Food and Chemical Toxicology 120 (2018) 616–624

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Food and Chemical Toxicology

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Cyanobacterial pigments: Perspectives and biotechnological approaches T

a b a,∗
Dinesh Kumar Saini , Sunil Pabbi , Pratyoosh Shukla
a
Enzyme Technology and Protein Bioinformatics Laboratory, Department of Microbiology, Maharshi Dayanand University, Rohtak, 124001, Haryana, India
b
Centre for Conservation and Utilisation of Blue Green Algae (CCUBGA), Division of Microbiology, ICAR - Indian Agricultural Research Institute, New Delhi, 110 012,
India

A R T I C LE I N FO A B S T R A C T

Keywords: Cyanobacteria are the oxygenic photosynthesis performing prokaryotes and show a connecting link between
Cyanobacteria plastids of eukaryotic autotrophs and prokaryotes. A variety of pigments, like chlorophyll, carotenoids and
Biopigments phycobiliproteins which exhibit different colors are present in cyanobacteria. Increasing consciousness about the
Phycobiliprotein harmful effects of synthetic or chemical dyes encouraged people to give more preference towards the usage of
Chlorophyll
natural products, such as plant or microbial-derived colors in food and cosmetics. That is why cyanobacteria are
Metabolic engineering
Systems biology
exploited as a source of natural colors and have high commercial value in many industries. This review mainly
focuses on different cyanobacterial pigments, their applications and modern biotechnological approaches such as
genetic engineering, systems biology to enhance the production of biopigments for their potential use in
pharmaceuticals, food, research, and cosmetics industries.

1. Introduction
Coloration provides attractiveness to the product, so a variety of
coloring agents are widely used in textile, food and cosmetic industries.
Coloring agents used in food and textile industries are called dyes,
whereas colorants used in cosmetics, ink, pharmaceutical are known as
a pigment (Dikshit and Tallapragada, 2018). Most of the colorants are
usually chemically derived due to high demand in different industries.
Most of these colorants are non-biodegradable in nature and hazardous
to human health. Now a days people are aware of the impact of che-
mically derived colors and their effect on the environment and the
human health. Free reactive species such as ROS (reactive oxygen
species) and RNS (reactive nitrogen species) have both toxic and non-
toxic nature (Rastogi et al., 2010). These free radicals, which can be
produced due to cellular metabolism or due to ex-situ sources such as
medication, radiation, etc., play a vital role in a metabolic disorder such
as diabetes, cataract and also of aging, arthritis etc (Sen et al., 2010).
Biopigments such as carotenoids and phycobiliproteins fluoresce at
particular wavelengths and express specific colors (Rastogi et al., 2014)
and also have excellent properties as an antioxidant. These can be de-
rived from different natural sources such as plant, microalgae including
cyanobacteria, fungi and bacteria. Cyanobacteria are a rich source of a
variety of biopigments and can be utilized as excellent sources of colors
(Dufossé et al., 2005; Mourelle et al., 2017).
Cyanobacteria are photoautotrophic, gram-negative prokaryotes
that are well recognized for their compelling role in global CO2 se-
questration and nitrogen fixation. Earlier these were known as blue
green algae and the precursor of eukaryotic chloroplast (Lane, 2017).
Cyanobacteria require primary growth factors and can be quickly
grown using solar energy, water and is a source of indispensable ele-
ments like C, K, P, S, N, and Fe. They are ubiquitous but abundantly
found in the different type of water bodies like lagoon, lakes, ponds,
rivers and different stagnant water bodies (Ho et al., 2017; Rastogi
et al., 2015). These contain chlorophyll-based photosystems and phy-
cobilisomes which absorb solar radiations and changes into photolytic
reactions of photosynthesis. Compared to other photosynthetic organ-
isms, cyanobacteria also utilize Ribulose-1, 5-bisphosphate carboxylase
oxygenase (Rubisco; EC 4.1.1.39) enzyme for the carbon fixation
(Durall and Lindblad, 2015). In cyanobacteria light-harvesting com-
plexes arrange themselves in a specific manner known as phycobili-
somes. Arrangement of different light-harvesting pigment in the phy-
cobilisome is shown in Fig. 1. The organisms whose existence depends
upon light such as plants, cyanobacteria or microalgae; these have
evolved a complex set of photoreceptors that control many aspects of
their physiology and metabolism (Ho et al., 2017). Cyanobacteria are
an excellent source of peptides, trans-fatty acids, amino acids, vitamins,
minerals and pigments (Mimouni et al., 2012). Phycobiliproteins used
as a food colorant is getting more attention globally as these are non-
toxic, non-carcinogenic and have therapeutic value as compared to
synthetic food colorants which may be toxic and carcinogenic

∗
Corresponding author..
E-mail address: pratyoosh.shukla@gmail.com (P. Shukla).

https://doi.org/10.1016/j.fct.2018.08.002
Received 9 April 2018; Received in revised form 26 June 2018; Accepted 1 August 2018
Available online 02 August 2018
0278-6915/ © 2018 Elsevier Ltd. All rights reserved.
D.K. Saini et al. Food and Chemical Toxicology 120 (2018) 616–624

in most cyanobacterial species (Gan and Bryant, 2015). The chlorophyll

Fig. 1. Flow of electron in different phycobilliproteins in phycobilisomes.
(Prasanna et al., 2007; Dasgupta, 2015). Similarly, pigment such as
carotenoids is essential for animals, including human, as they can't
produce these pigments, so they need these pigment from external
sources which include plants and microorganism (cyanobacteria and
microalgae). These pigments have properties such as antioxidant,
which mediate the oxidation of free radicals and also help to regulate
cell differentiation, apoptosis and cell cycle. Carotenoids also play a
vital role in modulation of the cellular immune system as well as cell
signaling pathways (Saini and Keum, 2018). The composition of media,
wavelength, intensity as well as the duration of light has a direct effect
on the growth, biomass content and purity of microalgal pigments
(Chakdar and Pabbi, 2012; Singh and Shukla, 2014; Lima et al., 2018).
2. Cyanobacterial pigments
Pigments are light absorbing compounds which absorb light in
different range of the visible spectrum. These pigments have a complex
conjugative structure which enables them to absorb and excite elec-
trons at different energy level. The backbone of pigments consists of
isoprene and tetrapyrrole rings. Chlorophyll and phycobiliproteins have
tetrapyrrole ring structure, whereas carotenoids are made of isoprene
units (Chakdar and Pabbi, 2017; Ariede et al., 2017).
2.1. Chlorophyll
Chlorophyll is the leading light-harvesting pigment in cyanobacteria
and other photoautotrophic organism (Kühl et al., 2005). Six different
types of chlorophyll (Chls a, b, d. f and divinyl-chls a and b) naturally
occur in cyanobacteria, but chl a was most copious chlorophyll pigment
structure contains four pyrrole rings which are arranged in a tetra-
pyrrole ring which is referred to as porphyrin, a tetrapyrrole ring
structure formed from protoporphyrin IX. Porphyrin ring contains
Mg++ in the center, attached by N molecules through coordinated and
covalent bonding. The Pyrole ring structure has four different subunits
named as A, B, C and D. Cyclopentone have attachment to ‘C’ ring, and
“D′ ring has a phytol in its side chain which was attached by ester-
ification of propionic acid. The hydrocarbon phytol structure has a long
branch having C-C bonding derived from isoprenoids structures and
derived from 4 isoprene units (Chakdar et al., 2012). As stated, different
variety of chlorophyll exists, which differ in their structure of the side
chain, chlorophyll ‘a,’ predominates in cyanobacteria. Chlorophyll is an
excellent photoreceptor because of the presence of interconnecting
single, double bonds, which allow delocalization of electron in their
structure (Song et al., 2015). This delocalization of electron permits
polyene structures to absorb light from different band of the visible
spectrum of sunlight and start the electron transfer chain reaction
which ultimately transfer to carbon dioxide. That's why the chlorophyll
pigment is present in the center of the redox reaction of water photo-
lysis and CO2 formation (Huang et al., 2016).
2.2. Carotenoids
Carotenoids are light harvesting pigments which are predominately
found with chlorophylls. These primarily absorb light in the region of
the visible spectrum, which was not absorbed by the chlorophyll
(Cerezo et al., 2012). It protects against excessive light by quenching
both singlet and triplet states of chlorophyll ‘a.’. The carotenoid struc-
tures are formed by 40 carbon isoprene unit. These are divided into
different groups by the presence or absence of oxygen at the terminal
end. The non-oxygenated derivatives are called carotene, and their
oxygenated derivatives are xanthophylls (primarily hydrocarbon).
Xanthophylls are hydrophilic due to the presence of hydroxyl and keto
groups at the end of the rings (Gong and Bassi, 2016). Carotenoids are
reactive to light, heat, and oxygen, which leads to problems in their
storage and utilization. The absorption spectrum of different type of
carotenoids is described in Table 1. Carotenoids have commercial value
because of antioxidant property, brilliant colors and health promoting
factors. The different kinds of carotenoids produced by cyanobacteria/
microalgae include β-carotene, astaxanthin, lutein (with zeaxanthin),
lycopene, canthaxanthin and Fucoxanthin to name a few.

Table 1
Major Cyanobacterial pigments and their uses.
S.No. Pigment Absorption Molecular weight Color Uses and activity Reference
spectrum (kda)

1. Chlorophyll a 662, 430 nm 892 Green Pharmaceutical and cosmetics (Deodorant) da Silva Ferreira and
Sant’Anna, 2017
Phycobiliproteins
2. Phycoerythrin 490–570 nm 240 000 Red Immunofluorescence techniques, antibody labeling Sonani et al., 2018
3. Phycoerythrocyanin 560–600 nm 232 000 Orange Chandra et al., 2017
4. Phycocyanin 610–625 nm 232 000 Blue Food colorant (ice Cream, sweets); cosmetics; Tavanandi et al., 2018
Immunofluorescence techniques; Antibody labeling,
5. Allophycocyanin 650–660 nm 105 000 Bluish green Rastogi et al., 2015
Carotenoids
6. β-Carotene 425, 450, 480 nm 536.87 Orange Antioxidants, used as pro-vitamin A Nagy et al., 2018
7. Astaxanthin 477 nm 105 000 Red Antioxidant, Anti-cancer Fonseca et al., 2015;
Guerin et al., 2003
8. Fucoxanthin 420, 444, 467 nm 658.91 Olive-green Anti-obesity, anti-proliferative activity Menichini et al., 2018
9. Lutein 425, 448, 476 nm 568.87 Yellowish red Zuluaga et al., 2017
10. Zeaxanthin 428, 454, 481 nm 568.87 Yellow Used as in age related eye diseases, anti-cancerous activity Zuluaga et al., 2017
11. Scytonemin 384 nm 544.56 Yellow-brown Anti-proliferative, anti-inflammatory. Rastogi et al., 2016; Soule
et al., 2007

617
D.K. Saini et al.
2.3. Phycobilisomes
Phycobiliproteins are colored tetrapyrrole biliprotein which absorbs
solar radiation in the region of the visible spectrum in which chlor-
ophyll show low absorption. These pigments are arranged in specific
arrangement called phycobilisomes (Kannaujiya et al., 2018) as shown
in Fig. 1. These proteins are generally divided into different categories
by their absorption spectrum, namely phycoerythrin (PE), phycocyanin
(PC), and Allophycocyanin (APC) having absorption maxima of
565 nm, 620 nm, and 650 nm respectively. These are further classified
into two categories by color viz,Phycoerythrin (red) and phycocyanin
(blue), the absorption spectrum and intensity of different phycobilli-
proteins are given in Table 1. Biliproteins primarily derived from heme
which reduced to form biliverdin were subjected to enzymatic reduc-
tion to different types of phycobilin structures. These phycobillin
chromophores structures were attached to their respective appropria-
tions through their cysteine residues by the diverse set of lyases en-
zyme. These are composed of two subunit α subunit (molecular weight
12–19 kDa) and β-subunit (molecular weight 14–21 kDa). These poly-
peptides present in an equal amount and for trimeric arrangements
(αβ3) but also found in hexamer structure {αβ6} (Chakdar and Pabbi,
2012).
Phycocyanin contains natural blue pigment and is present in almost
every phycobiliproteins containing organisms predominately in cya-
nobacteria (Udayan et al., 2017). Phycocyanin sub-divided into three
types viz C-phycocyanin (615–620 nm), Phycoerythrocyanin (575 nm)
and R-phycocyanin (615 nm). The different species of cyanobacteria,
which are reported to produce phycocyanin are Arthrospira (Spirulina)
plantesis, Arthrospira (Spirulina) maxima, Pyrophyridium sp. Synechocystis
sp. etc (Manirafasha et al., 2016). Phycocyanin has application in a
different domain, such as food additives, health food, cosmetic, phar-
maceutical and medicine (Dikshit and Tallapragada, 2018). It has
pharmaceutical application, as it is known to have anti-inflamtory,
anticancerous and anti antioxidant activities (Liu et al., 2013;
Manirafasha et al., 2016). As well as, it is used in diagonistics due to its
flourescent properties in a particular wavelength (Rastogi et al., 2016).
Phycocyanin is a rich source of protein supplements (Kent et al., 2015).
Phycoerythrin is a red colored phycobiliproteins which are also
divided into different classes like R-PE, B-PE, and C-PE (Leney et al.,
2018). These names were given on the basis of organism from which
these were first isolated (R-PE from rhodophytes, B-PE from Baigiales
(Red sea alga) and C-PE from cyanophytes). Their absorption maxima
are 565,545 and 563 nm respectively (Stadnichuk and Tropin, 2017).
2.4. Scytonemin
Scytonemin is an extracellular sheath pigment of cyanobacteria,
which is studied for its application as a photoprotectant (Gao and
Garcia-Pichel, 2011). The four gene clusters identified as NpR1271 to
NpR1274 contain sets of genes for the enzymes which are involved in
aromatic amino acid biosynthesis and it is shown that tyrosine and
tryptophan are the precursors for the scytonemin biosynthesis (Soule
et al., 2007). It acts as a covering to the cyanobacterial cell, as these
prokaryotic cells grow under UV-A radiation. It absorbs most of the UV
irradiance before they reach to photosystem and avoid any damage due
to high UV irradiances (Hernando et al., 2018) as it readily absorbs
radiation under UV spectrum. This property can be utilized to produce
UV sunscreen by mixing with ascorbic acid. It also has medical appli-
cations such as anti-inflammatory and anti-proliferative activities
(D’Orazio et al., 2012). The photoprotective nature of scytonemin al-
lows cyanobacteria to grow in harsh, rocky and highly radiated areas
(Pathak et al., 2017).
3. Beneficial application of cyanobacterial pigments
Cyanobacteria are used as nutritious food and were consumed from
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Food and Chemical Toxicology 120 (2018) 616–624
ancient times in human community because they contain a sig-
nificantnumber of bioactive compounds having numerous health ben-
efits. Spirulina and Athrospira contain rich amount of protein and used
commercially (Milledge, 2011). The species of Nostoc and Anabaena are
used as food due to their protein content in many countries such as
Chile, Mexico, Peru, and the Philippines. In addition, Nostoc spp. was
also consumed in Asia as food. Nagarkar et al. (2004) also reported that
different species of Spirulina and Phormidium have high commercial
value because of their high nutritional content. It was said that Spirulina
platensis, with a dose of 150 mg per Kg, can lower the glucose level in
the blood up to 33% and used for the treatment of diabetes mellitus
(Nagarkar et al., 2004). Now a days Spirulina sp. and Chlorella sp. are
sold in the open market at a price of about 40–50 US-$/kg. β-carotene
derived from carotenoids act as antioxidants and suppresses the adverse
effect of free radicals in the human digestion up-to multiple folds (Kaur
et al., 2017). That is one of the main reasons for using carotenoids as
“functional food” supplement. Also, β-carotene has a high requirement
in human metabolism for the synthesis of the retina, which is required
for biosynthesis of rhodopsin. In the last decade, there has been a rise in
the deficiency of β-carotene which mainly affects children and is ob-
served globally in many areas (Wells et al., 2017).
β-carotene is one of the most abundant sources of vitamin that is
also known as pro-vitamin and is used as a vitamin supplement (Kollera
et al., 2017). Astaxanthin is responsible for the pigmentation of various
aquatic organisms such as shrimps, lobster and other crustaceans
(Miyashita, 2009) that feed on microalgae. Different types of car-
otenoids like Lutein and Zeaxanthin have commercial value in Nu-
traceuticals. It has importance in the role in eye health because it is the
crucial pigment in the macula. Lutein also has been clinically confirmed
to inhibit cataract (Bernstein et al., 2016). Canthaxanthin also helps in
prevention of blood disorder diseases, however, it is also proven that it
is hazardous if taken in large quantity (Gierhart and Llc, 2015). Fu-
coxanthin is another carotenoid which is produced by cyanobacteria
and is, popular for its anti-cancer, anti-inflammatory and anti-obesity
properties (Sharma and Singh, 2017).
Phycobilins fluoresce at a particular wavelength due to which these
are used as chemical tags in research. These bind to specific antibodies
and also used in immunofluorescence technique. Phycobiliproteins
have high market value as they have high appealing applications beside
their use as biochemical tags, these are also used as food colorants and
in cosmetics industry due to their high coloration effects (Kollera et al.,
2017). Many cosmetic products use these pigments as anti-aging agents
as these act as an excellent antioxidant which inhibits the activity of
free radical to promote metalloproteinase (MMP) activity which da-
mage cell membrane and collagen in skin epidermis thus prevent aging
sign such as wrinkles formation, stretch marks etc. Cyanobacteria such
as Arthrospira, Chlorella vulgaris etc are used in many cosmetics products
reducing stretch marks and wrinkle formation (Tundis et al., 2015). C-
phycocyanin is known for its use in the treatment of cardiovascular and
renal diseases. C-phycocyanin is also related to chemotherapy of a
cancerous cell. According to most of the literature, C-phycocyanin acts
on the non-specific target from the membrane to the nucleus with dif-
ferent mechanisms. These phycocyanin proteins are capable of inter-
acting with targets and allow killing of cancerous cells which are re-
sistant to chemotherapy. An elaborate detail of interactions between
different targets has been discussed by Fernandes e Silva et al. (2018).
4. Modern biotechnological approach
Cyanobacteria and plant plastid have an evolutionary relationship.
The Synchocystis sp. PCC 6803 was the first cyanobacteria whose
complete genome sequence was done and available in the public do-
main. That is why Syenchocystis is generally used as a model organism
for cyanobacterial research. The biotechnological importance of species
belonging to cyanobacterial class is mainly due to their ability to adapt
in different environmental condition, simple growth requirement and
D.K. Saini et al.
production of high-value compounds and pigments (Singh et al., 2005).
Due to biotechnological importance, about 200 complete genome se-
quences are available in the public domain of different cyanobacterial
species (Shih et al., 2013). And due to the availability of whole genome
sequences, different approaches like transcriptomics and proteomics
can be used for the analysis of flux and system biology approaches
which can be performed using a separate ‘omics’ experiment. The first
metabolic network reconstruction in cyanobacteria was done on Sy-
nechocystis sp. in 2010. Like, earlier it was thought that the serine
biosynthesis is completed by using photorespiratory metabolism, but
now it is proved that it can be synthesised by phosphoserine pathways
(Klemke et al., 2015). A climate change due to increased levels of CO2
has raised the interest of people in eco-friendly sources of energy which
has increased the demand for photoautotrophic cyanobacteria. These
can be used for the production of different compounds like bioethanol,
hydrogen production, biodiesel and other sustainable fuels using algal
biomass (Sharma and Singh, 2017).
4.1. Genetic engineering and metabolic engineering
Variety, productivity and concentration of the product can be in-
creased by using metabolic and genetically engineered microorganism
strains, and this involves the use of different tools of genetic and me-
tabolic engineering resulting in a change in the biocatalytic pathway of
the cell to produce a different protein and novel compound (Liu et al.,
2013). Cyanobacteria are structurally similar to plant plastids and can
be potential candidates of genetic and metabolic engineering because of
simple genetic makeup (Hagemann and Hess, 2018; Panjiar et al.,
2017). Metabolic engineering in case of cyanobacteria mainly focuses
on the extracellular product formation, utilization of most photons for
the production and optimization of product production (Markou and
Nerantzis, 2013). Studies have been done for the pigment production
such as carotenoids (Astaxanthin, β-carotene, etc.) and phycobilipro-
teins (phycocyanin, Phycoerythrin etc.) observing the effect of the
different light source, temperature and the impact of different nutrients
in the metabolic process of pigment formation. As cyanobacteria are
ubiquitous, these can be found in different locations, which vary in
temperature, light intensity and wavelength, etc. These chemical and
physical factors modulate the synthesis of phycobiliproteins in respect
of required condition. Chakdar (2012) has extensively studied the effect
of nutrient (Fe), light intensity and salt (NaCl) stress on phycobilipro-
teins production and regulation of cpcb gene.
619
Food and Chemical Toxicology 120 (2018) 616–624
Fig. 2. A snapshot synthesis of biopigments and its
enzymatic machinery – {CAROTENOIDS SYNTHESIS
MEP (Methlyerythitol-4-phosphate), GGPP-
(Geranylgeranyl diphosphate),PSY- (Phytoene syn-
thase), ZDS –(ζ-carotene ketolase), BKT – (β-carotene
ketolase), PDS –(Phytoenedesaturase), CRISTO-
(Carotenoid isomerase). PHYCOBILIPROTEINS SYN-
THESIS- HeO- (Hemeoxygenase), PebA (bili-
verdinreductase), PebB (biliverdinreductase). CHLO-
ROPHYLL SYNTHESIS- CHLH (Magnesium chelates),
POR- (Protochlorophyllreductase), DVR-
(Divinylchlorophyll 8 vinyl reductase), CHLG
(chlorophyll Synthase), CLHM (magnesium protpor-
phin IX methyl transferase), CRD I (magnesium pro-
toporphrin IX methyl ester cyclase)}.
Biomass of phototrophic cyanobacteria depends upon the sunlight
quality and the amount of carbon dioxide change into biomass. The rate
of carbon fixation and utilization of sunlight vary among the species of
cyanobacteria (Rosgaard et al., 2012). Pigments (chlorophyll, car-
otenoid, and phycobiliproteins) are main light-harvesting complex
which have a direct effect on the sunlight absorption and formation of
biomass. The arrangement of phycobiliproteins in a specific manner
(phycobiliproteins) allows the single direction flow of energy towards
photosystem II (Prasanna et al., 2007). Recently, some genes which
were involved in the sunlight radiation absorption have been identified
and with genetic engineering approaches the activity of light harvesting
mechanism of these genes have been enhanced (Ducat et al., 2011). For
example, Gene (Tla 1) responsible for the antenna size of the photo-
autotrophic organism was identified (Kirst et al., 2017). A mutation in
the gene (Tla 1) in C. reinhardtii showed decreases in the size of light
harvesting complex or antenna size and drop in chlorophyll content
(Melis, 2009). It was demonstrated in C. reinhardtii that incomplete
synthesis of chlorophyll allows high absorption rate as compared to
regular size chlorophyll in high cell density (Jeong et al., 2002). Sy-
nechococcus elongatus strain UTEX 297 was recently genetically en-
gineered for the production of sucrose and it also has fast-growing
ability (Song et al., 2016).
Carotenoids are primarily synthesized using different isoprenoid
pathways like Mevalonic acid (MVA) pathway in the cytosol or
anMethylerythritol-4-phosphate (MEP) pathway in plastids (Fig. 2).
Most microalgae and cyanobacteria use Methylerythritol-4-phosphate
(MEP) pathway to get isopentenyl pyrophosphate (IPP) and dimethy-
lallyldihosphates (DMAPP). After the formation of IPP or DMAPP, in-
termediate like C15 farnesyl diphosphate or C20 greranlygranyldipho-
sphate is synthesized which condense in first C40 carotenoid structure,
Phytoene. Using desaturase enzyme ζ-carotene is formed which lead to
the formation of lycopene, the primary colored carotenoids. Following
this, two types of carotene structures were created which are β-carotene
and γ-carotene. After this, a different kind of chain transformation re-
action like ketolyation, glycosylation epoxidation, hydroxylation and
oxygen cleavage or addition leads to a formation of a different variety
of carotenoids structures. Most of the carotenoids are found both in
plant, algae and other photosynthesizing organisms, but astaxanthin in
mainly found in cyanobacterial species.
During the synthesis of carotenoids, many rate-limiting enzymes are
present like Phytoene synthase (PSY) which can be up-regulated or
down-regulated due to environmental stress. Many enzymes have been
D.K. Saini et al. Food and Chemical Toxicology 120 (2018) 616–624

identified, but PSY, BKT, PDS are mostly targeted for the overexpression

Manirafasha et al., 2017

Yu-Ju Lin et al., 2017

of different carotenoids. Each species has different encoding gene for

Gateau et al., 2017

Leney et al., 2018
Wells et al., 2017
these enzymes and targeting these genes has shown the tangible result,

Ho et al., 2017
e.g., PSY gene was overexpressed in Chlamydomonas, showing two-fold
increases in carotenoids expression (Kempinski et al., 2015). Through

Reference
mutagenesis in the corresponding gene also resulted in overexpression
of carotenoid synthesis level, e.g., increase in astaxanthin level were
seen in H. portfolios due to mutation in the PDS gene (Sathasivam and

9972 μg/g DCW

1.4 mg/g DCW
Ki, 2018.), overexpression of BKT genes in C. reinhardtii has shown

101 mg/L/day
0.234 mg/mL
Productivity
keto-carotenoid synthesis, which generally is not shown in a wild strain

54.6 mg/L

9.7 mg/g
(Varela et al., 2015). Many genes such as (CHYb) gene associated with
hydroxylase enzyme was associated with Astaxanthin overexpression in
C. zafingiensis. As nitrogen source is an essential factor for protein

Phycocyanin
synthesis and cell division, in nitrogen deficit condition many cyano-

Astaxanthin
bacterial species show increased LCYb enzyme synthesis which en-

Pigment
hances the pigment expression rate. As we know, for high production,
carotenoids also need overproduced storage space (Gateau et al., 2017).
As carotenoids biosynthesis is a very complicated process, it is essential

Engineered E.coli strain for the expression of gene cassettes of xanthophyll biosynthetic genes of Nostoc punctiform and Pantoea ananatis for the
Applied metabolic stress strategy by adding sodium glutamate and succinic acid with nitrates feeding help to overexpression of cobA/hemD,
to understand the metabolic network of carotenoids synthesis. As we
know biosynthesis of fatty acid and carotenoids are interdependent and

Genes for enzymes hydroxylate (CrtZ), β-carotene ketolase from Pantoea ananatis and Paracoccus sp inserted into Yarrowia lipolytica.
each carotenoid synthesis metabolically connected to each other. So to
increase pigment production, we need to enhance production of fatty
acid also. Transcription engineering is an emerging genetic tool for

hemG and ho genes which result in enhancing biomass, growth and high growth in the high phycocyanin accumulation.
improving production of pigments. As carotenoids synthesis is a mul-
tiple step process, so changes in single regulator may affect more than a

Applied limited nitrate supplied (50%), white LED as light sources and proper adjustment light – dark frequency
component of the pathway. There is also need to understand the
transport route for pigment coming out from photo system to the cy-

Repeated integration approach to express Mutated Hpchyb gene from Haematococcus pluvialis and bkt gene
toplasm for higher production of carotenoids (Mourelle et al., 2017).
Some strategies to enhance different biopigments in different micro-
organisms are summarized in Table 2.
Phycobiliproteins production was directly affected by the environ-
mental factors and the quality of the light (Chakdar, 2012; Khatoon
et al., 2018). The content of bilinprotein is also influenced by the cell
growth, cell biomass density and even by the amount of irradiance (Lao
et al., 2017). This biliprotein imparts different colors which express at a
different wavelength which makes them an excellent candidate for the
in vivo application. Optimization of cultivation condition and providing
different environmental stresses can enhance production of bilin pro-
Some strategies to induce pigment production through metabolic and genetic engineering.

tein (Dianursanti et al., 2018). Phycocyanin activity can stabilize by

additions such as glucose, fructose or sucrose. Due to polymerization
with sugar, phycocyanin show stability at a higher temperature
(Hernando et al., 2018). Nevertheless, many attempts are made to en-
hance production through genetic and metabolic engineering. Sy-
nechocystis sp. was subjected to the primary focus of the genetic and
metabolic studies as its whole genome was available in open access (Lin
et al., 2017). In many species such as Arthrospira platensis, Porphyridium
sp., Synechococcus sp., etc. most of the metabolic and genetic en-
gineering was focused on the rate-limiting factor such as rate limiting
enzymes.
production of astaxanthin.
Random mutagenesis

4.2. Systems biology

Systems biology is used to study the artificial biological systems for

further research or biotechnology. It is an emerging field of biology,
Strategy

which opens up the complicated natural process by applying the

mathematical and computational tool. Now days, these systems are
used to understand the complex metabolic system of cyanobacteria to
Arthrospira platensis FACHB-314

Xanthophyllomyces dendrorhous

enhance the production of various biochemical products (Singh et al.,

2017). Systems biology can be beneficial in cyanobacteria due to the
Kluyveromyces marxianus

small genome size and to discover the different ability of cyanobacterial

species, for example, the direct use of sunlight to convert into high
Yarrowia lipolytica
Spirulina platensis
Host organisms

reducing potential reaction which usually is used in lowering different

Escherichia coli

response that changes the CO2 into an organic compound. It was proven
that the expression of collective redox reaction can be enhanced by
Table 2

expressing cytochrome p450 derived from plants in cyanobacterial

species Synechocystis to produce secondary metabolite dhurrin by

620
D.K. Saini et al.
utilizing photosystem I. Cyanobacterial genomes are small and have
similarities between plant plastids which give outstanding ideas for the
use of systems biology in it. System analysis by using Transcriptomics
with DNA microarray allows studying gene expression of cyano-
bacterium among various environmental conditions. As proven that
carbon-concentrating mechanism (CCM) from cyanobacteria trans-
ferred in eukaryotic chloroplast that allowed RubisCo enzyme to act
under carbon dioxide depletion situation and reduces the chance of
photorespiration up to high range (Hagemann and Hess, 2018).
5. Cyanobacteria as cell-factories
Demand for energy fuel is rising day by day, but due to different
types of environmental issues, there is an increase in the need for eco-
friendly and sustainable fuel. Again cyanobacteria show its ability to
produce different kinds of biofuels like ethanol, acetone, fatty acids,
isobutanol, 2, 3-butanediol, 1-butanol,etc. using genetic engineering
(Nozzi et al., 2013). S. elongatus PCC 7942 was first genetically mod-
ified cyanobacteria, which efficiently produced bioethanol (Kopka
et al., 2017). Isoprene synthase gene isolated from Pueraria montana
was introduced in Synechocystis sp. (Lindberg et al., 2010). Cyano-
bacteria have a variety of hydrogen utilization enzymes for bidirec-
tional nitrogen and hydrogen, which help in the production of hy-
drogen (Ghirardi et al., 2009).
Plastic bags are one of the essential things in daily life. Plastic is a
petroleum based product which comes out during the refining of crude
petroleum (Naik et al., 2010). The fossil-based fuel is depleting and
hazardous effects of chemicals and plastics have made people con-
cerned about the pollution and the environment. So to overcome this
problem people have started thinking about biodegradable plastic
(Cerezo et al., 2012). Poly-3-hydroxybutyrate (PHB) was primarily a
bacterial based product. Bacteria use a variety of carbon sources such as
fatty acid, glucose and other sugar molecules for the production of PHB
which are found to be unfeasible in comparison to chemical based
plastic production (Meixner et al., 2018). Cyanobacteria primarily use
atmospheric CO2 as a source of carbon and can be quickly grown on
uncultivated land which lowers the production cost (Taepucharoen
et al., 2017). Synechocystis salina, used for the production of PHB can be
cultured easily, but the quality was lower than the commercially
available PHB. Diazotrophic cyanobacteria can also be exploited for
PHB production (Singh et al., 2017). Biopigment which are used to
absorb light, help in the production of biomass in cyanobacteria and
can be cultivated simultaneously, which lowers cost of downstream
processing (Meixner et al., 2018).
Cyanobacteria known for conversion of photon energy into the
chemical energy by the process of photosynthesis and this chemical
energy gets converted into different biochemical compounds which
have some biological activity, so known as bioactive compound (Fig. 3)
(Ariede et al., 2017). Many cyanobacteria species and microalgae like,
Spirulina, Nostoc, Botryococcus and Porphyridium are known for the
production of different kind of bioactive compounds. Nostoc sp. R76DM
is used in cosmetics due to the output of mycosporine-like amino acids
(MAA) which show UV absorbing capability (Rastogi et al., 2016).
Spirulina sp. use as moisturizer and allow retention of moisture and
viscosity in the skin (Ariede et al., 2017). Arthrospira extract has been
used as an anti-aging agent, it repairs sign of premature aging and re-
moves stretch marks (Hamed, 2016).
There are a variety of enzymes produced by cyanobacteria, which
have industrial potential like hydrolase, cellulase, amylolytic enzymes,
lipases, proteases, etc. Many proteins produced by cyanobacteria have
the fungicidal ability. Dunaliella genus has been found to contain genes
for enzymes which break downstarch. Two pathways carry out cata-
bolism of starch; hydrolytic pathways reported in D. tertiolecta and
phosphorolytic path stated in D. parva (Shang et al., 2016). Protease
enzyme is produced by many cyanobacterial species, for example,
serine and trypsin protease produced by Anabaena variablis (Izydorczyk
621
Food and Chemical Toxicology 120 (2018) 616–624
et al., 2005) can be exploited commercially, Arthrospira platensis pro-
duces lipases (Brasil et al., 2017). Lipase enzymes have applications in
chemical, agrochemical, cosmetic, detergent and other industries as
well. Wide range of substrates are utilized by lipase enzyme such as
phospholipids, lysophospholoipid, sphingolipids etc. These enzymes
were used to target many carodiovascular diseases and clinical trials
were done against inflammation, obesity, pain etc (Nomura and Casida,
2016). These also hydrolyze different substrates to module many cell
signaling, cell integrity, lipid signaling etc (Wymann and Schneiter,
2008). Lipase has vital role in fuel production such as in biodiesel
production from different cyanobacteria and microalgae (Chisti, 2007).
Cyanobacteria are unexplored genetic resources for lipases and their
production can be enhanced through genetic and synthetic engineering.
Cyanotoxin, a secondary metabolite secreted by the cyanobacteria
to inhibit their competing organisms. Vast variety of cyanotoxins are
secreted by cyanobacteria for example microcystin, ana toxin, homo-
toxin etc. The cyanotoxin can be toxic and non-toxic in nature. Many
class of cyanotoxin are produced by cyanobacteria which are toxic in
nature and can be divided on the basis of effects such as dermatoxin,
heptotoxin, neurotoxin etc. About 23 different classes of cyantoxins
with hundreds of metabolites were identified (Manning and Nobles,
2017). These can be synthesized through shikimate pathways to form
alkanoids molecules and through acetate pathway to synthesize he-
trocyclic polyether and other bioactive hydrocarbon. Anatoxin and
homoanatoxin are neurotoxic in nature which causes permanent neural
depolarization (Fonseca et al., 2015). Microcystin, cylindrospermopsin
are hepatotoxic in nature and taking water contaminated with cylin-
drospermopsin may cause liver necrosis (Botana and López, 2015).
These toxins are toxic to growth of crop plant if present in irrigation
water. Water bodies prevalent cyanotoxin is microcystin (MCs) and
cylindrospermopsin (CYN). Moreover, impacts of cyanotoxins on water
bodies were described by Manning and Nobles (2017). These cyano-
bacterial secondary metabolites have variety of application in the field
of biocides, biofertilizers, bioremediation, pharmaceutical supplements
etc. Recent studies on cyanotoxin, revealed that these secondary me-
tabolites can be used as allelochemical. These chemicals are biological
derived and used to inhibit different types of unwanted species. As
Cyanobacteria have potential to inhibit the growth of algae, microbes
and other eukaryotic organisms, commercially, it was thought to de-
velop the cyanotoxins as pesticides, herbicides, and algicides (Gerwick
and Sparks, 2014). Many cyanobacterial genera have shown anti-algal
activity such as Nostoc, Scytonema, Fischerella etc (Berry et al., 2008;
Haque et al., 2017). Inhibition of insect larvae (larvicide), is another
potential application of cyanotoxin. Microcystin and anatoxin-A have
appreciable inhibition potential (Rastogi et al., 2016). Another field
where cyanotoxin have proven to be beneficial is in pharmaceutical.
These toxins are involved in cancer, HIV and other diseases treatment.
But this research requires more study and clinical trials. Moreover,
main focus of cyanotoxin in therapeutic was towards drug development
having properties like anti-bacterial, anti-parasitic and anti-malaria
(Tarman et al., 2013).
6. Conclusion and future perspectives
Cyanobacteria can produce a wide range of colored pigments. Study
of pigment-producing cyanobacteria, their biosynthetic pathways and
use of genetic engineering can make the future of the cyanobacterial
pigment production most promising and attractive. Metabolic en-
gineering has been used and can further be exploited in a variety of
microalgae or cyanobacteria for the enhancement of pigment produc-
tion. Advances in the gene level study of cyanobacteria provide in-
formation about the complex metabolic system of pigment production,
which allows us to utilize different new technique to produce high
pigment producing species. The effect of light on the natural cyano-
bacterial growth has not been efficiently studied by the scientific
community which requires further insight both physiologically and
D.K. Saini et al.
Fig. 3. An overview of cyanobacterial cell producing potential metabolites.
genetically. The advancement in the field of DNA sequencing has re-
sulted in deciphering more information about the complex metabolic
network of the pigment-producing cyanobacteria and will assist us to
easily engineer these organisms for high production of the pigment
molecules.
In further research, extraction cost of the high-value pigment can be
minimized by using new metabolic approaches. The price of extraction
can be reduced by designing species which give dye and other com-
mercial product simultaneously. For this purpose, new and innovative
thinking is needed for scientific intervention. In the end, we can say
that pigment production through cyanobacteria has bright and attrac-
tive future in the field of cosmetics, pharmaceutical and different col-
oring industries. Cyanobacterial pigments require studies for their sta-
bility, compatibility and reduction of their toxicological effect to
increase their commercial value in the global market.
Acknowledgement
The authors acknowledge Maharshi Dayanand University, Rohtak,
India for providing infrastructure facility. PS acknowledges the infra-
structural support from Department of Science and Technology, New
Delhi, Govt. of India, through FIST grant (Grant No. 1196 SR/FST/LS-I/
2017/4). SP acknowledges the support from Department of
Biotechnology, Govt. of India (BT/PR15686/AAQ/3/811/2016).
Appendix A. Supplementary data
Supplementary data related to this article can be found at https://
doi.org/10.1016/j.fct.2018.08.002.
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