source of
tannins in wine. Tannins can also be added to juices and
ciders to make them more astringent. Tannic acid is utilized as an aroma component and clarifying agent in
alcoholic and soft beverages or juices. The shape of tannin molecules can vary significantly depending on their
source. Overall, tannins are a diverse group of chemical
substances that can be found in a wide range of sources.
Tannins are polyphenolic macromolecules found naturally in plant components, such as seeds, bark, wood,
leaves, and fruit skins [30, 34, 35]. They are complex chemical molecules composed of phenolic acids and categorized
as PC [29] prominent for astringent flavor and able to bind
and precipitate proteins and other molecules. These chemicals successfully prevent herbivores and insects in woody
blooming plants [36]. Tannins division as hydrolyzable tannins include gallic acid or ellagic acid esters that react with
glucose or other polyols to create the necessary sugar and
phenol while condensed ones are polymers made up of
flavan-3-ol molecules connected by carbon−carbon bonds.
Many foods and beverages contain tannins, including tea,
coffee, grapes, and wine. Tannins in wine can be found in
grape skins, seeds, stems, oak, and other components. Skin
tannins get bigger as a result of polymerization [30, 31]. It
is critical to underline that tannins are essential components that add to wine’s distinct flavor, and wine aficionados must understand them [33, 37].
10.2.6 Saponins
Plants, certain bacteria, and lower marine species create
saponins; which are surface-active glycosides. Saponins
are found in many plants, but only a handful are harmful
to mammals. Saponins are molecules that include a steroid or triterpenoid aglycone attached to one or more oligosaccharide moieties having bitter taste with astringency
of plant materials, hub of natural plant chemicals, and
their name stems from their capacity to produce soaplike foams in water. Saponins can form insoluble compounds with iron, zinc, and calcium. Saponins often have
a carbohydrate side chain attached to the sapogenin’s
three carbons. Saponins have hemolytic and foaming
effects. Cholesterol in the diet can counteract the negative effects of saponins, although saponins themselves
may benefit by reducing serum and tissue cholesterol
levels in experimental animals. Saponins with diverse
biological as well as pharmacological properties and are
key active principles in folk medicine, particularly traditional Chinese medicine. Chemical synthesis provides a
potential alternative to the use of natural saponins in
medical research and development with reference to folk
medicine [38, 39].
194 10 Classification and Therapeutic Applications of Plant Secondary Metabolites
Saponins are glycosides of triterpenes and steroids that
exist in a variety of forms. Members of the soyasaponin family can be found in a variety of agriculturally important legumes, including soybeans. These soyasaponins appear in
mono- and bisdesmosidic forms and have a pentacyclic
oleane triterpene structure. Another kind of saponin discovered is avenin. The addition of a γ-pyronyl group alters the
terminal monosaccharide of the C-22 sugar chain in several
bisdesmosidic legume saponins. Chromosaponin I, a
γ-pyronyl saponin found in soyasaponins, has been shown to
enhance plant development via controlling auxin influx.
Glycyrrhizin is a triterpenoid saponin produced from licorice
that has a variety of medical purposes and is also used as a
food sweetener. The primary bioactive components of ginseng are triterpenoid ginsenoside saponins, whereas avidins
are triterpenoid saponins derived from the Acacia victoriae
tree that exhibit antitumor activity and a variety of physiological effects in mammalian cells [40]. Overall, saponins are a
varied class of chemicals with numerous biological functions
and potential medicinal applications.
Saponins are natural chemicals found in numerous
plants, including food crops, such as soybeans and potatoes. They have a wide variety of biological activity and
play important ecological roles, from plant pest defense to
cholesterol-lowering properties in humans. Interestingly,
saponins are also found in fish-killing plants like the soapberry plant, which is used for fishing by cultures all over
the world [40, 42]. These saponins act as natural detergents, reducing the surface tension of water and causing
fish to suffocate. Saponins, due to their amphipathic
nature, can form micelles with hydrophobic molecules,
such as cholesterol, causing emulsification and solubilization. As a result, saponins have been researched for their
potential application as emulsifying agents in the food
business and as drug delivery systems in the pharmaceutical sector. Saponins are a fascinating subject of research
due to their richness and diversity in nature, as well as
their potential uses in a variety of industries.
10.3 Biosynthetic Pathways
PSMs are created in minute amounts to reduce metabolic
costs, and their production paths are intricate and dynamic.
More than a million PSMs have been identified in terrestrial
and aquatic plants, indicating the variety of these molecules.
Plant secondary metabolite biosynthesis generates a diverse
spectrum of specialized chemicals that serve a variety of purposes, including herbivore defense, pollinator attraction, and
environmental tolerance. Secondary metabolism in plants
employs biosynthetic enzymes derived from basic metabolic
processes to synthesize complex molecules with varied structures and activities. Secondary metabolism is generally less
well known than primary metabolism, necessitating interdisciplinary and cross-disciplinary research collaborations to
investigate the synthesis of PSMs [3, 43]. The usage of PSMs
is crucial for sustainability and efficiency, demanding the
study of their production pathways. In legumes, for example,
isoflavone synthase, an enzyme that converts naringenin to
genistein glycoconjugates, is involved in the production of
isoflavone phytoestrogens. Metabolite profiling can help us
understand the pathways of PSMs production, as evidenced
by transgenic Arabidopsis plants containing the enzymes isoflavone synthase and chalcone isomerase. Furthermore, jasmonates have been shown to have a significant role in
initiating de novo transcription of related genes, such as phenylalanine ammonia-lyase, in the production of PSMs. The
tricarboxylic acid cycle route produces nitrogen-containing
molecules, while the mevalonic pathway produces terpenes
and the shikimate pathway produces phenolic chemicals
[44]. Thus, more comprehensive metabolite profiling methodologies may provide further information on changes in
metabolic flux produced by heterologous overexpression of
enzymes involved in plant secondary metabolism [3].
10.4 Environmental Factors Affecting PSMs
Environmental conditions have an important influence
with reference to the formation of PSMs, such as salt works
as a stressor in plants, inducing secondary metabolite production. Plants produce PSMs in response to salt, and a disturbance in one environmental element may affect the
quantity of these metabolites even if other parameters
remain consistent [45]. The shikimate pathway and the aromatic amino acids it produces are important precursors.
Light, temperature, soil, water, soil quality, and salt are
some environmental factors that affect secondary metabolite deposition in plants. Abiotic and biotic elicitors in culture systems promote the synthesis of PSMs. During the
stress response, plants create PSMs that function as herbivore deterrents, pathogen barriers, and oxidative stress regulators. Furthermore, stress activates the shikimate
pathway, which produces tryptophan, tyrosine, and phenylalanine, boosting secondary metabolite production.
Furthermore, the buildup of PSMs in response to stress is
molecularly controlled by multiple genes and transcription
factors. The amount of stress is proportional to the various
PSMs accumulation in different plant sections [44]. Cell
wall modifications can stimulate the creation of PSMs in
cell cultures. The major four ranks of PSMs comprised of
10.6 Role of Enzymes in Plant Secondary Metabolite Production 195
terpenoids, PC, alkaloids, and sulfur-containing substances,
and elicitors or feeding precursors can increase their formation. PSMs have a variety of physiological and ecological
effects, including antibacterial, attractant/repellent, and
deterrent properties. Temperature, light, and metals might
be strong factors to restore the PSMs formulation, and aluminum exposure affects caffeine production in Coffea ara-
bica cell cultures. In vitro cell cultures are a great technique
to study biochemical and metabolic processes under carefully regulated environmental conditions [46].
10.5 Genetic Factors Affecting PSMs
Several genetic mechanisms control plants’ secondary
metabolite synthesis. Transcriptional factors (TFs) influence downstream gene expression in plant defense pathways. They sense stress signals and turn on downstream
defense genes [47]. Mutations in the MEDa/b gene impact
critical components of a large multisubunit transcriptional
complex that controls phenylpropanoid biosynthesis genes.
These genes are critical for the synthesis of PSMs during
stress. Mutants that lack the atypical myrosinase PEN2,
which is involved in glucosinolate breakdown, produce
less Trp-derived metabolites. Similarly, mutants lacking
the CYP83B1 enzyme make less of the phenylpropanoid
sinapoylmalate. In addition, investigations have found that
glucosinolates and benzoxazinoids impacts PSMs accumulation. Some Kelch Domain FBox genes involved in PAL
inactivation are up-regulated in indole glucosinolate
mutants, which is reliant on MED5. Furthermore, diverse
diterpene hexose decorating patterns have been demonstrated to alter floral morphology, and inhibiting diterpene
glycoside synthesis can affect bloom size and longevity.
Furthermore, mutations that overproduce certain PSMs
might affect plant development and growth, indicating
that the function of some PSMs is reliant on spatiotemporal accumulation patterns [48]. Overall, genetics influences
the formation of PSMs, controlling their activity and accumulation in response to varied stress circumstances.
Genetic factors influence secondary metabolite production
and regulation. The metabolic pathways involved in secondary metabolite metabolism and synthesis are controlled
by the bHLH and MYB transcription factor families.
Overexpression of the VvbHLH1 gene in grapes can
increase flavonoid concentrations and improve transgenic
plant tolerance to abiotic conditions like dehydration and
salt. MYB proteins also have a role in the production of
anthocyanin and proanthocyanidin. Flavonoids, an important type, exhibit a variety of anti-abiotic characteristics,
including signaling and antioxidant activity [49]. Damage
may have impacted the emergence of PSMs as defense regulators. Damage may have influenced the evolution of
PSMs as defensive regulators. PSMs may be influenced by
genetic factors during defense activation [48]. The altered
MEDa/b genes comprise essential elements of a vast multisubunit transcriptional complex that controls genes
involved in phenylpropanoid synthesis. As a result, genetic
variables are vital in PSMs production.
10.6 Role of Enzymes in Plant Secondary Metabolite Production
Enzymes are playing major role in biosynthesis of PSMs,
particularly artemisinin production in Artemisia annua.
Several ways have been investigated to boost artemisinin
synthesis, including the overexpression of genes, such as
CYP71AV1, CPR, ADS, and ALDH1. Transgenic A. annua
plants with β-caryophyllene synthase siRNA produce
54.9% more artemisinin than wild-type plants. This is
because inhibiting processes that compete with artemisinin
production is an efficient method for boosting output.
Caffeine production also involves enzymatic activities such
as methylation and oxidation events. Enzymes are responsible for the exact chemical processes that produce PSMs,
and the heterologous expression of enzymes involved in
caffeine biosynthesis could raise caffeine levels.
Furthermore, caffeine production in coffee cell cultures
depends on the activity of several enzymes [50].
The significance of enzymes in PSMs manufacturing
could be noticed by mentioned findings that also offer
insight into techniques for increasing their production.
Their classification into several groups, each exhibiting its
own production pathway and enzymatic activity. A wide
range of enzymes catalyze secondary metabolite formation,
including GTs, polyketide synthases (PKSs), nonribosomal
peptide synthases (NRPSs), and a slew of other modifying
enzymes [50, 51, 52]. Secondary metabolite biosynthesis
enzymes are functionally conserved across plant species, as
shown by the effective complementation of Arabidopsis flavonoid mutants with maize genes [53]. Enzymes are
involved in the biosynthesis as shown in Figure 10.1.
Secondary metabolite derivatives are essential components
producing polyamines such as spermidine, spermine, and
putrescine [46, 54]. Secondary metabolism generates a massive number of specialized chemicals, believed to be over
200 000, from building blocks and biosynthetic enzymes
obtained during primary metabolism [55].
Furthermore, secondary metabolite production is mediated by enzyme complexes [56]. As a result, knowing the
196 10 Classification and Therapeutic Applications of Plant Secondary Metabolites
Phenylalanine
PA L
Cinnamate
C4H
p-Coumarate
4CL
p-Coumaroyl-CoA
CHR
Isoliquiritigenin
Daidzein
IOMT
IFH
IFR
VTR
Glyceollins
Figure 10.1 Enzymes involved in the biosynthesis of some
important PSMs referring major role in plant defense [108].
CHS
CHI
Naringenin
IFS
Genistein
Salicylic acid
F3H
Dihydroavonol
Flavan 3, 4-diol
Anthocynanin
Lignin
RGAs, MAPKs
IPP, EREs, JRE
Condensed tannins
role of enzymes in the biosynthesis (of PSMs) is critical for
producing these molecules, which are extremely important
in pharmaceutical and agricultural businesses.
studied for antibacterial properties. The zone of inhibition, which is the region surrounding the circular well
through which the plant extract is given, is used to evaluate antimicrobial activity [58]. Multiple freezing/thawing
cycles and various light conditions showed no effect on
the stability of the released metabolites; nevertheless,
their antibacterial activity was considerably diminished
after certain treatments [59]. Moreover, phytochemical
research indicated the existence of PSMs such as tannins
and flavonoids, which may help with antibacterial action.
Many flavonoids are antibacterial, and PSMs such as flavonoids may contribute to anti-Pseudomonas aeruginosa
action. Ethanol extracts from plant materials have also
been demonstrated to have antimicrobial characteristics,
and various PSMs generated by plants have antibacterial
potential [68]. It should be noted, however, that PSMs are
slightly more efficient against Gram-positive bacteria than
Gram-negative bacteria, with Gram-negative germs frequently having higher minimum inhibitory concentrations (MICs) than Gram-positive bacteria. Furthermore,
specific components of natural extracts demonstrate varying degrees of activity due to their chemical makeup,
which might change depending on geographical origin
and harvesting season [60].
2. Mechanisms of action of PSMs against micro-
organisms
10.7 PSMs Therapeutic Applications
Following are some therapeutics applications seen in
PSMs:
10.7.1 Antimicrobial Properties
PSMs display a multitude of biological effects as many
different phytocomponents inhibit bacteria in different
ways, and they are found in varying concentrations in
various plant parts. PSMs isolated from plants such as
mosses and liverworts are effective producers of bioactive
compounds with antibacterial properties. PSMs from
plants may be employed to eliminate antibiotic-resistant
microorganisms. As a result, future research should focus
on discovering and understanding the routes that these
PSMs follow [58, 59].
1. Exhibition of antimicrobial properties
PSMs have been shown to have antibacterial characteristics, suggesting that they might be a natural antibiotic
source. Plant extracts and their constituents have been
PSMs are a natural source of antibacterial substances that
have been used for centuries to treat a wide range of illnesses. These metabolites are classified roughly into three
types: flavonoids and associated phenolic and polyphenolic
compounds, terpenoids, and alkaloids. Among the PSMs
studied, alkaloids and polyphenols manifested strong antibacterial activity averse to a wide range of pathogens,
including bacteria and fungi [61, 62]. Another significant
secondary metabolite, PC, has been shown to interact with
a range of bacterial targets, including the cytoplasmic
membrane. Other plant secondary compounds having
antibacterial, antifungal, and anticancer effects include
essential oils and saponins [63, 64]. Other PSMs, such as
quinones, resins, steroids, tannins, and terpenes, have
demonstrated various biological activities, including antibacterial properties [65]. It is worth noting that less than
1% of available plant species have been tested for potential
antibacterial action, highlighting the largely unexplored
potential of PSMs as a source of novel antimicrobial medications [58]. Several primary or PSMs have previously been
proven to have antibiotic properties against bacteria [60]
highlighting their significance as a source of novel antimicrobial medicines for the development of effective treatments for infectious diseases.
10.7 PSMs Therapeutic Applications 197
10.7.2 Anticancer Potential
PSMs are typically regarded as compounds that defend
against environmental stresses and predators. They do, however, possess pharmacological properties and have been
discovered as potential sources of plant-based pharmaceuticals. The structure of these compounds has been modified to
improve anticancer efficacy and selectivity while reducing
toxicity and side effects. The three most prominent PSMs
found in plants are flavonoids, phenolic acids, and alkaloids,
which have a variety of bioactivities, including anticancer
action [66, 67]. Furthermore, they have been shown to exhibit
genoprotective capabilities, such as preventing DNA damage
in healthy cells, as well as regulatory effects on metabolic and
signaling pathways [68].
1. Exhibition of anticancer potential
PSMs have demonstrated promising anticancer capabilities, with natural alkaloids acting as a successful case study
in cancer therapy. Some alkaloids are now undergoing
clinical studies or are already on the market as anticancer
medications. The molecular structure of natural alkaloids,
such as betulinic acid, influences their anticancer effects
[48, 67]. Betulinic acid has been demonstrated to have an
antimetastatic impact on highly aggressive melanoma cells
by blocking stearoyl-CoA desaturase (SCD-1), which is
overexpressed in cancer cells. Betulinic acid can also
inhibit the cell cycle during the G1 phase and significantly
increase autophagy as a survival strategy in response to
permeability transition pore opening and mitochondrial
damage. Betulinic acid has a wide-ranging anticancer
effect by boosting caspase activity and inhibiting both constitutive and inducible STAT3 phosphorylation, nuclear
translocation, and DNA binding. Natural alkaloids have
long been utilized to treat cancer, making them a potential
class of phytochemicals for treatment. Furthermore, structural changes might decrease the toxicity and negative
impacts of PSMs while enhancing their absorption, distribution, metabolism, and excretion properties [67]. These
mechanisms of action of PSMs in anticancer potential
open further avenues for research and development of natural product-based chemopreventive agents [68, 69].
betulinic acid, can help to prevent acquired chemoresistance. Additionally, tumor necrosis as well as betulinic acid
factor-related apoptosis-inducing ligand (TRAIL) can be
used to block the p53 signaling pathway and thereby prevent the development of liver cancer. Betulinic acid has
also been shown to suppress multidrug resistance proteins,
both in vivo and in vitro [67]. Vinca alkaloids and colchicine are two other PSMs with anticancer properties. These
chemicals disrupt the mitotic cell cycle by interacting with
the exchangeable GTP-binding region of two tubulin heterodimers. This connection induces microtubule depolymerization, which results in tubulin instability and
disruption. Tubulin dynamics disruption causes programmed cell death, often known as apoptosis. Vinorelbine,
a vinca alkaloid, binds to tubulin, preventing cell growth. It
slows microtubule development, resulting in increased
length and shorter duration. Vinblastine and its derivatives
interact with α- and β-tubulin, targeting cancer cells on
both sides.
Vindoline, is a precursor of vinblastine, a cancer-fighting
chemical originated from tabersonine. Vinblastine’s anticancer activity is derived from its interaction with tubulin,
which suppresses mitosis during metaphase, interacts with
microtubular proteins in the mitotic spindle, resulting in
microtubule crystallization, mitotic arrest, or apoptosis.
Lipophilic terpenoids and alkaloids compete to inhibit
P-gp, multiple resistance-associated proteins 1, and breast
cancer resistance protein in cancer cells. More polar phenols directly inhibit proteins in cancer cells [70]. Finally,
vincristine sulfate binds to malignant cells, inhibits cell
proliferation through tubulin dynamics altering ultimately
influencing overall cellular processes [68].
10.7.3 Anti-inflammatory and Immunomodulatory Effects
PSMs have shown potential toward therapeutic effects of
disease prevention and treatment, with compounds, such
as glucosinolates from the Brassicaceae family showing
anticancer effects and alkaloids from the Papaveraceae,
Solanaceae, and Apocynaceae families showing antimicrobial and immunomodulatory effects [71, 72].
2. Mechanisms of action of PSMs against cancer
cells
PSMs are recognized to have anticancer properties.
Betulinic acid, for example, has been shown to have a
strong synergistic effect with mithramycin A in suppressing cancerous cells in pancreatic cancer migration and
invasion by reducing Sp1 and uPAR levels. Combining
anticancer medications with chemosensitizers, such as
1. Exhibition of anti-inflammatory and immu-
nomodulatory effects
PSMs like polyphenols and phenolic acids have antiinflammatory and immunomodulatory properties. The
polyphenol Oenothein B, mostly found in Epilobium
angustifolium, activates myeloid cells while also stimulating innate lymphocytes such as bovine and human T and
NK cells. This increases CD25 or CD69 expression and IFN
198 10 Classification and Therapeutic Applications of Plant Secondary Metabolites
production in bovine and human NK cells and γδT cells.
Similarly, dihydroquercetin administration enhances
immune function and boosts phagocytic and respiratory
burst activity in gilthead sea bream. Plant PC have been
shown to promote cell-mediated immune responses in
numerous species [73]. Berberine and matrine from
Sophora sp. have also been demonstrated to decrease
inflammation by inhibiting COX-2 levels and PGE2 generation, resulting in anti-swelling properties. Modulating
inflammatory factors, such as TNF-α, IL-8, IL-6, MCP-1,
INF-γ, and IL-17A in cells can ameliorate chronic colitis.
Fritillaria spp. steroidal alkaloids suppress NO, IL-6, and
TNF-α production in RAW264.7 cells via reducing LPSinduced phosphorylation and degradation of IκBα and
JNK. Sinomenine and aconitine inhibit NF-κB activation
and lower TNF-α, IL-6, and IL-1β levels, resulting in
reduced LPS-induced acute lung injury in rats. Phenolic
acids promote immunity by producing NO, ROS, and
cytokines, such as TNF-α, IL-1β, IL-6, and IL-4. However,
their low bioavailability diminishes their effectiveness.
Conjugation with phospholipids is a successful technique
for increasing bioavailability. In melanoma animal models,
drugs containing phenolic acids can cause immunogenic
cell death, which is a cooperative autophagy-based immunomodulatory mechanism. Terpenoids, including
β-patchoulene and laurene can inhibit NF-κB, JNK, and
ERK1/2 activation in IL-1β-stimulated human chondrocyte cells. Soybean and quinoa saponins inhibit inflammation by regulating COX-2, iNOS, MCP-1, TNF-α, NO, and
IL-six levels in LPS-stimulated RAW264.7 cells [72]. To
summarize, PSMs have anti-inflammatory characteristics
along immunomodulatory properties through a variety of
pathways, making them a proposed source for the invention of novel therapeutics for inflammatory illnesses.
2. Study on potential and effects
Numerous plant-derived PSMs have been studied for their
immunomodulatory and anti-inflammatory properties.
For instance, the potent anti-inflammatory compound allicin is found in garlic. Onions (Allium cepa), which has
higher quercetin content, also exhibit the same function.
Research on the flavonoid quercetin’s anti-inflammatory
properties has been extensive. The anti-inflammatory qualities of several flavonoids, including rutin, quercetin, and
hesperidin, have been studied. Alkaloids have also been
studied for their potential to reduce inflammation.
Alkaloids frequently include nitrogen in a heterocyclic
ring. They are classified according to the kind of nitrogen
atoms in their structures. Abutilon indicum has a large
amount of quercetin, which has powerful anti-inflammatory
qualities. Glycyrrhizic acid (18β-GL), the main bioactive
component of licorice Glycyrrhiza glabra L. (Fabaceae), has
immunomodulatory activities [74, 75]. As a result, these
PSMs may be employed instead of standard pharmaceuticals
to treat inflammatory diseases.
10.7.4 Neuroprotective and Cognitive Benefits
Curcumin, quercetin, resveratrol, naringin, naringenin,
and chalcones are all PCs. These chemicals have the potential to treat neurological disorders, inflammatory illnesses,
and aging. The therapeutic benefits of PC stem primarily
from their antioxidant activity, free radical scavenging,
metal ion chelation, gene expression modification, and
interaction with cell signaling networks. Polyphenols alter
antioxidant and anti-inflammatory signaling pathways,
which reduce inflammation and oxidative stress, both of
which are associated with neurological diseases.
Carotenoids, another kind of plant secondary metabolite,
have been shown to improve memory performance and
reduce the incidence of dementia [76, 77].
Carotenoid consumption has also been linked to lower
glutathione peroxidase (GPx) and SOD levels. Although
the book does not clearly discuss how PSMs work in the
brain, it is clear that these substances have biological
impacts, including anti-inflammatory, immune systemboosting, and anti-carcinogenic properties. Clinical studies
are now being done to evaluate the potential of phytochemicals in Alzheimer’s disease (AD). Sulfur-containing
PSMs are another type of plant secondary metabolite that
has shown promise in treating or preventing a number of
neurological illnesses, including Alzheimer’s. The most
thoroughly studied PSMs include terpenes, flavonoids,
alkaloids, and sterols, which stimulate the brain’s serotonergic, noradrenergic, dopaminergic, or GABAergic neurotransmission systems. While PSMs have significant
biological actions, overstimulation of these systems might
result in unwanted side effects. Therefore, clinical research
on standardized extracts that have shown therapeutic efficacy in animal and human investigations is vital [76, 78].
Terpenes, flavonoids, alkaloids, and sterols are the most
extensively investigated PSMs. They stimulate the brain’s
serotonergic, noradrenergic, dopaminergic, and GABAergic
neurotransmission systems. While PSMs have important
biological functions, overstimulation of these systems may
cause undesired side effects. As a result, it is necessary to
do clinical research on standardized extracts that have
demonstrated therapeutic effectiveness in animal and
human studies [76, 78].
1. Exhibition of neuroprotective effects
PSMs are well-known for their neuroprotective capabilities, with several studies demonstrating their beneficial
10.7 PSMs Therapeutic Applications 199
effects on the nervous system. Formononetin, an active
metabolite found in red clover, has been demonstrated to
possess neuroprotective properties. One study found that
formononetin reduces inflammation and neuronal hyperexcitability via blocking NMDA receptors and the CREB
signaling pathway in the basolateral amygdala (BLA) [78].
Scopoletin, a coumarin derived from diverse plant species,
exhibited considerable neuroprotective properties against
glutamate-induced neuron cell damage and may be effective in the treatment of AD [77]. Sulforaphane, found in
cruciferous vegetables, has been shown to be neuroprotective in animal models of acute and chronic neurodegenerative diseases. In a mouse stroke model, sulforaphane
treatment reduced brain damage and edema while protecting the retinal pigment epithelium. It is also known to protect dopaminergic neurons from mitochondrial poisons.
[79]. Caffeic acid, a hydroxycinnamic acid present in many
plant species, has been demonstrated to increase dopamine
levels in the brain while decreasing the production of the
inflammatory cytokines TNF and IL-1. It inhibits the
expression of COX-2, iNOS, and NFB, which leads to considerable improvements in behavioral tests. Caffeic acid
has neuroprotective characteristics in a rotenone-induced
Parkinson’s disease rat model, lowering tau and GSK-3
phosphorylation and protecting cells against amyloid toxicity. Caffeic acid also reduces intracellular calcium and oxidative stress, contributing to its neuroprotective qualities
against 5-S-cysteinyl-dopamine-induced damage. Many
additional PSMs, including coumarins, flavonoids, alkaloids, and chromenes, have been demonstrated to exhibit
neuroprotective characteristics, potentially due to differences in chemical structures and mechanisms of action
[77] indicating neuroprotective properties.
2. Mechanism of action
PSMs have been shown to enhance cognitive function.
Caffeic acid, a plant-based secondary metabolite, demonstrated to lower ROS, has been found to improve cognitive
function by increasing the levels of Nrf2 and HO-1, both of
which have antioxidant and anti-inflammatory attributes.
Caffeic acid has been shown in studies to prevent Aβrelated cognitive impairments in mice. Caffeic acid may
improve cognitive performance by altering GSK3β activity
[77]. A neurotransmitter required for memory and learning, acetylcholine deficiency has been connected to cognitive diseases, including Alzheimer’s [79]. Through the
Nrf2/Keap1/ARE pathways, some PSMs have the ability to
activate or inhibit certain receptors or ion channels in the
brain, hence influencing cognitive performance. For example, substance K, a terpenoid molecule derived from red
ginseng, has been found to drastically increase memory
functions in a neurotoxic animal model, while gypenoside
XVII has been shown to mitigate neurotoxicity generated
by Aβ25-35 by activating the Nrf2/ARE pathways.
Furthermore, by reducing oxidative stress and neuroinflammatory activity, lycopene treatment might mitigate
amyloidogenesis and cognitive deficits brought on by LPS
[76, 79]. Gedunin works by blocking the NF-B and Nrf2
signaling pathways, which can help avoid neurotoxicity.
Green tea extract’s epigallocatechin-3-gallate (EGCG) signaling reduces cognitive decline. EGCG has been shown in
trials to prevent memory losses by decreasing neuroinflammatory biomarkers, reducing oxidative stress, and preventing astrocyte activation and cytokine increase in rats with
heightened neuroinflammation and memory impairment.
Green tea extract was studied for enhancing memory and
learning deficits over an extended period of time while
increasing antioxidant levels and hippocampal activity.
A single pilot study has shown that EGCG affects cerebral
blood flow, despite the majority of EGCG research being
preclinical [80]. These results suggest that PSMs may be
useful as a therapy to improve cognitive function.
10.7.5 Cardiovascular Health Benefits
Several cardiovascular health properties studied, particularly focusing on PSMs found in plants, such as flavonoids,
polyphenols, and carotenoids, possess antioxidant effects,
lowering the development of cardiovascular disorders,
such as atherosclerosis and hypertension [81].
1. Exhibition of cardiovascular health properties
Platelet activation is an important phase in the thrombosis
process, and several PSMs have been shown to influence
blood clotting and platelet aggregation. PSMs can operate
as molecular targets for certain signaling pathways involved
in platelet activation and thrombotic events. Specific agonists can activate platelets by targeting specific platelet
receptors, whereas AA derivatives, such as prostanoids and
isoprostanes can influence VSMC contractile and proliferative responses, as well as platelet aggregation. Platelets’
roles in signaling pathways are less well understood than
those of nucleated cells in the human body. However, these
findings suggest several phytochemical classes as potential
platelet inhibitors with antithrombotic, antiplatelet, and
fibrinolytic characteristics. Gardenia jasminoides J. Ellis,
which contains iridoid glycosides and crocins, can prolong
bleeding time while inhibiting platelet aggregation and
thrombosis in rats, whereas geniposide and its metabolite
genipin can prolong thrombotic occlusion time and platelet aggregation by inhibiting phospholipase A(2) (PLA(2))
activity. Geniposide, a component of G. jasminoides, shows
antithrombotic activity in mice. The most significant family of phytochemicals, flavonoids, is recognized for their
200 10 Classification and Therapeutic Applications of Plant Secondary Metabolites
venotonic activity, but the mechanism of action is
unknown. However, certain phytochemicals suppress the
AA cascade and its metabolites, which have a direct impact
on platelet aggregation control [82]. Furthermore, the antiplatelet activity of coumarins is independent of any possible interaction with blood coagulation, and this effect is
limited to dicoumarols. Platelet aggregation can be reduced
by medicines containing flavonoids and coumarins [83].
−1
Furthermore, at dosages larger than 100 mg kg
body
weight, Umbilicaria esculenta methanolic extract inhibits
ADP-induced platelet aggregation and greatly lowers
thrombotic mortality or paralysis, whereas aspirin inhibits
−1
thrombosis at levels between 10 and 20 mg kg
. In a dosedependent route, the U. esculenta extract shields mice
against thrombotic mortality or paralysis brought on by
collagen and adrenaline. There is no fibrinolytic activity
seen in the U. esculenta extract. Rather than anticoagulant
action, U. esculenta extract may have antiplatelet activity,
which might explain its antithrombotic effect [83]. These
results demonstrate plant-derived chemicals’ unique
antithrombotic and antiplatelet properties, which may
have enormous advantages in primary, secondary, and tertiary care. In the context of 3P medicine, accurate patient
classification using predictive diagnostics is essential for
tailored protection and therapies [82].
2. Mechanism of action
PSMs from plants have been shown to offer possible pathways for lowering the risk of cardiovascular disease. Plant
polysaccharides, for example, can raise serum insulin levels, reduce blood glucose levels, and enhance glucose tolerance, hence lowering the risk of hyperglycemia.
Phytochemicals, or complex plant components, have been
shown to be effective in treating hyperglycemia and hypercholesterolemia [84]. The antidiabetic activity of phytochemicals is one putative way by which PSMs might reduce
the risk of cardiovascular disease. Rhodiola rosea is a plant
that includes chemical components with pharmacological
and therapeutic effects that may help lower the risk of diabetes-related cardiovascular problems [85]. A nephroprotective effect of R. rosea extract has also been demonstrated.
Furthermore, R. rosea extract can stimulate bone formation
while blocking bone resorption, lowering the risk of early
alveolar bone loss in diabetic rats, and regulating bone
metabolism [86]. These findings show that PSMs might be a
viable way to reduce the risk of cardiovascular disease.
10.7.6 Antioxidant and Antiaging Effects
Flavonoids, phenolic acids, lignans, tocopherols, and tannins
are important bioactive compounds that serve as natural
antioxidants in both plants and animals. These chemicals are
produced through biosynthesis in plants and possess a high
antioxidant capability, protecting living organisms from a
variety of ailments [87].
1. Exhibition of antioxidant and antiaging properties
Phenols and flavonoids exhibited pharmacological effects,
including anti-inflammatory, cytotoxic, anticancer, and
antidepressant characteristics. Several studies have found
that dietary polyphenols, notably quercetin, can prevent
collagen-stimulated platelet activation by blocking several
glycoprotein VI signaling pathway components. Moreover,
they have the ability to scavenge free superoxide radicals,
which delays aging. Phenolic acids exhibit a range of pharmacological properties, such as heightened production of
bile, reduced levels of lipids and blood cholesterol, and
antimicrobial action directed against pathogens like
Staphylococcus aureus. PSMs aid in disease prevention for
both people and plants [87]. These metabolites are produced from amino acids and carbohydrates via the basic
glycolysis or shikimic acid pathway. Methylation, hydroxylation, and glycosylation are the processes that produce
them. PSMs are essential for the metabolism of ROS and
prevent important biomolecules from oxidizing uncontrollably. Moreover, these metabolites provide the cell with
both passive and active stress resistance by acting as antioxidants [88]. Studies have demonstrated that specific
compounds derived from plants can activate the ERK1/2
and AMPK pathways, lower serum levels of proinflammatory cytokines, such as IL-1, IL-6, and TNF-, suppress the
expression of ICAM and macrophage chemostatic protein
(MCP-1), prevent the activation of the NF-B pathway, and
decrease the infiltration of inflammatory cells. PSMs also
enhance insulin sensitivity and glucose tolerance. The
potential of PSMs’ antioxidant activities in the creation of
medicines has therefore been studied.
2. Mechanism of action
Before we can determine the therapeutic potential of PSMs
as antioxidants, we must first identify their targets and pathways. One method is to conduct both in vitro and in vivo anti-
oxidant activity assessment studies while addressing disease
etiology. To fulfill their goals, the low molecular weight antioxidants must have significant radical scavenging activity in
vitro. Before studying plant extracts or antioxidants, it is
important to identify major free radical-linked disease
pathophysiology targets, such as mitochondrial failure.
Furthermore, in silico approaches may be utilized to compare found antioxidants to speculated or known structural
analogs of mitochondria-targeted antioxidants, allowing for
a more tailored approach to antioxidant treatment. Once