Production of Primary and Secondary Metabolites Using Algae
Over the past few decades, there has been an increase in the number of research studies focused on all aspects of the ecology, physiology, biochemistry, cell biology, molecular biology, systematics and uses of algae. This chapter will provide an overview of the potential human health advantages associated with the use of algae as a source of high-value products, especially focused on those metabolites with biological activities and potential therapeutic applications in the pharmaceutical and food industries. Moreover, the production of polyphenols by marine microalgae will be also considered, as well their impact on the biogeochemical cycles of trace metals and the phytoplankton implications. These data will support as a baseline for future research in wastewater and marine environments.
The extensive research on extracting drugs from the sea organisms began in the mid-1970s. Since 1975, the reported applications of these drugs isolated from algae are numerous (Priyadarshani and Rath 2012). These studies have clearly demonstrated that algae represent valuable sources of a wide variety of compounds with different potential applications in food, cosmetic and pharmaceutical industries (Li et al. 2014; Machu et al. 2015). Developing new technologies after the 1980s has led to extract new metabolites from algae cultures and to determine the chemical structure of 15,000 novel compounds, decreasing the biomass needed from kilograms to grams (Borowitzka 1995). This also makes possible to increase the number of newly studied species, especially for microalgae.
Algae range from unicellular organisms such as diatoms to seaweeds extending over 30 m long. Diatoms have been widely investigated because they are a diverse group of microalgae (250 orders and more than 105 species) and the sole ones with a siliceous cell wall (Norton et al. 1996). Diatoms contribute as much as 25% of the global primary productivity (Scala and Bowler 2001). A high variety of phytoplankton species has been described (40,000 species), being 680 species of marine algae divided in Rhodophyta, Phaeophyta, Chlorophyta (Boopathy and Kathiresan 2010).
Marine algae can be considered an arsenal of metabolites with pharmaceutical potential, including anticancer, antitumor, antioxidant, antiobesity, neuroprotective, antimicrobial, antinociceptive, anti-inflammatory, and antiangiogenic activities (Cornish and Garbary 2010; Gupta and Abu-Ghannam 2011; Pangestuti and Kim 2011). Microalgae are able to produce highly bioactive compounds extracted from the marine environments (Shimizu 1996). The antibacterial activity of substances excreted by an aquatic microalga was first reported for Chlorella vulgaris (Pratt and Fong 1940). Currently, algae have attracted attention because they are biological systems capable of using solar energy to produce a large number of active metabolites via the photosynthetic process with the highest efficiency (Shalaby 2011). Blue-green algae produce a number of highly active antitumor compounds (Shimizu 2000).
The focus in this chapter is placed on the main classes of algal metabolites that could be of medicinal, nutritional and pharmaceutical value. Seaweeds may become a suitable natural source of bioactive compounds reported to possess strong antiviral, antitumor and anticancer properties, among others. Here, we discuss the pharmaceutical, health and research potential of different primary and secondary metabolites present in algae, with a focus on those from microalgae and paying special attention to the polyphenolic compounds and the involvement of these compounds in protection cell mechanisms in conditions of mental stress.
2 Primary Metabolites
Primary metabolism represents an essential biogeochemical pathway directly involved in cell growth and reproduction. The most important primary metabolites are carbohydrates, lipids, and proteins (Wen et al. 2015).
Lipids content of algal cells can achieve 90% of dry weight (Metting et al. 1996). These lipids consist in phospholipids, glycolipids, non-polar glycerolipids, saturated and unsaturated fatty acids (PUFA) (Kumari et al. 2013). Within the group of PUFA, linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid have great interest for many diseases as cancer, cardiovascular, diabetes, inflammatory, asthma, etc. (Andersen et al. 2008; Priyadarshani and Rath 2012).
Crude lipids have been extracted from a wide group of algal species (Laurencia popillose, Galaxoura cylindriea, Ulva fasciata, Taonia atomaria, and Dilophys fasciola), but the group of Dunaliella, Chlorella, and Spirulina species are the most interesting in terms of high concentration of lipids (El Baz et al. 2002; Abd El Baky et al. 2014a, b). On the other hand, Phaeodactylum tricornutum (marine diatom) is also considered the main producer of eicosapentaenoic acid (EPA) (Grima et al. 2003) and Nitzschia inconspicua (marine diatom) produces high levels of arachidonic acid, an essential polyunsaturated fatty acid (Chu et al. 1994) under deficiency in linoleic acid.
In general, crude lipids of several algal species such as Laurencia popillose, Galaxoura cylindriea, Ulva fasciata, Taonia atomaria, and Dilophys fasciola) showed different biological properties as antitumor, antioxidant, antimicrobial and antivirus with various degrees (Abd El Baky et. 2014a, b; Ghazala et al. 2010). PUFA microalgae-derived such as γ-linolenic acid, arachidonic acid, EPA and docosahexaenoic acid (DHA) are widely used as nutritional supplements, pharmaceutical, and functional food and their roles in promoting human health have been extensively studied (Borowitzka 2013; Michalak and Chojnacka 2015; Priyadarshani and Rath 2012).
Polyunsaturated fatty acids, phenolic and flavonoids from T. atomaria and L. papillose have shown an inhibitory effect against human hepatocarcinoma and human breast carcinoma. These complex lipids are usually rare in terrestrial plants but are present in relatively large amounts in some species of marine algae (Abd El Baky et al. 2014a, b; Castro et al. 2016; Harwood and Guschina 2009).
Marine algae have high protein content, up to 70% of the dry weight, depending on the season and the species (Abreu et al. 2014; Fan et al. 2014). According to Becker (2007), Arthrospira maxima (cyanobacteria with 60–71% proteins) is one of the most important microalgae in this sense. Currently, marine algae proteins have attracted great interest as a source of bioactive peptides for therapeutic uses (Kim and Kang 2011). Several studies have isolated various algal peptides possessing anti-infective activities (Kang et al. 2015a, b). Depending on the amino acid sequence, biopeptides isolated from marine algae may be associated with different biological functions, including antioxidant, anticancer, antihypertensive, anti-atherosclerotic, and immunomodulatory effects (Fan et al. 2014).
Carbohydrates can be found as glucose, sugars and other polysaccharides in microalgae, making relevant the production of carbohydrates because of their high overall digestibility (Becker 2004). In this sense, carbohydrates compounds may achieve from 10% (Scenedesmus obliquus) to 57% (Porphyridium cruentum) of dry biomass (Becker 2004).
Among marine biologically active metabolites, polyphenols and polysaccharides have shown more effective antioxidant and anticancer activities (Farvin and Jacobsen 2013; Li et al. 2014). In the last decades, the study of polysaccharides from marine algae has gained renewed interest for their many valuable biological properties and therapeutic applications (Barahona et al. 2014; Kang et al. 2015a, b). Hossain et al. (2005) suggested that algal glycolipids such as digalactosyl diacylglycerol and sulfoquinovosyl diacylglycerol combined with sodium butyrate might be used as potential colon cancer chemotherapy agents. Spirulina platensis accumulate a high amount of sulfated polysaccharides with biological activities as an anticoagulant, anticancer, antiviral, antimicrobial, and antioxidant (Abd El Baky et al. 2013). In addition, red algae are important sources of sulfated polysaccharides which show antiviral activities in human infectious diseases by viruses (Damonte et al. 1994; Witvrouw et al. 1994). The inhibitory effect is mostly due to the interaction with the positive charges on the viruses cell surfaces, preventing the penetration into the host cells (Ehresmann et al. 1979) Aghardhiella tenera and Nothogenia fastigiata are characteristics because of their capacity to produce polysaccharides with low cytoxoxic activities (de Clercq 1996). Another important use of polysaccharides is the antiviral action against two enveloped rhabdovirusees with high economic impacts, such as hemorrhagic septicemia virus and the African swine fever virus. Some algal polysaccharides and fibers are also able to reduced cholesterol absorption in the gut, such as alginate, carrageenan, funoran, fucoidan, laminaran, porphyrin and ulvan (Kiriyama et al. 1969; Lamela et al. 1989; Panlasigui et al. 2003). Accordingly, the production of polysaccharides seems to be a potential industrial option against viral therapy.
Several reviews focused on algae-derived polysaccharides (alginate, galactan, laminaran, and naviculan) with different antiviral activities and mechanisms of action have been recently reported (Ahmadi et al. 2015; Zubia et al. 2008).
3 Induction of Lipids, Peptides, and Carbohydrates of Commercial Value
Algae differ in their tolerance and adaptability to the environmental conditions. Under stress conditions, algae accumulate elevated amounts of some metabolites for protection and recovery from injury. The growth of Botryococcus braunii (race ‘A’) and production of its constituents, hydrocarbon, carbohydrate, fatty acid, and carotenoids were influenced by different levels of salinity (Ranga Rao et al. 2007a, b). Different microalgae species react to different stresses by producing different fatty acids or by altering their composition of fatty acids. The exact combination of induction stresses that provides optimum lipid productivity in a large-scale commercial cultivation system for biodiesel production will differ for every microalgae strain and depends on nutrient supply, environmental and climatic conditions (Mata et al. 2010; Sharma et al. 2012). Several studies have focused on the increase of lipid productivity by the cultivation of microalgae with different levels of CO2, (Yoo et al. 2010; Ranga Rao et al. 2007a, b), nitrogen concentration and temperature, to mitigate CO2 due to its C-fixation ability and for production of biodiesel. In algae and cyanobacteria, several protection mechanisms against ultraviolet stress have been reported (Xue 2005; Lee et al. 2014; Hartmann et al. 2015). Spirulina platensis produced relevant amounts of sulfated polysaccharides as adaptation mechanisms to nitrogen concentration (Abd El Baky et al. 2013).
4 Several Secondary Metabolites
Secondary metabolites have gained great attention over the last 50 years because they showed a wide variety of pharmacological uses. These molecules are mainly involved in the adaptation of organisms to their environment (Bourgaud et al. 2001).
The metabolism is the sum of all the biochemical processes that take place in an organism. Secondary metabolic pathways produce a huge number of compounds: alkaloids, carotenoids, phenolic compounds, lignin, phytosterols, and others (Hussain et al. 2012). The major metabolic reactions that occur in algae are unique and produce unique secondary metabolites: mechanisms of light harvesting, carbon acquisition and aspects of nitrogen (N) and sulfur (S) assimilation, growth in extreme environments, such as nutrient limitation and exposure to extremes of visible and UV light (Beardal and Ravenm 2012). It has been reported that algal species cultivated under stress conditions produce relevant amounts of metabolites for pharmaceutical uses (Leu and Boussiba 2014; Yu et al. 2015).
Microalgae are rich in carotenoids, being especially high in Dunaliella species where it is up to 14% of dry weight (Spolaore et al. 2006). They are over 400 known carotenoids but only one small fraction is commercially produced, highlighting β-carotene, astaxanthin, lutein, zeaxanthin, lycopene, and bixin (Radmer 1996; del Campo et al. 2000). The green flagellate microalgae Dunaliella salina is the most important species in the production of β-carotene (Metting 1996). In general, these carotenoids are a strong antioxidant, making them highly relevant in terms of industrial production.
Algal carotenoids are involved in different functions: in photosynthesis, as intermediates of carotenogenesis or as accumulated carotenoids (Takaichi 2011). They have been found to protect against several malfunctions and diseases triggered by oxidative stress (Abd El Baky 2003; Fassett and Coombes 2011).
Fucoxanthin is a marine carotenoid widely distributed in microalgae and brown macroalgae, involved in a multitude of molecular and cellular processes, showing a protective role and anti-proliferative behavior in several types of cancer (Kotake-Nara 2005; Mikami and Hosokawa 2013; Satomi 2012). In fact, the regular consumption of seaweeds containing high quantities of fucoxanthin is believed to be the reason for the longevity of certain populations (Kumar et al. 2013).
Astaxanthin, a rare ketocarotenoid synthesized only by limited numbers of organisms, has therapeutic applications, for example, against free radical-associated diseases like oral, colon, and liver cancers, cardiovascular diseases, and degenerative eye diseases (Han et al. 2013). Several reviews focused on carotenoids from algae have recently been published (Jin and Melis 2003; Guedes et al. 2011; Mezzomo and Ferreira 2016; Takaichi 2011). Moreover, astaxanthin is a main compound in the salmon feed industry with more than US$200 million (Hejazi and Wijffels 2004).
The most common phycobiliproteins in the industry are phycoerythrin and phycocyanin that can be produced by Arthrospira species and Porphyridium species (Viskari and Colyer 2003; Roman et al. 2002). The application of phycobiliproteins is focused in health-promoting properties, such as food pigment. On the other hand, phycobiliproteins are interesting in clinical applications due to their high molar absorbance coefficients, high fluorescence quantum yield, and high photostability. In this sense, phycobiliproteins can be used as labels in fluorescence medical diagnostics (Roman et al. 2002).
Recently has been published a review focused on microalgae-derived phytosterols applications in functional food and pharmaceutical industries (Luo et al. 2015). Phytosterols are important structural components of the cellular membrane and have important functions in regulating membrane fluidity and permeability. They also exist as hormones or hormonal precursors and are involved in signal transduction in the organisms. In addition, phytosterols reduce the level of cholesterol in blood helping to prevent cardiovascular disorders (Ras et al. 2013; Gylling et al. 2014).
Waterman and Mole (1994) defined polyphenolic secondary metabolites as a large and diverse group of chemical compounds, which are common both in terrestrial plants and in aquatic macrophytes (without citing microalgae). The term phenolic includes more than 8000 naturally compounds with one common structural feature, a phenol. The phenolic compounds are divided into two groups according to the number of phenol subunits: simple phenols and polyphenols (with at least two phenol subunits) (Leopoldini et al. 2011), and tannins were described as compounds possessing three or more phenol subunits (Clifford 1999). Polyphenols are primarily recognized for their antioxidant capability toward free radicals normally produced by cells metabolism or in response to external factors. In living systems under stress, the excessive generation of hydroxyl radical (OH•) and other highly reactive oxygen species (ROS) produce oxidative damage through the reaction of these species with almost every cellular biomolecules including DNA. Many studies on pharmacological research have evidenced that oxidative stress and increased amounts of free radicals are features of chronic diseases including cancer (Klaunig and Kamendulis 2004), aging and neurodegenerative diseases such as Alzheimer’s and Parkinson’s (Nunomura et al. 2006; Wood-Kaczmar et al. 2006) and cardiovascular diseases such as atherosclerosis (Siti et al. 2015). They are the primary causes of cell death and tissue damage resulting from a heart attack and stroke (Perron and Brumaghim 2009). Phenolic compounds are radical scavengers and inhibit metal-mediated oxyradical formation preventing various processes of oxidative stress considered the origin of the above-cited diseases (Jomova and Valkoa 2011; Zhaoa et al. 2005; Aprioku 2013). Therefore, polyphenols display a number of pharmacological, medicinal and biochemical properties extensively reviewed: they present antiviral, anti-inflammatory, antibacterial, and antihistamine activities, cardiovascular effects and are implicated in the prevention of neurodegenerative diseases (Brit et al. 2001; Dai and Mumper 2010; Graf et al. 2005; Hertog et al. 1993; Mandel et al. 2006; Lambert and Yang 2003; Pandey and Rizvi 2009; Quideau et al. 2011).
Several mechanisms have been proposed for polyphenol prevention of oxidative stress: they are able to inhibit free radicals according to the hydrogen atom transfer and to the single electron transfer mechanisms. In the first one, the bond dissociation enthalpy of the phenolic O–H bond is an important parameter in evaluating the antioxidant action, while in the second the ionization potential is the most significant parameter for the scavenging activity evaluation. These mechanisms often take place simultaneously and depend on the pH (Leopoldini 2011; Perron and Brumaghim 2009). Polyphenols are also capable of chelating metal ions leading to stable complex compounds and avoiding them to take part in the reactions generating free radicals (Flora 2009).
Among phenolic compounds, phlorotannins (polymers of phloroglucinol units linked to each other in various ways) have only been detected in brown algae (Koivikko et al. 2007; Li et al. 2011; Ragan and Glombitza 1986) such as seaweeds Ecklonia sp., which have provided various phlorotannins with diverse biological activities (Kang et al. 2004; Kim et al. 2006: Shin et al. 2014; Wijesinghe et al. 2011). Consumption of phlorotannin-rich algae Fucus distichus and Ecklonia cava may be useful for the treatment of diabetes (Kellogg et al. 2014; Lee and Jeon 2015). Phlorotannin dieckol, isolated from the edible brown algae Ecklonia cava, suppresses ovarian cancer cell growth (Ahn et al. 2015) and shows antithrombotic activity among others, useful in the development of agents for the anticoagulation (Kim et al. 2012).
On the other hand, only a few references have dealt with the beneficial effects of phenolic compounds from microalgae in human health. Despite marine microalgae are known to produce numerous useful products, have attracted little attention in the search of polyphenolic compounds. Recently, several methodologies for identification and quantification of polyphenolic compounds from microalgae extracts have been reported (Rico et al. 2013; López et al. 2015). These publications are focused on the implications of polyphenols in microalgae growing under metal stress paying special attention to the influence of Cu(II) and Fe(III) metals on the cells and exudated phenolic profiles of the marine green microalgae Dunaliella tertiolecta and the marine diatoms Phaeodactylum tricornutum. In these studies, the authors measured the concentration of gallic acid, protocatechuic acid, (+) catechin, vanilic acid, (−) epicatechin, syringic acid, gentisic acid, caffeic acid, coumaric acid, ferulic acid, rutin, myricetin and quercetin.
Cells exposed to copper excreted a larger amount of polyphenols as a protective mechanism to alleviate the toxicity of the copper in the solution: these phenolic compounds are implicated countering metal toxicity at the membrane surface and slowing down the toxicity of metals in the extracellular media.
The extracts of Dunaliella tertiolecta and Phaeodactylum tricornutum showed antioxidant activity and high amounts of phenolics confirming their pharmaceutical and medicinal value.
Authors thank the Project CTM2014-52342-P given by the Ministerio de Economia y Competitividad from Spain. Aridane G. Gonzalez thanks the French “Agence Nationale de la Recherche” through the “Laboratoire d’Excellence” LabexMER (ANR-10-LABX-19-01) program, and co-funded by a grant from the French government through the “Investissements d’Avenir” and the Brittany Region.
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