Approximate number of known natural metabolites.
The metabolism can be defined as the sum of all the biochemical reactions carried out by an organism. Metabolites are the intermediates and products of metabolism and are usually restricted to small molecules. The term “secondary” introduced by A. Kossel in 1891 implies that while primary metabolites are present in every living cell capable of dividing, the secondary metabolites are present only incidentally and are not of paramount significance for organism’s life. Though secondary metabolites are derived from primary metabolism, they do not make up basic molecular skeleton of the organism. Its absence does not immediately curtail the life of an organism, a feature contrary to primary metabolite, but survival of the organism is impaired to a larger extent. Its presence and synthesis are observed in ecologically disadvantaged species within a phylogenetic group .
The difference between primary and secondary metabolite is ambiguous since many of the intermediates in primary metabolism is overlapping with the intermediates of secondary metabolites . Amino acids though considered a product of primary metabolite are definitely secondary metabolite too. Contrary to the observation that sterols are secondary metabolites that are indispensable part of many structural framework of a cell. The mosaic nature of an intermediate indicates common biochemical pathway being shared by primary and secondary metabolism . The secondary metabolites serve as a buffering zone into which excess C and N can be shunted into to form inactive part of primary metabolism. The stored C and N can revert back to primary metabolite by the metabolic disintegration of secondary metabolite when on demand. There is dynamism and a delicate balance between the activities of the primary and secondary metabolism (Figure 1) being influenced by growth, tissue differentiation and development of the cell or body, and also external pressures .
Hence, secondary metabolites or natural products can be defined as a heterogeneous group of natural metabolic products that are not essential for vegetative growth of the producing organisms, but they are considered differentiation compounds conferring adaptive roles, for example, by functioning as defense compounds or signaling molecules in ecological interactions, symbiosis, metal transport, competition, and so on . The multitude of secondary metabolite secretions is harvested by human kind to improve their health (antibiotics, enzyme inhibitors, immunomodulators, antitumor agents, and growth promoters of animals and plants), widen the pyramid of healthy nutrition (pigments and nutraceuticals), enhancing agricultural productivity (pesticides, insecticides, effectors of ecological competition and symbiosis and pheromones), and hence impacting economics our society in a certain positive way. They are a source of antibiotics.
2. Classification of secondary metabolites
Over 2,140,000 secondary metabolites are known and are commonly classified according to their vast diversity in structure, function, and biosynthesis. There are five main classes of secondary metabolites such as terpenoids and steroids, fatty acid-derived substances and polyketides, alkaloids, nonribosomal polypeptides, and enzyme cofactors .
2.1. Terpenoids and steroids
They are major group of substances derived biosynthetically from isopentenyl diphosphate. Currently, over 35,000 known terpenoid and steroid compounds are identified. Terpenoids have different variety of unrelated structures, while steroids have a common tetracyclic carbon skeleton and are modified terpenoids that are biosynthesized from the triterpene lanosterol.
There are over 12,000 known compounds of alkaloids, and their basic structures consist of basic amine group and are derived biosynthetically from amino acids.
2.3. Fatty acid-derived substances and polyketides
Around 10,000 compounds are identified and are biosynthesized from simple acyl precursors such as propionyl CoA, acetyl CoA, and methylmalonyl CoA.
2.4. Nonribosomal polypeptides
These amino acids derived compounds are biologically synthesized by a multifunctional enzyme complex without direct RNA transcription.
2.5. Enzyme cofactors
Enzyme cofactors are nonprotein, low-molecular enzyme component .
3. Functions of secondary metabolites
The major functions of the secondary metabolites including antibiotics are:
competitive weapons against other livings such as animals, plants, insects, and microorganisms
metal transporting agents
agents for symbiotic relation with other organisms
reproductive agent and
agents of communication between organisms
The other functions include interference in spore formation (not obligatory) and germination . Predominantly, the secondary metabolites are used for variety of biological activities like antimicrobial and antiparasitic agents, enzyme inhibitors and antitumor agent, immunosuppressive agents, etc. .
4. Sources of secondary metabolites
4.1. Secondary metabolites of plants
Plant secondary metabolites represent highly economically valuable products. These are used as high value chemicals such as drugs, flavors, fragrances, insecticides, dyes, etc. Plants are rich in a wide variety of secondary metabolites, such as tannins, terpenoids, alkaloids, and flavonoids, which have been found to have
Many alkaloids are used in medicine, usually in the form of salts. Some examples include vinblastine which has antitumor properties ; quinine which has antipyretics and antimalarial properties ; and reserpine which can be used to treat high blood pressure. Alkaloids are regarded as reserve materials for protein synthesis, as protective substances discouraging animal or insect attacks, and as plant stimulants or regulators or simply as detoxification products. Alkaloids currently in clinical use include the analgesics morphine and codeine, the anticancer agent vinblastine, the gout suppressant colchicine, the muscle relaxant tubocurarine, the antiarrhythmic ajmalicine, the antibiotic sanguinarine, and the sedative scopolamine.
Terpenoids are commercially important fragrance and flavoring agents . Prenol and α-bisabolol are used in fragrance due to fruity odor and sweet floral aroma, respectively. Mono and sesqui terpenes are basis of natural perfumes and also of spices and flavorings in the food industry. The roles of terpenoids as pharmaceutical agents with activities such as antibacterial and antineoplastic are still under investigation. There are examples of diterpenes that exhibited
|Source||All known compounds||Bioactives||Antibiotics|
|Natural products||Over one million||200,000–250,000||25,000–30,000|
|Insects/ worms/ ||8000–10,000||800–1000||150–200|
|Vertebrates (mammals, fishes, amphibians, ||200,000–250,000||50,000–70,000||~1000|
|S. No.||Secondary metabolites||Biological activity|
|25.||Thebaine||Source of codeine|
|31.||Rosamarinic acid||Spice, antioxidant, perfume|
|37.||Gutla percha||Essential oils|
4.2. Production of secondary metabolites from plants
The conventional method of secondary metabolite production relies on extraction of metabolite, not production, from the tissues of plant by different phytochemical procedures like solvent, steam, and supercritical extraction. The recent developments in biotechnological methods like plant tissue culture, enzyme and fermentation technology have facilitated
Cell or biocatalysts are confined within a matrix by entrapment, adsorption or covalent linkage. On addition of suitable substrate and provision on optimum physico chemical parameters, the desired secondary metabolites are synthesized. Immobilization with suitable bioreactor system provides several advantages, such as continuous process operation, but for the development of an immobilized plant cell culture process, natural or artificially induced secretion of the accumulated product into the surrounding medium is necessary.
In vitro tissue, organ, and cell culture
Plant cell and tissue cultures can be established routinely under sterile conditions from explants, such as plant leaves, stems, roots, meristems, etc., both for multiplication and extraction of secondary metabolites. Shoot, root, callus, cell suspension, and hairy root culture are used to synthesize metabolite of interest. Metabolites which are localized in multiple tissues can be synthesized through unorganized callus or suspension cultures. But when the metabolite of interest is restricted to specialized part or glands in host plant, differentiated microplant or organ culture is the method of choice. Saponins from ginseng are produced in its roots, and hence
The quantum of secondary metabolite production in cell cultures can be enhanced by treating plant cells with biotic and/or abiotic elicitors. Methyl jasmonate, fungal carbohydrates, and yeast extract are the commonly used elicitors. Methyl jasmonate is an established and effective elicitor used in the production of taxol from
The production of metabolites through hairy root system based on inoculation with
4.3. Secondary metabolites of microorganisms
Microbial secondary metabolites are low molecular mass products with unusual structures. The structurally diverse metabolites show a variety of biological activities like antimicrobial agents, inhibitors of enzymes and antitumors, immune-suppressives and antiparasitic agents , plant growth stimulators, herbicides, insecticides, antihelmintics, etc. They are produced during the late growth phase of the microorganisms. The secondary metabolite production is controlled by special regulatory mechanisms in microorganisms, as their production is generally repressed in logarithmic phase and depressed in stationary growth phases. The microbial secondary metabolites have distinctive molecular skeleton which is not found in the chemical libraries and about 40% of the microbial metabolites cannot be chemically synthesized .
4.3.1. Features of microbial secondary metabolites
The principle and process of natural fermentation product synthesis can be successfully scaled up and employed to maximize its application in the field of medicine, agriculture, food, and environment.
The metabolite can serve as a starting material for deriving a product of interest, extended further through chemical or biological transformation.
New analog or templates in which secondary metabolite serve as lead compounds will lead discovery and design of new drugs.
4.4. Applications of microbial secondary metabolites
The discovery of penicillin initiated the researchers for the exploitation of microorganisms for secondary metabolite production, which revolutionized the field of microbiology . With the advent of new screening and isolation techniques, a variety of β-lactam-containing molecules  and other types of antibiotics have been identified. About 6000 antibiotics have been described, 4000 from actinobacteria (Table 3). In the prokaryotic group, unicellular bacteria
|Name of secondary metabolites||Source of secondary metabolites||Biological activities||References|
|Resistomycin||HIV-1 protease inhibitor||Shiono et al. |
|Himalomycins A and B||Antimicrobial||Maskey et al. |
|Bonactin||Antibacterial||Schumacher et al. |
|Trioxacarcins||Antitumor and antimalarial||Maskey et al. |
|Chinikomycins A and B||Antitumor and antiviral||Li et al. |
|Daryamides||Cytotoxic polyketides||Asolkar et al. |
|Resistoflavine||Antibacterial||Gorajana et al. |
|Chalcomycin A and terpenes||Antibacterial||Wu et al. |
|Napyradiomycin (C-16 stereoisomers)||Antibacterial||Motohashi et al. |
|Oxohexaene and Cephalaxine||Antibacterial||Remya and Vijayakumar |
|Citreamicin θ A, Citreamicin θ B, and Citreaglycon A||Antibacterial||Liu et al. |
|Spiramycin||Antibacterial||Vijayakumar and Malathi |
|N-isopentyltridecanamide||Antibacterial||Thirumurugan et al. |
|Staurosporine||Antimicrobial||Cholarajan and Vijayakumar |
|Coagulin||Bactericidal, Bacteriolytic||Le Marrec et al. |
|Bacthurucin f4||Fungicidal sub sp., ||Kamoun et al. |
|Cerein||Bactericidal, bacteriolytic||Bizani et al. |
|Megacin||,||Lisboa et al. |
|Thuricin S||,||Chehimi et al. |
|Thuricin CD 19||,||Rea et al. |
|Halobacillin 5b||Hemolytic, cytotoxic||Kalinovskaya et al. |
|Bacillomycin||Antifungal hemolytic||Ramarathnam et al. |
|Bacilysocin||Fungicidal, antibacterial||Tamehiro et al. |
|Bacilysin 1||Antifungal, antibacterial||Steinborn et al. |
|Pseudomonine||Competitive inhibition of phytopathogens||Lewis et al. |
|Hydrogen cyanide||Antifungal||Ayyadurai et al. |
|Lovastatin||Enzyme inhibitor||Dewick |
|Limonene and guaiol||Antimicrobial||Awad et al. |
|Tuberculariols||Anticancer||Xu et al. |
|Oxaline||Anti-cell proliferation||Sumarah et al. |
|Benzomalvin C||Antimalarial||Stierle et al. |
|Roquefortine C||Neurotoxin||Kim et al. ; Xu et al. |
|Pravastatin||Anticholesterolemics||Gonzalez et al. |
The pharmaceutical product, especially anti-infective derivatives comprise 62% antibacterials, 13% sera, immunoglobulins, and vaccines, 12% anti-HIV antivirals, 7% antifungals, and 6% nonHIV antivirals. There are over 160 antibiotics.
4.4.2. Antitumor agents
Natural product and its derivatives account for more than 60% of anticancer formulations. Actinobacteria derived antineoplastic molecules currently in use are actinomycin D, anthracyclines (daunorubicin, doxorubicin, epirubicin, pirarubicin, and valrubicin), bleomycin, mitosanes (mitomycin C), anthracenones (mithramycin, streptozotocin, and pentostatin), enediynes (calicheamicin), taxol, and epothilones .
Taxol is the nonactinobacterial molecule derived from plant
4.4.3. Pharmacological and nutraceutical agents
One huge success was the discovery of the fungal statins, including compactin, lovastatin, pravastatin, and others which act as cholesterol-lowering agents. Lovastatin is produced by
4.4.4. Enzymes and enzyme inhibitors
Enzymes produced from microorganism have annual sales of US $ 2.3 billion enzymes that find application in detergents (34%), foods (27%), agriculture and feeds (16%), textiles (10%), and leather, chemicals, and pulp and paper (10%). The protease subtilisin used in detergents has an annual sale of $ 200 million. The other major enzymes include glucose isomerase (100,000 tons) and penicillin amidase (60,000 tons). Nitrilase (30,000 tons) and phytase are amounting for $135 million worth of production.
The most important enzyme inhibitors are clavulanic acid, synthesized by
4.4.5. Agricultural and animal health products
Secondary metabolites find wide applications in the field of agriculture and animal health: kasugamycin and polyoxins are used as biopesticides;
4.5. Production of secondary metabolites from microorganisms
Secondary metabolites branch out from the pathways of primary metabolism. Commercially, important secondary and primary metabolic pathways are given in Table 4.
|S. No.||Intermediates from primary metabolic pathway||Secondary metabolites derived|
|1.||Shikimic acid||Ergot alkaloids, antibiotics: candicidin and chloramphenicol|
|2.||Amino acids||Antibiotics: penicillin, cephalosporins and cephamycins, and gramicidin, immunosuppressive cyclosporine|
|3.||Acetyl-CoA and other Kreb’s cycle intermediates||Antibiotics: erythromycin, antiparasitic avermectin antitumor doxorubicin, taxol|
|4.||Sugars||Antibiotics: streptomycin and kanamycin.|
4.5.1. Liquid fermentation
Batch or fed-batch culture in submerged fermentation is employed for production of secondary metabolites. Inoculum is developed after careful strain improvement of producing organism. Initially, shake flasks culture is employed, and the culture which are in active growth phase are transferred to a small fermenter and later into a larger fermenter with production medium. Several parameters, like medium composition, pH, temperature, and agitation and aeration rate, are controlled. An inducer such as methionine is added to cephalosporin fermentations, phosphate is restricted in chlortetracycline fermentation, and glucose is avoided in penicillin or erythromycin fermentation.
4.5.2. Solid-state fermentation
Solid-state fermentation, defined as a microbial culture that develops on the surface and at the interior of a solid matrix and in the absence of free water, holds an important potential for the production of secondary metabolites. Two types of SSF can be distinguished, depending on the nature of solid phase used : (a) solid culture of one support-substrate phase solid phase and (b) solid culture of two substrate-support phase solid phase. The advantages of solid-state fermentation in relation with submerged fermentation include: energy requirements of the process are relatively low, since oxygen is transferred directly to the microorganism. Secondary metabolites are often produced in much higher yields, often in shorter times, and often sterile conditions are not required .
It is important here to note our own experience of deriving actinobacterial secondary metabolite. Actinobacteria from terrestrial and marine habitats were screened for their antimicrobial activity. The bioactive metabolites were extracted and purified by thin layer and column chromatography, and the structure of the metabolite was elucidated by UV-spectrometry, FT-IR, mass spectrum analysis, and NMR. The derived metabolites staurosporine, octa-valinomycin, methyl-4,8-dimethylundecanate, and N-isopentyltridecanamide are known for their biological activity (Figure 2).
This review emphasizes the importance of secondary metabolites from various sources like plants, microorganisms including bacteria, actinobacteria, and fungi and its classification, production and applications in various fields. Since there is a constant and crucial requirement for new pharmaceutical agents to fight cancers, cardiac disorders, pests, cytotoxic, mosquitoes, infectious diseases, and autoimmune disorders of both animals and plants as climate changes provide conditions favorable to repeated outbreaks of these events. The battle against any disease is a vibrant symmetry between advances in chemotherapy and natural selection on infectious or invasive agents. If the scientific community is to put constant importance in this never ending effort, then new sources of bioactive secondary metabolites with novel activities must be found. Secondary metabolites are one of their essential means of growth and defense, and these metabolites are readily available for discovery. Secondary metabolites with noteworthy biological activity are considered as an alternative to most of the synthetic drugs and other commercially valuable compounds.
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