Abstract
Carotenoids are naturally produced by plants, algae, and some bacteria and fungi, fulfilling functions as accessory photosynthetic pigments and antioxidants. Among carotenoids, the xanthophyll astaxanthin stands out for its antioxidant and nutraceutical properties, which are beneficial to human health, and also for its use in the aquaculture industry as nutritional supplement of salmonid fish. Many studies have focused on the search of natural sources of astaxanthin as an alternative production that guarantees the beneficial properties of this compound. In nature, few astaxanthin-producing organisms are known, being the microalgae Haematococcus pluvialis and the yeast Xanthophyllomyces dendrorhous the most promising microbiological systems for the biotechnological production of this carotenoid. In this chapter, we describe the carotenogenic pathways in these microorganisms and the proposed carotenogenesis regulation mechanisms. As an example, the influence of the carbon source, the regulation by catabolic repression and by sterols in the carotenogenesis in the yeast X. dendrorhous is described.
Keywords
- astaxanthin
- Xanthophyllomyces dendrorhous
- ergosterol
- catabolite repression
1. Introduction
Currently, carotenoids are valuable molecules due to their use in different industries such as chemical, pharmaceutical, poultry, food and cosmetics. These pigments have coloring and antioxidant properties that have attracted the attention of researchers and industries as they have useful applications on several fields [1]. Carotenoids are naturally occurring lipid-soluble pigments, the majority being C40 terpenoids, which act as membrane-protective antioxidants scavenging O2 and peroxyl radicals; their antioxidant ability is apparently attributed to their structure, which in some cases (for example: astaxanthin) contain two terminal rings joined by a double conjugated chain or polyene system. Carotenoids are classified in two major groups: i) carotenes, composed only by carbon and hydrogen, and ii) xanthophylls, which are oxygenated derivatives [2]. Approximately 600 different carotenoid structures have been described to date that can be found in most life forms and have various functions ranging from their original role as photosynthetic pigments to antioxidants, precursors of vitamin A or pigments involved in the visual attraction of pollinating animals [2].
Commercial carotenoids are mainly obtained by extraction from plants and by chemical synthesis. However, some problems regarding seasonal and geographic variability that cannot be controlled arise in the case of production and marketing of several colorants of plant origin. On the other hand, the chemical synthesis may generate hazardous waste that can affect the environment. Unlike these traditional methods, the microbial production of carotenoids turns into a great opportunity of safe use. Microbial production has the advantage to use low-cost substrates, resulting in lower production costs. This explains the increasing interest in the production of microbial carotenoids as substitutes for synthetic carotenoids used as colorants in food and feed industries [1]. Among carotenoids, the xanthophyll astaxanthin stands out for its antioxidant and nutraceutical properties that are beneficial to human health, and for its use in the aquaculture industry as nutritional supplement of salmonid fish [3]. Many studies have pointed to search for a natural source of astaxanthin as an alternative production method that guarantees the beneficial properties of the mentioned compound. In nature, few astaxanthin-producing organisms are known, being the microalgae
Despite the potential of
This chapter is focused on the microbiological synthesis of astaxanthin, taking as example the microorganisms
2. Importance of astaxanthin
Astaxanthin (3,3′-dihydroxy-β, β′-carotene-4,4′-dione) belongs to the xanthophyll group and its structure consists of two terminal rings joined by a polyene chain (Figure 1). In addition to the existence of cis or trans geometric isomers, astaxanthin presents 3 configurational isomers: two enantiomers (
Being a xanthophyll, astaxanthin possesses chemical properties and physiological characteristics of these compounds: it is highly lipophilic and shows an intense red color based on the light absorbed by its polyene system [22]. Due to its 3-hydroxyl and 4-keto functional groups in the terminal rings, astaxanthin has a higher polarity than other carotenoids and an antioxidant activity greater than that of β-carotene, lutein, zeaxanthin and canthaxanthin [5, 23, 24]. Due to its high antioxidant activity, there is an increasing number of studies referring to the astaxanthin beneficial properties for human health including several properties such as anti-inflammatory, anti-diabetic, antibacterial, immunostimulant, photoprotective, neuroprotective, anticancer and benefits to cardiovascular health, among others [2, 5, 22]. From an economical point of view, astaxanthin is the third most important carotenoid in the carotenoid global market after β-carotene and lutein. Astaxanthin market reached the 29% of total carotenoid sales with a global market size of $225 million, estimating to increase to $253 million by 2018, approximately [1]. Currently, the vast majority of the commercial offer corresponds to synthetic astaxanthin. However, the use of chemical compounds as food additives has been strictly regulated, favoring food free of them from both, the consumers and the authorities [1, 2, 5]. In this context, the society nowadays is looking toward “green” solutions; thus, astaxanthin from natural sources, as from microorganisms, seems to be more favorable than its synthetic counterpart due to structure, function, application and security [25, 26].
3. Microbiological synthesis of astaxanthin
In general, the microbiological synthesis of carotenoids has conservative steps among the different species of carotenogenic microorganisms. The most conserved carotenoid biosynthesis pathways in eukaryotic microorganisms involve three general steps [1]:
The synthesis begins with the conversion of acetyl-CoA to 3-hydroxy-3-methyl glutaryl-CoA (HMG-CoA), catalyzed by HMG-CoA synthase. Then, HMG-CoA is converted into mevalonic acid (MVA), being the first precursor of the terpenoid biosynthetic pathway. The following steps include two sequential phosphorylation reactions performed by the enzymes mevalonate kinase and phosphomevalonate kinase, respectively, and a final decarboxylation step catalyzed by phosphomevalonate decarboxylase to produce IPP [1, 20].
IPP is isomerized to dimethylallyl pyrophosphate (DMAPP). The addition of three IPP molecules to DMAPP, catalyzed by prenyltransferases, produce geranylgeranyl pyrophosphate (GGPP). Then, the condensation of two molecules of GGPP produces phytoene (the first C40 carotene of the pathway), which is subsequently desaturated to produce lycopene [1].
Lycopene undergoes many modification reactions and several cyclic carotenoids derived from lycopene such as β-carotene, γ-carotene, torulene, torularhodin and astaxanthin [1].
Despite the common steps in carotenogenesis, there are particular differences in the synthesis pathways between different microorganisms. In the following sections, the carotenogenic pathways in the microalgae
3.1. Astaxanthin biosynthesis in X. dendrorhous
It is currently believed that the main function of carotenoids in
The synthesis pathway preserves the basic steps of carotenoid synthesis in this yeast; however, some steps involve characteristic enzymes in fungi and other characteristic enzymes in
3.2. Biosynthesis of astaxanthin in the microalgae H. pluvialis
Several algae and microalgae are able to produce astaxanthin, but
For the production of pigments, the microalgae
As in
The carotenogenic pathway described for
4. Potential mechanisms that regulate the synthesis of astaxanthin
The astaxanthin synthesis pathway has been extensively studied, and most of genes and enzymes involved are currently known. More recent studies have focused on elucidating the possible regulation mechanisms of carotenogenesis. In the case of yeast
4.1. Regulation of carotenogenesis in X. dendrorhous
An important function of astaxanthin in
It is known that
As in other yeasts,
On the other hand, studies of carotenogenic gene transcripts (
It is well known that glucose has a global effect on cellular metabolism; generally, when this sugar is present in the culture medium, the expression of genes involved in the metabolism of alternative to glucose carbon sources and secondary metabolism is repressed [52]. This phenomenon is known as “catabolic repression” or “repression by glucose” [53] and could be responsible for the repression of carotenogenic genes in
4.1.1. Catabolic repression: mechanism and components
In microorganisms of free life, the availability of nutrients is in constant change and is the main factor regulating their growth and development. For yeasts, as for many other microorganisms, glucose is the preferred source of carbon and energy. Therefore, it is not surprising that glucose, in addition to its function as a nutrient, plays an important regulatory role in the metabolism of microorganisms. Thus, a high concentration of glucose in the medium resembles optimal growth conditions to the cellular machinery, causes the induction of various signal transduction pathways, and the activation or inactivation of various proteins. The regulatory role of glucose is more prominent at the transcription level and the general mechanism of catabolic repression involves a parallel decrease in the transcript levels of the target genes and, consequently, of the proteins they encode [52, 54].
Catabolic repression has been widely studied in
One of the ways in which glucose influences gene expression is by facilitating the action of negative regulators [52], among them, the Mig1 factor (homologous to CreA in
In general, glucose repression in
4.1.2. Catabolic repression and carotenogenesis regulation in X. dendrorhous
In view of the diverse background that suggests that carotenogenesis is regulated by catabolic repression, recent studies have advanced characterizing the catabolic repression mechanism in
Moreover, according to descriptions of other yeasts, one consequence of catabolic repression is the preferred use of glucose over other alternative carbon sources, deferring their use until glucose has been completely consumed. The preferential use of glucose over an alternative carbon source can be evidenced by a characteristic growth rate change of the microbial culture, known as diauxic growth [59, 64]. This aspect has been evaluated in
As mentioned before, the Mig1 factor recruits a co-repressor complex formed by the Cyc8 and Tup1 proteins to perform repression at transcriptional level. Thus, in other study, the role of these co-repressors in catabolic repression and carotenogenesis was assessed in
So, many studies support the hypothesis that carotenogenesis in
4.1.3. Relation between carotenogenesis and sterol biosynthesis
Ergosterol is the main sterol in fungi, fulfilling similar roles as cholesterol in mammalian cells. Since the synthesis of ergosterol and of fatty acids derive from the same precursors as the synthesis of astaxanthin in
In
Similar to these results, other studies have demonstrated an increased astaxanthin production in
All together these results suggest that in
4.2. Regulation of carotenogenesis in H. pluvialis
It has been extensively accepted that carotenoid synthesis in
Studies at the mRNA levels of the carotenogenic genes:
5. Conclusions
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