Secondary Metabolite Production by Cyanobacteria

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1		Sang-Hyeok Cho	+ 4720 word(s)	4720	2020-12-02 09:01:28	\|
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This entry is adapted from the peer-reviewed paper 10.3390/microorganisms8121849

Cyanobacteria are naturally capable of producing valuable secondary metabolites through photosynthesis. These photosynthetic bacteria can be further improved via engineering to produce more in terms of diversity and yield. Recent advances in systems and synthetic biology approaches are being adopted in the cyanobacterial engineering field to push the industrial capabilities even further.

cyanobacteria photosynthesis secondary metabolites metabolic engineering synthetic biology systems biology genome-scale model

1. Introduction

Cyanobacteria are oxygenic photosynthetic bacteria that can produce various secondary metabolites. Given the ability to utilize sunlight and atmospheric carbon dioxide (CO₂) as a part of the renewable photosynthetic process, cyanobacteria are considered sustainable bioproduction hosts ^[1]. A number of secondary metabolites naturally synthesized by cyanobacteria, such as carotenoids, phycocyanins, and squalene, are used in the pharmaceutical, cosmetic, and healthcare industries ^[2]^[3]^[4]. In addition, owing to their rapid growth and increased scope for engineering, multiple efforts have been made to utilize cyanobacteria as production hosts for valuable biochemicals by introducing heterologous pathways ^[5]^[6].

While continuous development has been reported in metabolic engineering strategies for producing biochemicals in bacterial hosts, the synthetic biology approach accelerated the development by providing diverse genetic parts and engineering tools. For other model platforms such as Escherichia coli, there is an abundant catalog of genetic parts including synthetic promoters and ribosome binding sites (RBSs), which have been successfully introduced to improve gene expression in heterologous pathways ^[7]. However, owing to the lack of genetic parts for pathway engineering in cyanobacteria, application of metabolic engineering tools is limited ^[8]. Thus, development of various tools for pathway engineering and subsequent engineering strategies are required for industrial-scale production of target compounds in cyanobacteria.

With the recent progress in systems biology, genome-wide information of diverse layers such as the genome, transcriptome, translatome, proteome, metabolome, and interactome are being constantly accumulated ^[9]. Massive amounts of data formed the basis for establishment and development of an in silico genome-scale model (GEM) ^[10]. It is expected that the application of system-level approaches with the integration of omics data and GEM would address the existing limitations of cyanobacterial engineering.

2. Secondary Metabolite Production by Cyanobacteria

Bacteria produce two kinds of metabolites: primary metabolites essential for survival and secondary metabolites required for auxiliary purposes, such as stress responses, defense mechanisms, metal carrying, and signaling ^[11]. Secondary metabolites include terpenes, alkaloids, polyketides (PKs), non-ribosomal peptides (NRPs), and ribosomally synthesized and post-translationally modified peptides (RiPPs), which are produced via biosynthetic gene clusters (BGCs). BGCs are clusters of genes positioned in approximate proximity to each other for the production and processing of a compound. Cyanobacteria, being rich in BGCs, are capable of producing diverse secondary metabolites for various purposes, including toxins for defenses or protectants for relieving photodamage and oxidative stress (Table 1).

Table 1. Bioactive secondary metabolites produced in cyanobacteria.

Class	Metabolite	Bioactivity	Producing Species	Ref.
Terpene	Phycocyanin	Antioxidant, anti-inflammatory, neuroprotective, hepatoprotective	All cyanobacteria	^[12]^[13]^[14]^[15]^[16]
Terpene	Carotenoids	Antioxidant, sunscreen	All cyanobacteria	^[17]^[18]
Terpene	Squalene	Antioxidant	Phormidium	^[19]
Alkaloid	Saxitoxin	Neurotoxin	Anabaena, Aphanizomenon, Cylindrospermopsis, Lyngbya, Planktothrix,	^[20]^[21]^[22]
Indole	Nostodione	Antifungal	Nostoc	^[23]
Indole alkaloid	Scytonemin	Anti-inflammatory, sunscreen	Scytonema, Nostoc	^[24]^[25]^[26]^[27]
Indole alkaloid	Hapalindole	Antibacterial, anti-tuberculosis, anticancer	Hapalosiphon	^[28]^[29]
Alkaloid/Polyketide synthase (PKS)	Anatoxin-a	Neurotoxin, anti-inflammatory	Anabaena, Aphanizomenon, Cylindrospermum, Oscillatoria, Planktothrix	^[30]^[31]
Alkaloid/PKS	Aplysiatoxin	Cytotoxin, antiviral	Moorea	^[32]^[33]
Alkaloid/Non-ribosomal peptide synthetase (NRPS)	Lyngbyatoxin	Cytotoxin, dermatotoxin	Moorea	^[34]
Alkaloid/PKS-NRPS	Cylindrospermopsin	Cytotoxin	Aphanizomenon, Cylindrospermopsis, Oscillatoria, Raphidiopsis	^[35]^[36]^[37]
PKS	Fischerellin	Antifungal, antialgal, anti-cyanobacterial	Fischerella	^[38]
NRPS	β-N-methylamino-l-alanine	Neurotoxin	Anabaena, Nostoc	^[39]
NRPS	Cyanopeptolin	Protease inhibitor	Planktothrix, Microcystis	^[40]^[41]
PKS-NRPS	Microcystin	Hepatotoxin	Microcystis, Nostoc, Planktothrix, Anabaena	^[40]^[42]^[43]^[44]^[45]
PKS-NRPS	Nodularin	Hepatotoxin	Nodularia	^[46]
PKS-NRPS	Apratoxin	Anticancer	Lyngbya	^[47]
PKS-NRPS	Aeruginoside	Protease inhibitor	Planktothrix	^[48]
PKS-NRPS	Aeruginosin	Protease inhibitor	Microcystis, Planktothrix	^[40]^[49]
PKS-NRPS	Cryptophycins	Cytotoxin	Nostoc	^[50]
PKS-NRPS	Nostophycins	Cytotoxin	Nostoc	^[51]
PKS-NRPS	Curacins	Cytotoxin	Moorea	^[52]
PKS-NRPS	Hectochlorin	Cytotoxin	Moorea	^[53]
PKS-NRPS	Jamaicamides	Neurotoxin	Moorea	^[54]
PKS-NRPS	Dolastatin	Cytotoxin, anticancer, antiprotozoal	Moorea, Lyngbya, Symploca	^[55]^[56]
Lipopeptide	Antillatoxin	Neurotoxin	Moorea	^[57]
Lipopeptide	Carmabin	Antimalarial, anticancer, antiproliferative	Moorea	^[58]^[59]
Lipopeptide	Lyngbyabellin	Cytotoxin, antifungal	Moorea, Lyngbya	^[60]^[61]
Lipopeptide	Kalkitoxin	Neurotoxin	Moorea	^[57]
Ribosomally synthesized and post-translationally modified peptide (RiPP)	Patellamide	Moderate cytotoxicity	Prochloron	^[62]
RiPP	Microviridin	Protease inhibitor	Microcystis, Planktothrix	^[63]^[64]
RiPP	Shinorin	Sunscreen	Anabaena, Nostoc	^[65]
Fatty acid amide	Besarhanamide A	Moderate toxicity to brine shrimp	Moorea	^[66]
Fatty acid amide	Semiplenamide	Toxicity to brine shrimp	Lyngbya	^[67]
Lipopolysaccharide	Lipopolysaccharides	Endotoxin	All cyanobacteria	^[68]
Polysaccharide	Polysaccharide	Antitumor, antiviral, antibacterial, anti-inflammatory, immunostimulant	All cyanobacteria	^[69]^[70]^[71]
Nucleoside	Toyocamycin	Antifungal	Tolypothrix	^[72]
Nucleoside	Tubercidin	Antifungal	Tolypothrix	^[73]

2.1. Prediction of Biosynthetic Gene Clusters (BGCs) in Cyanobacterial Genomes

To investigate the secondary metabolites produced by cyanobacteria, 196 complete genome sequences of cyanobacteria available at the National Center for Biotechnology Information (NCBI) genome portal were inspected for BGCs using antiSMASH ^[74]. Thirty-three different types of BGCs were identified. The 196 complete genome sequences of cyanobacteria used in the BGC search were arranged according to the phylogenetic tree. The heatmap representing the numbers of each type of BGC found in each cyanobacterium showed that the cyanobacteria from the same genera had similar classes and numbers of BGCs (Figure 1A). It was evident that a single genome contained several BGCs with multiple occurrences. In particular, there were cyanobacteria with large number of bacteriocin, terpene, and non-ribosomal peptide synthetase (NRPS) BGCs, which accounted for 74.4% of the total predicted BGCs (n = 2119). For example, it was predicted that the genome of Moorea producens PAL-8-15-08-1 carries 18 NRPS BGCs. The most widely distributed BGC was the terpene BGC, which was found in all cyanobacteria except for two species (Limnospira fusiformis SAG 85.79 and Nodularia spumigena UHCC 0039). Terpene is essential for photosynthetic organisms. Undetected terpene BGCs in the two species could have resulted from the deviations in the BGC search criteria of antiSMASH. The 33 BGCs were classified according to their structural and functional similarities to the following categories: terpene, indole, PK synthase (PKS)/NRPS (type 1, 2, 3 PKSs, NRPS, cyclodipeptide synthase-based tRNA-dependent peptide, resorcinol, and siderophore), RiPP (bacteriocin, lanthidin, linear azole-containing peptide, microviridin, lasso peptide, cyanobactin, thiopeptide, trifolitoxin, proteusin, and lanthipeptide), lipid/saccharide/nucleoside (heterocyst glycolipid synthase, ladderane, arylpolyene, aminoglycoside/aminocyclitol, oligosaccharide, and nucleoside), and others (phosphonate, phenazine, ectoine, β-lactone, and homoserine lactone).

2.2. Terpenes

Terpene is a family of compounds with varying structures that occupies a large proportion of the natural products ^[75]. Terpenes are mainly produced by plants or fungi, as well as the bacterial species via mevalonate (MVA) pathway or methylerythritol-phosphate (MEP) pathway using acetyl-CoA or glyceraldehyde 3-phosphate and pyruvate as substrates ^[76]. While MVA and MEP pathways are mutually exclusive in most organisms, cyanobacteria mainly utilize the MEP pathway, using substrates generated during photosynthesis. The MEP pathway produces isomeric 5-carbon compounds, isopentyl pyrophosphate (IPP), and dimethylallyl pyrophosphate (DMAPP), which are further condensed into geranyl pyrophosphate (GPP), the building block in terpene biosynthesis. From the GPP, terpenes of varying structures can be generated. Terpenes conduct various cellular processes necessary for survival, such as the ubiquinone in the electron transport chain associated with cellular respiration, chlorophyll, carotenoids, and plastoquinones in photosynthetic processes, and hopanoids in cell membrane biosynthesis and stability (Figure 1B) ^[77]. In particular, photosynthetic cyanobacteria contain a wide variety of carotenoids. Most of the genome-sequenced cyanobacteria have β-carotene BGC. Production of other carotenoids, such as zeaxanthin and nostoxanthin are dependent on the presence of carotenogenesis pathway connected to β-carotene ^[3]^[78]. The terpene compounds, including the carotenoids obtained from cyanobacteria are of industrial value owing to their various applications. For example, β-carotene, astaxanthin, and canthaxanthin are used as color additives or animal feeds. Phycocyanin exhibits anti-oxidant, anti-inflammatory, neuroprotective, and hepatoprotective effects ^[2]^[13]^[79].

Figure 1. Cyanobacterial secondary metabolites. (A) Heatmap of the predicted cyanobacterial secondary metabolite biosynthstic gene clusters (BGCs). The left-most phylogenetic tree is constructed by up-to-date bacterial core gene (UBCG) phylogenetic analysis of the 196 cyanobacterial complete genome sequences. The evolutionary distances were provided by UBCG and plotted by RAxML ^[80]^[81]. The tree is not to scale. Red: Nostoc, purple: Calothrix, green: Synechocystis, pink: Synechoccus, blue: Microcystis, and yellow: Prochlorococcus. (B–F) Molecular structures of cyanobacterial secondary metabolites. (B) Terpenes, (C) alkaloids, (D) polyketides (PKs), non-ribosomal peptides (NRPs), (E) RiPPs, and (F) fatty acid amide. Abbreviations; NRPS, non-ribosomal peptide synthetase; HglE, heterocyst glycolipid synthase; LAP, linear azol(in)e-containing peptide; TfuA, ribosomally synthesized peptide antibiotic trifolitoxin; CDPS, cyclodipeptide synthase-based tRNA dependent peptide; PKS, polyketide synthase; Amglyccycl, aminoglycosides/aminocyclitols; TransAT, trans-acyltransferase type I PKS.

2.3. Alkaloids

Alkaloids comprise various nitrogen containing compounds that are produced from diverse organisms, including fungi, plants, bacteria, and animals. Alkaloids produced by cyanobacteria often show toxic characteristics. For example, the anatoxin-a produced by species of the Anabaena genera is a neurotoxin that binds irreversibly to nicotinic acetylcholine receptors causing paralysis or even death in fish and mammals (Figure 1C) ^[31]. Anatoxin-a is also categorized as a PK, which is synthesized by PKS ^[82]. Another well-known example, saxitoxin, blocks the sodium (Na⁺) channels in shellfish and induces paralytic shellfish poisoning in humans on consumption of saxitoxin-accumulated seafood. The chemical derivatives carrying the indole rings are classified as indole alkaloids. They are biosynthesized using tryptophan as a precursor. Cyanobacterial indole alkaloids have diverse functions. For example, the hapalindole synthesized from cyanobacteria Hapalosiphon fontinalis exhibits antibacterial, anti-tuberculosis, and anticancer activities ^[83]. In addition, the scytonemin produced by Scytonema sp. renders photoprotective effects to the cyanobacterial cells by absorbing the harmful ultraviolet (UV)-A radiation ^[84].

2.4. Polyketides/Non-Ribosomal Peptide/Lipopeptides/Siderophores

PKS and NRPS are representatives of enzymes responsible for the biosynthesis of secondary metabolites in various organisms. Enzymes of these classes consists of at least three essential modular domains that facilitate chain elongation and modification ^[85]. First, the catalytic domain binds to and activates the building block, which then is transferred to the carrier protein domain. Second, the carrier protein domain loads the activated building block to the growing PK/NRP chain it holds. Third, the other catalytic domain catalyzes the bond formation between the growing chain and the newly loaded building block. PKS and NRPS differ in their use of precursors for the building block. While PKS utilizes malonyl-CoA or methylmalonyl-CoA, the NRPS uses proteinogenic and non-proteinogenic amino acid monomers. In addition, there are cases wherein compounds are synthesized via the PKS–NRPS hybrid system. A well-known example could be microcystin, the BGC of which contains two PKS, single PKS–NRPS, and three NRPS ^[42]^[86]. Microcystin produced from various cyanobacterial species belonging to the genus Microcystis, Nostoc, Planktothrix, and Anabaena, shows hepatotoxic activity in humans (Figure 1D). Various other toxins synthesized by the PKS, NRPS, or PKS–NRPS hybrid system includes lyngbyatoxin, apratoxin, and aplysiatoxin.

The NRPS includes lipopeptides owing to their lipid linked peptide structures synthesized by a combination of lipid tails and amino acids. Examples of lipopeptides include antillatoxin and carmabin from M. producens, and lyngbyabellin from M. bouillonii (Figure 1D). Antillatoxin and lyngbyabellin show neurotoxic activity and cytotoxicity, and carmabin exhibit anti-malarial activity. Siderophores are included in the NRPS-produced compounds. Iron is essential for bacterial survival. However, since it exists in an insoluble form in the environment, some bacteria have evolved to facilitate iron uptake by producing small molecules with high affinity to ferric iron, called siderophores.

2.5. Ribosomally Synthesized and Post-Translationally Modified Peptides

RiPP is a class of secondary metabolites that includes, as its name depicts, ribosomally synthesized and post-translationally modified peptides. Post-translational modifications include leader peptide hydrolysis, cyclization, and disulfide bond formation. RiPP BGC generally consists of a short precursor peptide with an N-terminal leader and a C-terminal core sequence, and post-translational modification (PTM) enzymes ^[87]^[88]. The PTM enzymes shape the linear peptide by several modifications that provide structural and functional diversity to the mature scaffold. Compounds that were previously classified as lanthipeptide, lasso peptide, microviridin, cyanobactin, and microcin are now re-classified under RiPP, which have a broad range of bioactivities such as protease inhibition, cytotoxicity, signaling, anti-cancer, and anti-human immunodeficiency virus (anti-HIV) (Figure 1E) ^[87]. For example, microviridin, which was first isolated from M. viridis, is a serine protease inhibitor, and patellamide A produced by Prochloron didemni has moderate cytotoxicity ^[62].

2.6. Lipids/Saccharides/Nucleosides/Others

Lipids, saccharides, and nucleosides are generally categorized as primary metabolites. However, there are exceptions, when they are considered as secondary metabolites instead of primary metabolites. For example, besarhanamide A and semiplenamide exhibiting toxicity against brine shrimp are fatty acid amides isolated from M. producens and Lyngbya semiplena, respectively (Figure 1F) ^[66]^[89]. It is known that cyanobacterium Cyanothece sp. 113 can produce up to 22 g/L of polysaccharide, which exceeds the producing ability of eukaryotic microalgae, such as Dunaliella salina ^[90]^[91]. Polysaccharides are generally used as stabilization or thickening agents for emulsions. In some cases, they are used as bioactive compounds owing to their antitumor, antiviral, antibacterial, anti-inflammatory, and immunostimulatory properties ^[92]^[93]^[94]^[95]. Toyocamycin and tubercidin are both anti-fungal nucleoside chemicals isolated from Tolypothrix tenuis ^[96]. In addition, a small number of phosphonate, phenazine, ectoine, and β-lactone BGC were also detected.

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