Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.
We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.
Natural products are substances that are confined from living organisms, they are in the form of primary or secondary metabolites. Secondary metabolites are compounds with varied chemical structures, produced by some plants and strains of microbial species. Unlike primary metabolites (nucleotides, amino acids, carbohydrates, and lipids) that are essential for growth, secondary metabolites are not. Secondary metabolites are produced or synthesized during the stationary stage. In this chapter, we will discuss secondary metabolites from natural products synthesized mainly by plants, fungi, and bacteria. Plants synthesize a large diversity of secondary metabolites; plant secondary metabolites are split into four groups namely alkaloids, phenolic compounds, terpenoids, and glucosinolates. Several classes of fungal and bacterial secondary metabolites, their sources, and pharmacological uses associated with the secondary metabolites are also discussed. Therefore, several classes of secondary metabolites are responsible for the biological and pharmacological activities of plants and herbal medicines.
Faculty of Pharmaceutical Sciences, Department of Pharmacognosy and Traditional Medicine, Nnamdi Azikiwe University, Awka, Nigeria
*Address all correspondence to: stellaobruce@yahoo.com
1. Introduction
Secondary metabolites are natural products synthesized mainly by plants, fungi and bacteria. Secondary metabolites are molecules with low molecular weight and various biological activities and chemical structures [1]. Secondary metabolites are also called specialized metabolites; they generally mediate ecological interactions by increasing their ability to survive [2]. Secondary metabolites function as a defense against herbivores and other interspecies in plants; and it was first established by A. kossel in 1910, and was discovered 20 years later as an end product of nitrogen metabolism by Friedrich Czapek a Botanist [3].
Plants are capable of manufacturing diverse types of organic compounds which are grouped into primary and secondary metabolites [3]. Some secondary metabolites are phenylpropanoids or cinnamic acids, which protect plants from UV damage [4]. Since ancient times, the plant secondary metabolite’s biological effects in humans have been known. The herb Artemisia annuacontains Artemisinin, which is widely used in herbal or traditional medicine. Plant secondary metabolites can be divided into four major classes: alkaloids, phenolic compounds, terpenes, and glucosinolates [5, 6].
2.1 Alkaloids
Plants are natural products and the oldest source of alkaloids, examples of the most widely recognized alkaloids are morphine, quinine, strychnine, and cocaine [7]. Alkaloids are present as water-soluble salts of organic acids, esters, tannins (Cinchona bark) or in plant tissues [7, 8].
Most alkaloids are isolated in the form of crystalline, non-odorous, nonvolatile and amorphous compounds, low molecular weight alkaloids, such as arecoline and pilocarpine, non-oxygen atom alkaloids such as sparteine and nicotine occur in the liquid form, these are all from plant matrices. Majority of alkaloids are colorless with a bitter taste, apart from colchicine and berberine. Alkaloids are derived from plant sources and a diverse group of nitrogen-containing basic compounds, which contain one or more nitrogen atoms. Chemically they are heterogeneous. Based on chemical structures, they are classified into two broad categories [9]:
Examples of plants with alkaloids include, Datura stramonium, Atropa belladonna, Erythroxylum coca, Solanaceae(nightshade) plant family, Papaver somniferum, and Catharanthus roseus[9].
Alkaloids (about 20,000) are isolated from plants, but it have also been found in microorganisms, marine organisms such as algae, dinoflagellates, and pufferfish, and terrestrial animals such as insects, salamanders, and toads [10].
Classification based on the botanical origin of the alkaloids, their Sources and pharmacological properties are listed below (Table 1). For example., Papaver(opium)alkaloids, Cinchonaalkaloids, Rauvolfiaalkaloids, Catharanthusalkaloids, Strychnosalkaloids, Ergot alkaloids, cactus alkaloids, and Solanumalkaloids [10], while the structures of some alkaloids are shown in Figure 1.
Alkaloid
Source
Properties
Ajmaline
Rauvolfia serpentina
Antiarrhythmic, antihypertensive
Caffeine
Coffea arabica
Stimulant, insecticide
Camptothecin
Camptotheca acuminata
Antineoplastic
Cocaine
Erythroxylon coca
Analgesic, narcotic, local anesthetic
Codeine
Papaver somniferum
Analgesic, antitussive
Emetine
Uragoga ipecacuanha
Antiamoebic, expectorant, emetic
Hyoscyamine
Atropa belladonnaand others
Anticholinergic
Morphine
P. somniferum
Analgesic, narcotic
Nicotine
Nicotiana tabacum
Stimulant
Pilocarpine
Pilocarpus jaborandi
Cholinergic
Quinidine
Cinchonaspp.
Antiarrhythmic
Quinine
Cinchonaspp.
Antimalarial
Reserpine
R. serpentina
Tranquilizer
Scopolamine
Hyoscyamus nigerand others
Sedative, anticholinergic
Strychnine
Strychnos nux-vomica
Stimulant, poison
Taxol
Taxus brevifolia
Antineoplastic
Vinblastine and vincristine
Catharanthus roseus
Antineoplastic
Table 1.
Spurces and pharmacological uses of selected plant-derived alkaloids.
Figure 1.
Structures of some alkaloids. Note that the structures of morphine and codeine are based on the same skeleton, but are decorated with different functional groups in the position represented by ‘R’. In morphine, this group is −OH, while in codeine it is CH2O. Similarly, vinblastine and vincristine are based on the same skeleton, but differ in the nature of the R-group, which for vinblastine is −CH3 and for vincristine is −CHO.
2.2 Phenolic compounds
Plant secondary metabolism produces phenolic compounds with chemical structures of one hydroxyl aromatic ring. These phenolic compounds are classified based on their carbon chain. [11]. Phenolic compounds are found in plant tissues, fruits and vegetables and are also ubiquitously distributed phytochemicals. Phenolic compounds are synthesized through phenylpropanoid and shikimic acid pathways [12]. Phenolic compounds possess numerous bioactive properties and health-protective effects, although they are not nutrients, therefore postharvest treatments have been used to enhance or preserve the phenolic compounds in fruits and vegetables [12]. Phenolic compounds possess an aromatic ring with one or more hydroxyl substituents that can be divided into several classes, which are common chemical structures essential for health benefits [13].
Plant materials like (Tropical Root and Crops) contain two classes of phenolic compounds as hydroxybenzoic acids and hydroxycinnamic acids. Phenolic compounds are present in Nigerian Centaurea perrottetiiDC. [family COMPOSITAE]and other related genera (Cheirolophus, Rhaponticoides,and Volutaria) [14].
The phenolic compounds found in plants are represented in Table 2, while the categories of phenolic compounds and their representative compounds are shown in Figure 2. Phenolic compounds survive in plant material, in either a soluble or a bound form [15, 16].
Grape seed/skin, apple juice, strawberries, raspberries, pomegranate, walnuts, peach, blackberry, and plum
Lignans
Secoisolariciresinol Matairesinol
Pear
Table 2.
Selected phenolic compounds found in plants.
Figure 2.
Categories of phenolic compounds.
2.3 Terpenoids
Terpenes are a unique group of hydrocarbon-based natural products whose structures are derived from isoprene. Terpenoid secondary metabolites occur in plant tissue types often secured in secretory structures [17]. Over 30,000 members of terpenes are in an enormous class of natural products, they have been used for a broad variety of purposes including medicine, flavoring and perfume [18]. Terpenes as a broad group with ecological roles, that exhibit a range of deadly to entirely edible toxicity, which include antimicrobial properties and other properties [19, 20].
Plants and flowering plants (angiosperms) subdivisions have colonized the majority of the terrestrial surface, courtesy of rich levels of specialization and the relationships with other organisms [21].
Terpenes are important plant metabolites that include substances like floral fragrances that serve as plant hormones (gibberellic and abscisic acid), growth inhibitors, insect attractants, pine oil, and insecticides [22].
Terpenoids or isoprenoids are high in plants where many can be considered secondary metabolites and have fundamental roles in the metabolism of all organisms [23]. Terpenoid secondary metabolism in plants began with the recruitment of genes from primary metabolism [24] and accelerated due to the proliferation of cytochrome P450 and terpene synthase gene families in the genomes of plants [25].
Terpenoids play various physiological and ecological functions in plant life and human through direct and indirect plant defenses, because of their enormous applications in the pharmaceutical, food and cosmetics industries [26]. Examples of terpenoids from plant species are 1). Artemisinin, present in A. annua, Chinese wormwood. 2). Tetrahydrocannabinol, present in Cannabis sativa,cannabis. 3). Azadirachtin, present in Azadirachta indica,the (Neem tree). 4). Saponins, glycosylated triterpenes present in Chenopodium quinoa, quinoa [27, 28].
2.4 Glucosinolates
The pungent smell of plants (mustard, cabbage, and horseradish) is due to mustard oils produced from glucosinolates [29]. Glucosinolates are biosynthesized from amino acids, which consists of three glucosinolate subtypes (aliphatic, indole and aromatic glucosinolates) that have their corresponding precursors. Aliphatic glucosinolates are derived from isoleucine, alanine, valine, methionine, and leucine. Indole and aromatic glucosinolates are obtained from phenylalanine or tyrosine and tryptophan. Examples of the three classes of glucosinolates represented by 3methylsulfinylpropyl glucosinolate; indol3ylmethyl glucosinolate; and benzyl glucosinolate in Figure 3.
Figure 3.
Glucosinolates.
Glucosinolates are responsible for the pungent properties present in mustard, rucola, horseradish, cruciferous vegetables, and nasturtium and they are sulfur and nitrogen-containing glycosides, which protect against carcinogenesis [30].
The glucosinolates of sulforaphane (Glucoraphanin) present in broccoli, cabbage, and cauliflower (cruciferous vegetables) are responsible for protection against carcinogenesis. The Brown (Brassica juncea), white (Brassica alba) and black (Brassica nigra) mustards are examples of mustard seed with the family Brassicaceae [31, 32].
Secondary metabolites in plants (glucosinolates, isothiocyanates, S-methyl cysteine, allyl sulfurs, phytates, phytoestrogens) likely to protect against cancers, and antioxidant properties (phenolic compounds, flavonoids) [32].
Isothiocyanates are present in cruciferous vegetables, which is the product of the degradation of glucosinolates. S-methyl cysteine is a sulfur-containing phytochemicals found in all brassica vegetables [33, 34].
Glucosinolates contain metabolites found in the plant Arabidopsis thaliana. The strong taste of foods (horseradish, wasabi, and mustard) is as a result of glucosinolates [35, 36].
Over 130 glucosinolate compounds have been identified in plants, and one way that they vary is by the amino acid precursor that is incorporated during glucosinolates biosynthesis [37].
Fungi are eukaryotic organisms that can utilize various solid substrates of their biochemical and biological evolution and are also known to inhabit almost all ecological niches of the Earth. Some of the solid substrates utilized by fungi are decaying and dead material, such as live plants (endophytic, parasitic, and mycorrhizal fungi), lichens (lichenicolous and endolichenic fungi), insects (entomopathogenic fungi) and herbivore dung (saprophytic and coprophilous fungi). A characteristic feature of many of these fungi (filamentous growth and complex morphology), is their ability to produce secondary metabolites which are useful in pharmaceutical, agrochemical industries and food with different biological activities [38, 39].
In the production of secondary metabolites which occurs after fungal growth has stopped because of nutrient limitations but an abundant carbon source available, it is then possible to manipulate their formation. Some endophytic fungi can produce secondary metabolites known from plants. Examples include production paclitaxel (Taxol®) and camptothecin, by Taxomyces andreanaeand Nothapodytes foetida, respectively, and a synthetic precursor of an anticancer drug, podophyllotoxin, by Phialocephala fortinii[39].
The several classes of fungal secondary metabolites are polyketides (aflatoxin and fumonisins), nonribosomal peptides (sirodesmin, peramine, siderophores) and terpenes (T-2 toxin, deoxynivalenol (DON)), indole terpenes (paxiline and lolitrems) as represented in Figure 4. Polyketides are building blocks of natural products and are the largest group of metabolites occurring in their greatest number. They are the most sought-after molecules because of their wide spectrum of activities (clinical, industrial and economical activities). Non-ribosomal peptides are catalyzed without mRNA template by a complex enzyme called Nonribosomal peptide-synthetase (NRPS) enzymes. The peptide is modified by accessory enzymes similar to polyketides and often includes noncanonical amino acids. Nonribosomal peptide-synthetase (NRPS) enzymes include B-lactam antibiotics, cyclosporine A and echinocandin [40, 41].
Figure 4.
Several classes of fungal secondary metabolites; a) Polyketides b) non-ribosomal peptides c) Terpenes and d) Indole terpenes.
The first FDA-approved secondary metabolite was Lovastatin, to lower cholesterol levels. In oyster mushrooms [42], red yeast rice [43], and Pu-erh [44], Lovastatin occurs naturally in low concentrations. Their mode of action is inhibition of HMG-CoA reductase, and it is the enzyme responsible for converting HMG-CoA to mevalonate.
Fungal secondary metabolites are dangerous to humans. The fungi Claviceps purpurea, a member of the ergot group, typically growing on rye, when ingested results in the death of humans. In C. purpurea, a build-up of poisonous alkaloids lead to spasms and seizures, Itching, diarrhea, psychosis or gangrene and paresthesias [45].
Fungi are organisms that produce a wide range of natural products often called secondary metabolites; many natural products are of agricultural, medical, and industrial importance. Examples of natural products causing harm (mycotoxins), while others are advantageous (antibiotics) to humans [46, 47]. The biosynthesis of natural products is usually associated with cell differentiation or development, the establishment of a G-protein-mediated growth pathway in Aspergillus nidulansregulates both asexual sporulation and natural product biosynthesis [48].
Secondary metabolism is connected with sporulation processes in microorganisms [49, 50], including fungi [51, 52]. Secondary metabolites connected with sporulation can be classified into three groups: (i) Sporulation activated by metabolites (A. nidulans[53, 54, 55, 56]), (ii) Sporulation structures from pigments (melanins [57, 58]), and (iii) toxic metabolites secreted at the time of sporulation by growing colonies (the biosynthesis of some deleterious natural products, such as mycotoxins [48, 59]). These examples of fungal secondary metabolites are shown in Table 3.
Secondary metabolite
Producing fungus
Association with development
References
Linoleic-acid derived psi factor
Aspergillus nidulans
Induces sporulation; affects ratio of asexual to sexual spore development
Natural products are essential for sporulation, examples of fungal strains that are sporulated and deficient in secondary metabolite production are Penicillium urticaepatulin mutants [52] and A. nidulanssterigmatocystin mutants [67]. Secondary metabolites such as brevianamides A and B produced by Penicillium brevicompactum[60], some natural products have subtle effects on sporulation, as recent studies of A. nidulanssterigmatocystin mutants suggest that they display a decrease in asexual spore production [61, 62].
Secondary metabolites have easily visible effects on morphological differentiation in fungi, mycelium excretes compounds that can prompt sexual and asexual sporulation in other fungi [63, 64, 65], these compounds have not been identified but are assumed to be natural products produced as the mycelia ages. Other natural product such as Fusarium graminearumenhances perithecial production in F. graminearumand produces an estrogenic mycotoxin called zearalenone, an inhibitor of zearalenone synthesis, which inhibits the sexual development of this fungus [66].
Butyrolactone I, produced by the fungus Aspergillus terreus,is an inhibitor of eukaryotic cyclin-dependent kinases, which increases sporulation [68]. Some secondary metabolites trigger sporulation and influence the development of the producing organism and neighboring members of the same species. Natural product biosynthetic gene clusters can be conserved between organisms, for example, the sterigmatocystin-aflatoxin biosynthetic gene cluster in several Aspergillusspp. [69].
The bacterial secondary metabolites are natural products source of anticholesterol agents, immune suppressants, antibiotics, antitumor agents, and other medicines; secondary metabolite-producing microorganisms synthesize these bioactive and complex molecules at the late phase and stationary phase of their growth [70, 71, 72] as shown in Figure 5a. In bacteria, the actinomycetes (streptomycetes) produce a significant number of chemically distinct secondary metabolites [73, 74, 75, 76]. Other major sources include soil pseudomonas, bacilli, and myxococci [77, 78, 79, 80]. An example of a bacterial secondary metabolite is botulinum toxin synthesized by Clostridium botulinum, with a positive and negative effect on humans. However, botulinum toxin has multiple medical uses for the treatment of muscle spasticity, migraine and cosmetics use [81].
Figure 5.
a) the secondary metabolite-producing microorganisms synthesize these bioactive and complex molecules at the late phase and stationary phase of their growth. b) Secondary metabolic pathway reactions are conducted by an individual enzyme or multienzyme complexes. Intermediate or end-products of primary metabolic pathways are channeled from their systematic metabolic pathways that lead to the synthesis of secondary metabolites.
Bacterial production of secondary metabolites starts in the stationary phase in response to environmental stress and lack of nutrients. Secondary metabolite synthesis in bacteria, allow them to better interact with their ecological niche and it is not essential for their growth. The b-lactam, shikimate, polyketide and non-ribosomal are the synthetic pathways for secondary metabolite production [82] as shown in Figure 5b. B-lactam family of cephalosporins antibiotics have been used to treat bacterial infections for 40 years and above. Gram-positive bacteria, Gram-negative bacteria, and fungi are the major sources of b-lactam antibiotics. The shikimate pathway contributes to the basic building blocks for aromatic metabolites and amino acids, which can serve as antibacterial agents. In the bacterial secondary metabolite, two enzymes can transfer a complete enolpyruvoyl moiety to a metabolic pathway, 5-enolpyruvoyl shikimate 3-phosphate synthase and chorismate synthase that require a reduced cofactor, flavin mononucleotide, for its activation. When secreted those found in the prokaryotic cell wall are endotoxins, while those poisonous compounds are known as exotoxins. Other examples of bacterial secondary metabolites are phenazine, polyketides, nonribosomal peptides, ribosomal peptides, glucosides, and alkaloids.
4.1 Phenazine
Bacteria are natural phenazines, phenazines are heterocyclic, nitrogenous compounds that differ in their physical and chemical properties. Phenazines are significant for their potential impact on bacterial interactions and biotechnological processes. It exhibits a wide range of biological activities, Pyocyanin, from Pseudomonas aeruginosa. Other phenazines from Pseudomonassp. and Streptomycessp. (Natural Products of Actinobacteria Derived from Marine Organisms) [83].
Phenazines produced by various bacteria species and excrete them in high quantities in the environment in a visible form to the naked eye, they are nitrogen-containing colored aromatic secondary metabolites. The main use of phenazines is to protect plants (biocontrol field), because of their antimicrobial properties. Examples of bacteria species able to produce phenazines are Pseudomonasspp. (including P. aeruginosa,P. fluorescens, and Pseudomonas chlororaphis) [84].
4.2 Polyketides
Polyketides from plants, bacteria, fungi, and animals, are a large group of secondary metabolites known to possess remarkable properties [85, 86]. Polyketides possess some bioactivities such as antibacterial (e.g., tetracycline), antifungal (e.g., amphotericin B), immune-suppressing (e.g., rapamycin), anti-cholesterol (e.g., lovastatin), anti-inflammatory activity (e.g., flavonoids), antiviral (e.g., balticolid), and anticancer (e.g., doxorubicin) [87, 88, 89, 90, 91, 92, 93]. Some organisms that can produce polyketides are plants (e.g., emodin from Rheum palmatum), fungi (e.g., lovastatin from Phomopsis vexans), bacteria (e.g., tetracycline from Streptomyces aureofaciens), protists (e.g., maitotoxin-1 from Gambierdiscus australes), mollusks (e.g., elysione from Elysia viridis), and insects (e.g., stegobinone from Stegobium paniceum) [94, 95, 96, 97, 98, 99]. These organisms can use the polyketides they produce for pheromonal communication in the case of insects and also as protective compounds.
Polyketides are a family of natural products which are synthesized by polyketide synthase (PKS) enzymes with different biological activities and pharmacological properties. They are divided into three types: type I polyketides (macrolides produced by multimodular megasynthases), type II polyketides (aromatic molecules produced by the iterative action of dissociated enzymes), and type III polyketides (small aromatic molecules produced by fungal species) [100]. Polyketides are also found in bacteria, fungi, plants, mollusks, protists, sponges, and insects. They have notable variety in their structure and function. Some examples of polyketides antibiotics are Erythromycin, Avermectin, Nystatin, and Rifamycin [100].
4.3 Nonribosomal peptides
Nonribosomal peptides (NRPs) are peptide secondary metabolites that are synthesized by nonribosomal peptide synthetases (NRPSs) (multidomain mega-enzymes), without messenger RNAs and cell ribosomal machinery [101]. Nonribosomal peptides are naturally synthesized by bacteria, fungi, and higher eukaryotes [101]. Nonribosomal peptides are also synthesized by indigoidine (pigment). Some examples of nonribosomal peptide antibiotics are; Vancomycin, bacterium, Ramoplanin, Teicoplanins, Gramicidin, Bacitracin, Polymyxin [102].
4.4 Ribosomal peptides
Streptomyces azureusis produced from several strains of streptomycetes (Thiostrepton), Escherichia coliproduced from Microcins and Bacteriocins [82].
4.5 Glucosides
Streptomycesspecies produced from Nojirimycin [82].
4.6 Alkaloids
Pseudoalteromonasproduced by Tetrodotoxin, a neurotoxin [82].
Natural products originate as secondary metabolites Plants possess different indigenous defensive mechanisms to cope with certain environmental stresses. Secondary metabolites are natural tools used by plants to combat biotic and abiotic stresses. Microorganisms can produce several antibiotics and other pharmaceutically important drugs to treat bacterial and fungal infections. The secondary metabolites from natural products help us to understand their classes, sources, pharmacological importance and examples associated with the secondary metabolites derived from plants, fungi, and bacteria.
References
1.Návarová H, Bernsdorff F, Döring AC, Zeier J. Pipecolic acid, any endogenous mediator of defense amplification and priming, is a critical regulator of inducible plant immunity. Plant Cell. 2012;24(12):5123-5141
2.Bourgaud F, Gravot A, Milesi S, Gontier E. Production of plant secondary metabolites: A historical perspective. Plant Science. 2001;161(5):839-851
3.Bruce SO, Onyegbule FA. Biosynthesis of natural products. In: Zepka LQ, do TC, Jacob-Lopes E, editors. Bioactive Compounds - Biosynthesis, Characterization and Applications. London: IntechOpen; 2021. DOI: 10.5772/intechopen.97660. Available from:https://www.intechopen.com/chapters/76931
4.Seigler DS. Plant Secondary Metabolism. New York: Springer US; 1998
5.Korkina L, Kostyuk V, Potapovich A, Mayer W, Talib N, De Luca C. Secondary plant metabolites for sun protective cosmetics: From pre-selection to product formulation. Cosmetics. 2018;5(2):32
6.Kumar P, Mina U. Life Sciences: Fundamentals and Practice. 3rd ed. New Delhi: Pathfinder Academy; 2013
7.O’Connor SE. In: Mander L, Lui H-W, Alkaloids. In book: Comprehensive Natural Products II Chemistry and Biology. Vol. 1. Oxford: Elsevier; 2010. pp. 977-1007. DOI: 10.1016/B978-008045382-8.00013-7
8.Croteau R, Kutchan TM, Lewis NG. Natural products (secondary metabolites). In: Civjan N, editor. Natural Products in Chemical Biology. Hoboken, New Jersey: Wiley; 2012. pp. 1250-1319
9.Kukula-Koch WA, Widelski J. Chapter 9 - Alkaloids. In: Delgoda R, editor. Pharmacognosy. Fundamentals, Applications and Strategies. Lublin, Poland: Academic Press; 2017. pp. 163-198. DOI: 10.1016/B978-0-12-802104-0.00009-3
10.Twyman RM, Stöger E, Christou P. Molecular farming. In:Encyclopedia of Applied Plant Sciences. 2nd ed. Vol. 2. Amsterdam: Elsevier Science B.V; 2003. pp. 77-82
11.Das PR, Eun J-B. Tea antioxidants in terms of phenolic and nonphenolic metabolites. In: Preedy VR, editor. Pathology: Oxidative Stress and Dietary Antioxidants. 1st ed. London: Academic Press; 2020. pp. 357-367
12.Bruce SO, Onyegbule FA, Ihekwereme CP. Evaluation of hepato-protective and anti-microbial activities of ethanol extracts and fractions ofPicralima nitidaseed and pod. Journal of Phytomedicine and Therapeutic. 2016;1(2):1-21
13.Ayad R, Akkal S. Phytochemistry and biological activities of AlgerianCentaureaand related genera. In: Atta-ur-Rahman, editor. Bioactive Natural Products, Studies in Natural Products Chemistry. Vol. 63. Amsterdam, The Netherlands: Elsevier; 2019. pp. 357-414
14.Saranraj P, Behera SS, Ray RC. Chapter 7 - Traditional foods from tropical root and tuber crops: Innovations and challenges. In: Galanakis CM, editor.Innovations in Traditional Foods. Chania, Greece: Woodhead Publishing; 2019. pp. 159-191. DOI: 10.1016/B978-0-12-814887-7.00007-1
15.Gan RY, Chan CL, Yang QQ , Li HB, Zhang D, Ge YY, et al. Bioactive compounds and beneficial functions of sprouted grains. In: Feng H, Nemzer B, DeVries JW, editors.Sprouted Grains. United States: Woodhead Publishing and AACC International Press; 2019. pp. 191-246
16.Tiwari R, Rana CS. Plant secondary metabolites : A review. International Journal of Engineering Research and General Science. 2015;3(5):661-667. ISSN 2091-2730
17.Bruce SO, Onyegbule FA, Ezugwu CO. Pharmacognostic, physicochemical and phytochemical evaluation of the leaves ofFadogia cienkowskiiSchweinf (Rubiaceae). Journal of Pharmacognosy and Phytotherapy. 2019;11(3):52-60
18.Maimone T. Classic Terpene Syntheses I. In: An introduction to Terpenes. Baran Lab; 2002. pp. 1-18
19.Mazid M, Khan TA, Mohammad F. Role of secondary metabolites in defense mechanisms of plants. Biology and Medicine. 2011;3(2):232-249
20.Kennedy DO, Wightman EL. Herbal extracts and phytochemicals: Plant secondary metabolites and the enhancement of human brain function. Advances in Nutrition. 2011;1:32-50
21.Wang G, Tang W, Bidigare RR. Terpenoids as therapeutic drugs and pharmaceutical agents. In: Zhang L, Demain AL, editors. Natural Products. Vol. 12. Totowa, NJ: Humana Press; 2013. pp. 153-175
22.Onyegbule FA, Bruce SO, Onyekwe ON, Onyealisi OL, Okoye PC. Evaluation of the in vivo antiplasmodial activity of ethanol leaf extract and fractions of Jatropha gossypifolia in Plasmodium berghei infected mice. Journal of Medicinal Plant Research. 2019;13(11):269-279
23.Cho KS, Lim Y, Lee K, Lee J, Lee JH, Lee I. Terpenes from forests and human health. Toxicological Research. 2017;33(2):97-106
24.Bouvier F, Rahier A, Camara B. Biogenesis, molecular regulation and function of plant isoprenoids. Progress in Lipid Research. 2005;44:357-429
25.Weng JK, Philippe RN, Noel JP. The rise of chemodiversity in plants. Science. 2012;336:1667-1670
26.Roba K. The role of terpene (secondary metabolite). Holeta, Ethiopia: Holeta honeybee research center. Natural Products Chemistry & Research; 2020;9(8):411
27.Kabera J, Semana E, Mussa AR, He X. Plant secondary metabolites: Biosynthesis, classification, function and pharmacological classification, function and pharmacological properties. Journal of Pharmacy and Pharmacology. 2014;2(7):377-392
28.Castells AA. The Role of Terpenes in the Defensive Responses of Conifers against Herbivores and Pathogens. Spain: Universitat Autònoma de Barcelona; 2015. pp. 1-185
29.Ishida M, Hara M, Fukino N, Kakizaki T, Morimitsu Y. Glucosinolate metabolism, functionality and breeding for the improvement of Brassicaceae vegetables. Breeding Science. 2014;64(1):48-59
30.Bone K, Mills S.Principles of herbal pharmacology. In:Principles and Practice of Phytotherapy. Modern Herbal Medicine. 2nd ed. London, United Kingdom: Churchill Livingstone; 2013. pp. 962-967
31.Bruce SO, Onyemailu VO, Orji CE. Evaluation of The antiulcer activity and GC-MS spectroscopic analysis of the crude ethanolic extract ofPeuraria PhaseoloideLeaf (Roxb) Benth. (FABACEAE). World Journal of Pharmaceutical Research. 2021;10(7):39-59
32.Gerber M.Oxidative stress, antioxidants and cancer. In: Sen C, Packer L, Hänninen O, editors.Handbook of Oxidants and Antioxidants in Exercise. Vol. 1220. Amsterdam: Elsevier; 2000
33.Paluszczak J, Baer-dubowska W. DNA methylation as a target of cancer chemoprevention by dietary polyphenols. In:Polyphenols in Human Health and Disease. Elsevier; 2014. pp. 1385-1392. DOI: 10.1016/B978-0-12-398456-2.00105-5
34.Halkier BA, Gershenzon J. Biology and biochemistry of glucosinolates. Annual Reviews of Plant Biology. 2006;57:303-333
35.Baenas N, Villaño D, Cristina G-V, Moreno DA. Optimizing elicitation and seed priming to enrich broccoli and radish sprouts in glucosinolates. Food Chemistry. 2014;204:314-319
36.Angelino D, Dosz EB, Sun J, Hoeflinger JL, Van Tassell ML, Chen P, et al. Myrosinase-dependent and –independent formation and control of isothiocyanate products of glucosinolate hydrolysis. Frontiers in Plant Science. 2015;6:831
37.Agerbirk N, Olsen CE. Glucosinolate structures in evolution. Phytochemistry. 2012;77:16-45
38.Gunatilaka AA. Fungal Secondary Metabolites. Tucson, Arizona:LeslieOffice of Arid Lands Studies, Southwest Center for Natural Products Research and Commercialization. The University of Arizona; 2010. DOI: 10.1036/1097-8542.YB100063
39.Onyemailu VO, Bruce SO, Iloh ES. UV-Visible and FTIR Spectroscopic Analysis of The Crude Ethanolic Extract ofPeuraria phaseoloideLeaf (Roxb) Benth. (FABACEAE). International Journal of Modern. Pharmaceutical Research. 2021;5(3):148-153
40.Quin MB, Flynn CM, Schmidt- Dannert C. Traversing the fungal terpenome. Natural Product Reports. 2014;31(10):1449-1473
41.Boruta T. Uncovering the repertoire of fungal secondary metabolites: From Fleming's laboratory to the International Space Station. Bioengineered. 2018;9(1):12-16
42.king R, Marahiel MA. Biosynthesis of nonribosomal peptides 1. Annual Review of Microbiology. 2004;58:453-488
43.Liu J, Zhang J, Shi Y, Grimsgaard S, Alraek T, Fønnebø V. Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta-analysis of randomized controlled trials. Chinese Medicine. 2006;1(1):4
44.Zhao ZJ, Pan YZ, Liu QJ, Li XH. Exposure assessment of lovastatin in Pu-erh tea. International Journal of Food Microbiology. 2013;164(1):26-31
45.Uys H, Berk M. A controlled double blind study of zuclopenthixol acetate compared with clothiapine in acute psychosis including mania and exacerbation of chronic psychosis. European Neuropsychopharmacology. 1996;6:60
46.Bruce SO, Usifoh SF, Nduka SO, Anetoh MU, Isidienu CP. A retrospective study of antimalarial drug utilization in a secondary healthcare institution in Nigeria. World Journal of Pharmaceutical Research. 2019;8(13):271-281
47.Demain AL, Fang A. The natural functions of secondary metabolites. Advances in Biochemical Engineering/Biotechnology. 2000;69:1-39
48.Hicks J, Yu JH, Keller N, Adams TH. Aspergillus sporulation and mycotoxin production both require inactivation of the FadA G-alpha protein-dependent signaling pathway. The EMBO Journal. 1997;16:4916-4923
49.Bruce SO, Ugwu RN, Onu JN, Iloh ES, Onwunyili AR. Pharmacognostic, antimicrobial and hepatoprotective activities of the sub-fractions ofPicralima nitida(Durand and Hook) (APOCYNACEAE) seeds. World Journal of Pharmaceutical Sciences. 2021;9(8):77-91
50.Stone MJ, Williams DH. On the evolution of functional secondary metabolites (natural products). Molecular Microbiology. 1992;6:29-34
51.Ihekwereme CP, Bruce SO, Orji CE, Ibe CI, Iloh ES. Aqueous extracts ofOcimum gratissimumandAnacardium occidentalesynergises in anti-diarrhoeal property. International Journal of Modern Pharmaceutical Research (IJMR). 2020;4(4):06-11
52.Sekiguchi J, Gaucher GM. Conidiogenesis and secondary metabolism inPenicillium urticae. Applied and Environmental Microbiology. 1977;33:147-158
53.Calvo AM, Gardner HW, Keller NP. Genetic connection between fatty acid metabolism and sporulation inAspergillus nidulans. The Journal of Biological Chemistry. 2001;276:20766-20774
54.Champe SP, El-Zayat AAE. Isolation of a sexual sporulation hormone fromAspergillus nidulans. Journal of Bacteriology. 1989;171:3982-3988
55.Champe SP, Rao P, Chang A. An endogenous inducer of sexual development inAspergillus nidulans. Journal of General Microbiology. 1987;133:1383-1388
56.Mazur P, Nakanishi K, El-Zayat AAE, Champe SP. Structure and synthesis of sporogenic psi factors fromAspergillus nidulans. Journal of the Chemical Society, Chemical Communications. 1991;20:1486-1487
57.Alspaugh JA, Perfect JR, Heitman J.Cryptococcus neoformansmating and virulence are regulated by the G-protein alpha subunit GPA1 and cAMP. Genes & Development. 1997;11:3206-3217
58.Kawamura C, Tsujimoto T, Tsuge T. Targeted disruption of a melanin biosynthesis gene affects conidial development and UV tolerance in the Japanese pear pathotype ofAlternaria alternata. Molecular Plant-Microbe Interactions. 1999;12:59-63
59.Trail F, Mahanti N, Linz J. Molecular biology of aflatoxin biosynthesis. Microbiology. 1995;141:755-765
60.Bird BA, Remaley AT, Campbell IM. Brevianamides A and B are formed only after conidiation has begun in solid cultures ofPenicillium brevicompactum. Applied and Environmental Microbiology. 1981;42:521-525
61.Ramaswamy A. Ecological analysis of secondary metabolite production inAspergillusspp. Master's thesis. College Station: Office of Graduate Studies of Texas A & M University; 2002
62.Sim SC. Characterization of Genes in the Sterigmatocystin Gene Cluster and Their Role in Fitness ofAspergillus nidulans.Master’s thesis. College Station: Office of Graduate Studies of Texas A & M University; 2001
63.Hadley G, Harrold CE. The sporulation ofPenicillium notatumwestling in submerged liquid cultures. Journal of Experimental Botany. 1958;9:418-428
65.Onyegbule FA, Okoli OG, Bruce SO. In vivo evaluation of the antimalarial activity of the aqueous ethanol extract of Monodora myristica seed in Albino Mice. International Journal of Science and Research (IJSR). 2019;8(6):1530-1538
66.Wolf JC, Mirocha CJ. Regulation of sexual reproduction inGibberella zeae(Fusarium roseum‘Graminearum’) by F-2 (zearalenone). Canadian Journal of Microbiology. 1973;19:725-734
67.Shimizu K, Keller NP. Genetic involvement of cAMP-dependent protein kinase in a G protein signaling pathway regulating morphological and chemical transitions inAspergillus nidulans. Genetics. 2001;157:591-600
68.Schimmel TG, Coffman AD, Parsons SJ. Effect of butyrolactone I on the producing fungus,Aspergillus terreus. Applied and Environmental Microbiology. 1998;64:3703-3712
69.Ana M. Calvo, Richard A. Wilson, Jin Woo Bok, Nancy P. Keller. Relationship between secondary metabolism and fungal development microbiology and molecular biology reviews. ASM Journals. 2020;66(3):447-459
70.Moore BS, Hopke JN. Discovery of a new bacterial polyketide biosynthetic pathway. Chembiochem. 2001;2:35-38
71.Rokem JS, Lantz AE, Nielsen J. Systems biology of antibiotic production by microorganisms. Natural Product Reports. 2007;24:1262
72.Katsuyama Y, Funa N, Miyahisa I, Horinouchi S. Synthesis of unnatural flavonoids and stilbenes by exploiting the plant biosynthetic pathway inEscherichia coli. Chemistry & Biology. 2007;14:613-621
73.Chopra I, Roberts M. Tetracycline antibiotics: Mode of action, applications, molecular biology, and epidemiology of bacterial resistance tetracycline antibiotics: Mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiology and Molecular Biology Reviews. 2001;65:232-260
74.Onyegbule FA, Ezenwa CJ, Bruce SO, Umeokoli BO. Standardization, chemical composition and antipyretic evaluation of methanol leaf extract and fractions of chrysophyllum albidum (Sapotaceae). Tropical Journal of Natural Product Research. 2020;4(6):216-222
75.Tacar O, Sriamornsak P, Dass CR. Doxorubicin: An update on anticancer molecular action, toxicity and novel drug delivery systems. The Journal of Pharmacy and Pharmacology. 2013;65:157-170
76.Shushni MAM, Singh R, Mentel R, Lindequist U. Balticolid: A new 12-membered macrolide with antiviral activity from anAscomycetousfungus of marine origin. Marine Drugs. 2011;9:844-851
77.Li J, Kim SG, Blenis J. Rapamycin: One drug, many effects. Cell Metabolism. 2014;19:373-379
78.Van de Donk NWCJ, Kamphuis MMJ, Lokhorst HM, Bloem AC. The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells. Leukemia. 2002;16:1362-1371
79.Hleba L, Charousova I, Cisarova M, Kovacik A, Kormanec J, Medo J, et al. Rapid identification ofStreptomycestetracycline producers by MALDI-TOF mass spectrometry. Journal of Environmental Science and Health, Part A. 2018;169(12):940-947
80.Parthasarathy R, Sathiyabama M. Lovastatin-producing endophytic fungus isolated from a medicinal plantSolanum xanthocarpum. Natural Product Research. 2015;29:2282-2286
81.Huang Q , Lu G, Shen HM, Chung MCM, Ong CN. Anti-cancer properties of anthraquinones from rhubarb. Medicinal Research Reviews. 2006;27:609-630
82.Gokulan K, Khare S, Cerniglia C.Metabolic pathways: Production of secondary metabolites of bacteria. In: Encyclopedia of Food Microbiology. London: Academic Press; 2020. pp. 561-569
83.Karuppiah V, Sun W, Li Z.Natural products of actinobacteria derived from marine organisms. In: Studies in Natural Products Chemistry. Vol. 48. Amsterdam, Netherlands: Elsevier; 2016. pp. 417-446
84.Hadla M, Halabi MA.Fundamentals of quorum sensing, analytical methods and applications in membrane bioreactors1st Edition. In: Chormey D, Bakirdere S, Turan N, Engin G, editors.Comprehensive Analytical Chemistry. Vol. 81. Elsevier; 2018. pp. 1-308
85.Bruce SO, Nwafor OI, Omoirri MA, Adione NM, Onyeka IP, Ezeoru VC. GC-MS, FTIR and Antiulcer screening of aqueous seed extract and oil ofNigella sativain Wistar rats. Journal of Drug Delivery and Therapeutics. 2021;11(6):48-60
86.Watve MG, Tickoo R, Jog MM, Bhole BD. How many antibiotics are produced by the genusStreptomyces? Archives of Microbiology. 2001;176:386-390
87.Okoye VO, Bruce SO, Onyegbule FA. Phytochemical screening and pharmacognostic properties ofPeuraria phaseoloidesleaves (roxb) benth (fabaceae). International Journal of Public Health, Pharmacy and Pharmacology. 2020;5(2):11-24
88.Kinashi H. Giant linear plasmids inStreptomyces: A treasure trove of antibiotic biosynthetic clusters. Journal of Antibiotics (Tokyo). 2011;64:19-25
89.Baltz RH. Renaissance in antibacterial discovery from actinomycetes. Current Opinion in Pharmacology. 2008;8:557-563
90.Zotchev SB. Marine actinomycetes as an emerging resource for the drug development pipelines. Journal of Biotechnology. 2012;158:168-175
91.Clardy J, Fischbach MA, Walsh CT. New antibiotics from bacterial natural products. Nature Biotechnology. 2006;24:1541-1550
92.Sansinenea E, Ortiz A. Secondary metabolites of soilBacillusspp. Biotechnology Letters. 2011;33:1523-1538
93.Bruce SO, Onyegbule FA, Ezugwu CO, Nweke ID, Ezenwelu CR, Nwafor FI. Chemical composition, hepatoprotective and antioxidant activity of the crude extract and fractions of the leaves ofFadogia CienkowskiiSchweinf (Rubiaceae). Tropical Journal of Natural Product Research. 2021;5(4):720-731
94.Wenzel SC, Muller R. Myxobacteria—‘Microbial factories’ for the production of bioactive secondary metabolites. Molecular BioSystems. 2009;5:567-574
95.Gross H, Loper JE. Genomics of secondary metabolite production byPseudomonasspp. Natural Product Reports. 2009;26(11):1408-1446
96.Witting K, Sussmuth RD. Discovery of antibacterials and other bioactive compounds from microorganisms-evaluating methodologies for discovery and generation of non-ribosomal peptide antibiotics. Current Drug Targets. 2011;12(11):1547-1559
97.Kohli GS, John U, Figueroa RI, Rhodes LL, Harwood DT, Groth M, et al. Polyketide synthesis genes associated with toxin production in two species ofGambierdiscus(Dinophyceae). BMC Genomics. 2015;16(1):410
98.Florian P, Monika H. Polyketides in insects: Ecological role of these widespread chemicals and evolutionary aspects of their biogenesis. Biological Reviews. 2008;83:209-226
99.Adele C, Guido C, Guido V, Angelo F. Shaping the polypropionate biosynthesis in the solar-powered molluscElysia viridis. Chembiochem. 2008;10:315-322
100.Monfil VO, Casas-Flores S. Molecular mechanisms of biocontrol inTrichodermaspp. and their applications in agriculture. In: Gupta VK, Schmoll M, Herrera-Estrella A, Upadhyay RS, Druzhinina I, Tuohy MG, editors.Biotechnology and Biology of Trichoderma. Dordrecht: Elsevier; 2014. pp. 429-453. DOI: 10.1016/B978-0-444-59576-8.00032-1
101.Ding K, Dai LX. Organic Chemistry - Breakthroughs and Perspectives. Weinheim: Wiley-VCH; 2012. pp. 1-802
102.Soltani J. Chapter 22 -Secondary metabolite diversity of the genus Aspergillus: Recent advances. In: Gupta VK, editor.New and Future Developments in Microbial Biotechnology and Bioengineering. Elsevier; 2016. pp. 275-295. DOI: 10.1016/B978-0-444-63505-1.00035-X
Written By
Stella Omokhefe Bruce
Submitted: December 1st, 2021Reviewed: December 20th, 2021Published: February 16th, 2022
Open access peer-reviewed chapter - ONLINE FIRST
