Science Progress (2015), 98(2), 145 – 168

Paper 1500125 doi: 10.3184/003685015X14298590596266

Cyanobacteria and microalgae: a renewable source of

bioactive compounds and other chemicals
TELMA ENCARNAÇÃO, ALBERTO A.C.C. PAIS, MARIA G. CAMPOS
and HUGH D. BURROWS

Telma Encarnação  is carrying out  research on novel value added fine

chemicals using microalgal biomass from industrial carbon dioxide fixation
for pharmaceutical applications and isotopic labelling for her PhD in the
Department of Chemistry, University of Coimbra, Rua Larga, 3004-535
Coimbra, Portugal. She holds a Master’s degree in Chemistry (2009) and
a First Degree in Industrial Chemistry (2007), both from the University of
Coimbra. She may be contacted at E‑mail: tencarnacao@qui.uc.pt

Alberto Pais received his PhD in Chemistry in 1993, and is currently

Associate Professor at the Department of Chemistry of the University of
Coimbra. His research focuses on Molecular Simulation, Chemometrics and
Pharmaceutics. He was a guest editor for Advances in Colloid and Interface
Science, and co‑editor of the book “Simvastatin delivery: challenges and
opportunities”. He is co‑author of about 120 ISI articles, a book and several
book chapters, ranging from molecular physics to food safety.

Maria da Graça Campos completed her PhD in 1997 from Coimbra

University. She followed this with postdoctoral studies in 2000 at Industrial
Research Ltd, Lower Hutt, New Zealand. She is Auxiliary Professor in the
Faculty of Pharmacy, University of Coimbra, Director of Observatory of
Herbal–Drug Interactions, Head of the project IciPlant at the Oncological
Hospital of Coimbra, and team leader of the International Bee pollen
Working Group at IHC. She is co‑author of three books, seven book
chapters, and 66 scientific papers. She is also a member of the editorial
boards of five scientific journals.

Hugh Burrows is Professor in the Department of Chemistry, University

of Coimbra, Portugal. He is a native of England and did his first degree
(University of London) and PhD (University of Sussex) there. He has since
worked in universities in the UK (Warwick), Israel (Tel-Aviv), Nigeria
(Obafemi Awolowo) and Portugal (Coimbra). He has been in Portugal
for over 30 years, and his research has concentrated on various aspects of
materials chemistry, polymers and photochemistry. Much of his current
interests concentrate on interactions between light and molecules, particularly photophysical
and aggregation behaviour of conjugated materials for applications in sensing, nanostructuring,
illumination and artificial photosynthesis. He is Sócio Correspondente of the Academia de Ciências
de Lisboa and Fellow of the Royal Society of Chemistry. He is author/co-author of seven books,
14 book chapters, over 350 scientific articles and two Portuguese patents. He is also the Scientific
Editor of the IUPAC journal Pure and Applied Chemistry.

www.scienceprogress.co.uk Cyanobacteria and microalgae 145

ABSTRACT

Microalgae and cyanobacteria are rich sources of many valuable compounds, including important
bioactive and biotechnologically relevant chemicals. Their enormous biodiversity, and the
consequent variability in the respective biochemical composition, make microalgae cultivations a
promising resource for many novel chemically and biologically active molecules and compounds
of high commercial value such as lipids and dyes. The nature of the chemicals produced can
be manipulated by changing the cultivation media and conditions. Algae are extremely versatile
because they can be adapted to a variety of cell culture conditions. They do not require arable
land, can be cultivated on saline water and wastewaters, and require much less water than plants.
They possess an extremely high growth rate making these microorganisms very attractive for use in
biofuel production – some species of algae can achieve around 100 times more oil than oil seeds.
In addition, microalgae and cyanobacteria can accumulate various biotoxins and can contribute
to mitigate greenhouse gases since they produce biomass through carbon dioxide fixation. In this
review, we provide an overview of the application of microalgae in the production of bioactive and
other chemicals.

Keywords: microalgae, cyanobacteria, antibiotics, anticancer activity, antiviral activity,

secondary metabolites, value added compounds, lipids, biofuels, bioremediation

1. Introduction
Microalgae belong to a wide group of microorganisms, primary producers, present in
almost all ecosystems around the globe. It has been estimated that between 200, 000 and
several million species of microalgae exist1. This remarkable diversity is reflected in their
biochemical composition. As a consequence, microalgae possess great biotechnological
potential for applications in the pharmaceutical, food, cosmetic, and other industries.
The phytoplankton biomass present in the ocean is less than 1% of the total carbon
contained in all photosynthetic biomass. However, it is estimated that phytoplankton
store between 30 and 50 × 1015 g of carbon annually2. This gives these photosynthetic
microorganisms a crucial role in the most critical natural cycles of the planet, as well
as being the base of the food chain. One of the major consequences of the activity of
these life forms is their influence on the climate, and the reduction of the greenhouse
effect to capture CO2 from the atmosphere and deposit it in the bottom of the oceans3.
Phytoplankton and plants, that evolved about 500 million years ago, use the energy of
the Sun to split water molecules into hydrogen and oxygen. The oxygen is released as
waste, allowing the survival of all animal life on Earth, while the carbon cycle depends
on the use of the hydrogen atoms of water by the photosynthetic organisms for primary
conversion of inorganic carbon as CO2 into organic matter, such as sugars, amino acids
and other biological molecules within their cells. Factors such as light, pH, temperature,
salinity and nutrient availability affect both photosynthesis and biomass productivity,
and influence the activity and mechanisms of cellular metabolism, thus influencing the
chemical and biochemical composition of cells4,5.
The biodiversity of microalgae represents a tremendous resource for production of
a variety of interesting chemicals, many of them with considerable commercial value.
However, despite this diversity, only a dozen species of microalgae are cultivated on a
large scale. Table 1 indicates some of the companies that are producers of microalgae.
The major obstacle to large scale production is that the cost of production is still too high.
Many studies have been focused on the technology of the production. Most are about
146 T. Encarnação, A.A.C.C. Pais, M.G. Campos and H.D. Burrows
cultivation reactors, while others have been conducted to evaluate variations of growth
parameters in the cellular composition to optimise production.
The most common biotechnological applications of microalgae have been in
aquaculture for feeding fish and other organisms of economic interest, such as molluscs
and crustaceans. Pigments, anti-oxidants and food supplements can also be derived from
microalgal extracts. Microalgae can synthesise toxins, but can also produce a wide range
of other bioactive molecules with antibiotic, anticancer, anti-inflammatory and antiviral, or
other pharmacological properties, see below. In addition, they can be used in wastewater
treatment, in numerous industrial processes for the biological detoxification and removal
of contaminants from the environment, in the synthesis of biopolymers and cosmetics, and
in the production of biofuels. In agriculture, the biomass can be used as a soil biofertiliser.
The algal biomass consists of about 50% carbon which means that approximately 1.8 kg
of CO2 is required to produce 1 kg of algae6. Since pure CO2 is expensive, cost effective
alternatives of this gas, such as gases emitted from industrial combustion processes,
fermentation processes or engines have been tried. Furthermore, microalgae can be used
in the reduction of greenhouse gas emissions from industrial plants, such as thermal power
plants and cement factories, through the CO2 flue gas assimilation.
The purpose of this review is not to catalogue all the compounds from the species
studied to date, but to provide a general overview, with a glimpse into the fascinating
world of microalgae. In the following sections, a brief description of the biochemical
composition of microalgae and cyanobacteria is included, as well a summary of their
evolutionary history. Some of the most promising applications will be described and their
advantages and disadvantages addressed. Emphasis will be placed on the most studied
species and those with the greatest potential in biotechnological applications. A short
description of the most relevant drugs extracted from microalgae is also provided.

Table 1 Companies producing microalgae and microalgal products

Microalgae species Application/product Company Country
Nannochloropsis
Tetraselmis Cosmetics and aquaculture Astaxa Germany
Phaeodactylum
Nannochloropsis
Haematococcus pluvialis PUFA, omega 3, Bluebiotech Germany
Spirulina EPA astaxanthin
Chlorella
Astaxanthin/human, fish and
Haematococcus pluvialis animal consumption Alga Technologies Israel
Nannochloropsis sp.
Phaeodactylum tricornutum
Amphora sp.
Navicula sp. Food additives, animal and Seambiotic Israel
Dunaliella sp. fish feed, biofuel
Chlorococcum sp.
Tetraselmis sp.
Nannochloris sp.
Haematococcus pluvialis Astaxanthin Biogenic Co., Ltd. Japan
Spirulina Astaxanthin Cyanotech USA
Haematococcus pluvialis
Biofuels, nutritional, health
Chlorella sciences, chemicals Solazyme USA
Spirulina DHA/dietary supplements,
Chlorella aquaculture feeds, cosmetics Femico Taiwan
Crypthecodinium Cohnii

www.scienceprogress.co.uk Cyanobacteria and microalgae 147

2. The early history of microalgae

The first living organisms, bacteria and unicellular prokaryotic primitive organisms
appeared on Earth at least 3.5 billion years (Gyr) ago, during the Archean period (Figure 1).
Although controversial, geological evidence suggests that, in southwest Greenland,
3.8 Gyr old Isua rocks present what may be the oldest sediment record of life on Earth7.
If confirmed, this life has existed possibly by anoxygenic photosynthesis. In the later
Archean period, the Earth’s atmosphere was rich in carbon dioxide and, prior to 2.5 Gyr,
was free of oxygen. The current values of oxygen concentration would be found only
from 600 million years (Mya) ago8. Around 3.5 Gyr, data from the signature RuBisCo
(ribulose-1,5-bisphosphate carboxylase) suggest a global oxygenic photosynthesis and
evolution of cyanobacteria. According to geological and palaeontological evidence,
cyanobacteria are the most ancient photosynthetic organisms, and producers of oxygen
on Earth. Fossil populations of cyanobacteria, known as stromatolites, and carbon isotope
ratios confirm that autotrophs may have existed 3.5 Gyr ago, which fixed carbon through
the Calvin cycle. Oxygen production by these organisms and their possible accumulation
in the atmosphere caused the first mass extinction of anaerobic organisms (ca 2000 Myr
ago)9. The eukaryotic cell arose during the Proterozoic, dating back 2.5 billion years and
extending to 542 million years ago. There is a view that green algae may have emerged
through the symbiosis between cyanobacteria and eukaryotic non-photosynthetic
ancestors, leading to photosynthetic eukaryotes that would give rise to the first algae
1.5 billion years ago10. Fossil records suggest the appearance of seaweed eukaryotes
around 1.2 Gyr with the possible colonisation of freshwater lakes around 1.1 Gyr. These
organisms, and most of photoautotrophs that evolved from them, used the enzyme
Rubisco to catalyse the photosynthetic reduction of carbon11. Terrestrial bryophytes
started appearing from around 550 Myr followed by vascular land plants 440 Myr ago
during the Devonian period. Other species such as lichens and fungi are believed to have
appeared around the earliest appearance of the first bryophyte9.

3. Biochemical composition of microalgae and cyanobacteria

As with other food sources (Table 2), microalgae are composed primarily of proteins,
lipids, carbohydrates and nucleic acids in different proportions, that vary both from species
to species and with the growth conditions. They also contain polysaccharides, minerals,
vitamins and pigments. For example, cells of Nannochloropsis (Figure 2), a marine
microalgae, contain the pigments β‑carotene, violaxanthin, vaucheraxanthin, zeaxanthin
and anteraxanthin, in addition to aspartate, glutamate, proline, methionine, tryptophan,
cystine, histidine, hydroxyproline and several fatty acids, such as eicosapentaenoic acid12.
Table 3 presents the chemical composition of some microalgae species. It should be
noted that the values presented correspond to specific growth conditions and microalgae
species, and have not necessarily been optimised for each compound.

4. Microalgae and cyanobacteria as sources of bioactive compounds

Many of the molecules used for therapeutic purposes have their origins in nature, more
specifically, in plants. Studies of natural products based on biological diversity have
continuously unveiled novel chemical structures that, in many cases, lead to new drugs.
148 T. Encarnação, A.A.C.C. Pais, M.G. Campos and H.D. Burrows
Figure 1 Timeline with important biological events. In discussing geological time, 1 Gyr corresponds
to 109 years.

Many molecules of natural origin also serve as structural models for creating synthetic
analogues. Cyanobacteria, commonly called blue-green algae, comprise a vast and
varied morphological group of oxygenic phototrophic bacteria, and represent one of the
largest phyla of bacteria22. Falkowski and Raven23 estimated that there are approximately
1025 cells of cyanobacteria in the oceans, so that the fixation of photosynthetic carbon
and nitrogen in modern oceans is carried out by cyanobacteria. These phototrophic
prokaryotes produce oxygen as a waste product, which has made possible the evolution
of complex multicellular organisms. These simple prokaryotes have drawn considerable
attention due to secondary metabolites and their fascinating structures. Cyanobacteria
are known to contain a huge variety of toxic and bioactive substances. These metabolites
have been explored as potential anticancer, antiviral, antibiotics and anti-inflammatory
www.scienceprogress.co.uk Cyanobacteria and microalgae 149
Table 2 Chemical composition of some food sources
Lipids
Carbohydrates Proteins
Food (% dry weight Ref.
total sugar (%) (g/100 g) biomass)
Milk 4.9 3.6 3.5 13,14
Rice (white, raw) – 6.7 1.4 13
Soybean (dry, raw) – 34.1 17 13
Meat (beef) – 16.5 10 – 30 13
Fish (haddock) – 18.3 0.1 13

Figure 2 (a) Cyanobacteria Lyngbya

majuscula. (figure downloaded with
permission from Florida Fish and
Wildlife Conservation Commission)25.
(b) Marine microalgae Nannochloropsis
sp. cells.

Table 3 Chemical composition of some species of algae

Carbohydrates Proteins Lipids
Microalgae species (% dry weight (% dry weight (% dryweight Pigments Ref.
biomass) biomass) biomass)
Amphora sp. – – 26.4 – 81.5 – 15
Aphanothece microscopica Nägeli 13.4 – 17.6 41.3 – 49.3 7.1 – 7.9 – 16
Arthrospira (spirulina) Platensis 15.0 – 26.97 45.0 – 62.2 8.04 – 13.79 – 17,18
Botryococcus braunii 2.38 39.61 33 13.05 19
Chlamydomonas reinhardtii 17 48 21 – 14
Chlorella vulgaris 16.74 40.95 9.95 12.41 19
Dunaliella tertiolecta 13.95 29.41 11.44 7.61 19
Nannochloropsis sp. 8 – 14 33 – 44 22 – 31 – 20
Porphyridium cruentum 22.8 – 39.3 27.7 – 40.8 5.78 – 7.55 – 21
Scenedesmus obliquus 10 – 17 50 – 56 12 – 14 – 14
Spirulina platensis 11 42.33 11 16.12 19
Synechococcus sp. 15 63 11 – 14

drugs (Figure 3). This remarkable chemical diversity has been particularly evident in
studies with the marine cyanobacteria Lyngbya majuscula (Figure 2). This unique species
is known to cause the dermatitis knowns “swimmers itch”, and has been shown to produce
a wide range of metabolites which include polyketides, lipopeptides, potent toxins and
many others24.
Analysis of 424 marine cyanobacterial natural products showed that 40.2% are
lipopeptides, 5.6% are pure amino acids, 4.2% fatty acids, 4.2% macrolides and 9%
amides26 (Figure 3). Also, cyanobacteria remain a largely unexplored resource of new
bioactive compounds.
150 T. Encarnação, A.A.C.C. Pais, M.G. Campos and H.D. Burrows
Figure 3 (a) Compounds isolated from cyanobacteria. (b) Reported biological activity of marine
cyanobacterial compounds (adapted from ref. 26).

Dinoflagellates, which are eukaryotes, also demonstrate an extraordinary chemical

diversity. However, apart from producing bioactive molecules of interest, such as
macrolides and polyethers, they also yield potent toxins. For example, the species
dinoflagellate Gambierdiscus toxicus, which is very common near reefs, produces the
gambiertoxin. This toxin enters the food chain through fish that have ingested toxic
microalgae27. The dinoflagellate marine genus Amphidinium, in turn, produces a wide
range of polyketides and cytotoxic macrolides that may lead to new anticancer drugs.
Table 4 shows the biological activity of the compounds obtained from several species
of microalgae and cyanobacteria.

5. Bioactive secondary metabolites

Secondary metabolites serve no obvious function in the cell. These metabolites are
present in algae, plants and other living organisms. Their production requires additional
energy (ATP, NADPH) and C and N allocation, with genes encoding their biogenetic
pathways9. It is speculated that their respective function is part of the defence mechanism
of the cell. Under conditions of stress, they induce a mechanism of protection (against
excessive UV radiation, bacteria, competitive species) producing secondary metabolites,
thus representing an adaptive character that has been subjected to natural selection during
evolution63. Secondary metabolites may find themselves active or dormant in the cell.
It is known, for example, that the biosynthesis of some of these metabolites in plants
is induced, and they are synthesised again after damage or infection of pathogenic
organisms. Many of these metabolites exhibit antibiotic, anticancer and antiviral and
other properties, which will be discussed below.

5.1 Antibiotics
The abusive and negligent use of antibiotics has led to an inevitable and continuing global
crisis of resistance to antibiotics, without any short-term solution in perspective. While
infectious agents are becoming more and more resistant to the drugs currently in use,
not enough new drugs are being developed to combat them64. Over the past two decades,
antibiotic research has experienced an exponential decline. One reason for this is the
poor economical return; antibiotics, are taken only for a short period of time until the
disease is cured. In contrast, chronic conditions, such as high blood pressure, require
a daily intake for the rest of the patient´s life. In 2008, only five major pharmaceutical
www.scienceprogress.co.uk Cyanobacteria and microalgae 151
Table 4 Biological activity of the compounds obtained from several species of microalgae and cyanobacteria
Microalgae (genus/species)
Amphidinium operculatum
var. nov. Gibbosum
Anabaena flos-aquae
Botryococcus braunii
Calothrix sp.
Chlorella stigmatophora
Cochlodinium polykrikoides
Dunaliella primolecta
Dunaliella Salina
Dunaliella tertiolecta
Fischerella sp.
Gymnodinium catenatum
Gyrodinium impudicum
Haematococcus pluvialis
Isochrysis galbana
Lyngbya majuscula
Lyngbya majuscula Harvey
ex Gomont
Products and molecular
class of compounds
Amphidinolide N (macrolide)
Saxitoxins
Carotenoids
Calothrixin (aromatic)
Sulfated polysaccharides.
There are no references about
the compounds for the reported
effects on the CNS.
A1
A2
Pheophorbides
β-carotene
There are no references about the
compounds or their biological
activities
Isonitrile-containing alkaloids
Hapalindole T
Saxitoxin, Saxitoxin analogues
p-KG03
Astaxanthin
There are no references about
the compounds for the reported
biological activity
Lyngbyatoxin-a
Apratoxin A (cyclodepsipeptide)
Biological activity reported and additional information Ref.
Cancer cell cytotoxicity 28
Neurotoxic alkaloid, potent blocker of nerve conduction that can be
produce prolonged anaesthesia 29
Antioxidant activity 30
Antimalarial and anticancer activities 31
T. Encarnação, A.A.C.C. Pais, M.G. Campos and H.D. Burrows
Antiviral, anti-inflammatory and immunomodulatory activities
Aqueous extracts showed effects on the CNS 32,33
Anti-HIV‑1 activity and antiviral activity against parainfluenza virus
type 2 and against HSV-1 34
Anti-Herpes Simplex Virus activity 35
Free radical scavenger, anti-tumour and cancer preventative activity 24,36
Aqueous extracts showed effects on the CNS. Activity as a CNS
depressant, potential muscle relaxant 37
Antibacterial and antimycotic activity 38,39
Sodium channel blocking activity
Aesthetic 40,41
Effects on the cardiovascular system, hypotensive effect
Extraordinary antiviral activity in vitro against influenza virus
42,43
Activity against EMCV
Anti-inflammatory, anti-oxidant and treatment of muscular lesions 44
Aqueous extracts showed effects on the CNS 45
Potent activator of protein kinase C 41
The compound showed a potent cancer cell cytotoxicity in vitro. 46
However, it was only marginally active
152
(Table 4 continued)
Lyngbya majuscula/Schizothrix sp. Somocystinamide A (lipopeptide)
Assemblage of marine cyanobacteria
Lyngbya sp.
Microcystis aeruginosa
Microcystis sp.
Nannochloropsis
Nodularia harveyana
Nostoc commune
Nostoc ellipsosporum
Nostoc insulare
Nostoc muscorum
Oscillatoria agardhii
Phaeodactylum tricornutum
Skeletonema costatum
Spirulina platensis
Symploca sp.
Tetraselmis suecica
153
Compound showed cytotoxicity against mouse neuro‑2a
neuroblastoma cells 47
Caspase‑8 activation
Cyanobacteria and microalgae
Exhibited cytotoxicity, against Hella cells, potent protein kinase
Bisebromoamide inhibition 48
Microvirin Lectin 49
The micropeptins showed inhibitory activity for the serine
Micropeptins protease trypsin. 50
Arterosclerosis, cancer, rheumatoid arthritis, Alzheimer’s disease,
EPA, DHA macular degeneration, cardiovascular development and protection 51,52
of human central nervous system
9H-pyrido(3,4-b)indole Antibacterial and antifungal activities 53
Showed antibacterial activity against Bacillus cereus,
Noscomin 54
Staphylococcus epidermidis, and Escherichia coli
Lectin
Cyanovirin-N Active against HSV‑1, Ebola, hepatitis C, influenza 55
4,4´-dihydroxybiphenyl Antibacterial and antifungal activities 53
C-phycocyanin Antimalarial activity 56
Oscillatoria agardhii agglutinin
Antiviral activity 57
(OAA)
Anti-inflammatory effects, immunostimulant
immunomodulatory activity
Sulfated polysaccharides Aqueous extracts showed effects on the CNS. Activity as a CNS 30,58
depressant, potential muscle relaxant
There are no indications about the Aqueous extracts showed anti-dopaminergic activity and muscle
compounds which produce the 59
www.scienceprogress.co.uk
relaxing activity
reported biological activity
Allophycocyanin Anti-inflammatory, anti-oxidant and antiviral activities 60
Largazole
Dolastatin 10 Compounds which exhibit cancer cell cytotoxicity 61,62
There are no indications about the
compounds which produce the Aqueous extracts showed effects on the CNS 45
reported biological activity
companies (GlaxoSmithKline, Novartis, AstraZeneca, Merck and Pfizer) still had active
antibacterial discovery programmes65. According to the European Medicines Agency and
European Centre for Disease Prevention and Control joint report entitled The bacterial
challenge: time to react66, in 2008 only 15 antibiotics of 167 under development had a
new mechanism of action, with the potential to face the multidrug resistance challenge.
One possible solution includes the discovery of novel compounds with antimicrobial
activity, finding new classes of antibiotics, together with effective improvements in drug
prescribing as well in the appropriate use of antibiotics in order to slow the emergence
and transmission of resistance.
Many of the antibiotics produced by microalgae, Figure 4, have their source in
cyanobacteria, haptophytes, chrysophytes, diatoms, dinoflagellates and chlorophytes.
Those active compounds belong to a diverse range of chemical classes, including
fatty acids, bromophenols, tannins, polysaccharides, alcohols, halogenated compounds,
peptides, lipopeptides, alkaloids, amides, tertiary sulfoniums, and many other unique
substances67,68. From the cyanobacterium Nostoc commune, an extracellular metabolite
was isolated and identified as 8-[(5-carboxy-2-hydroxy)-benzyl]-2-hydroxy-1,1,4a,7,8-
pentamethyl-1,2,3,4,4a,6,7,8,8a,9,10,10a-dodecahydrophenanthrene and designated
as noscomin54 (5). The noscomin showed antibacterial activity against Bacillus cereus,
Staphylococcus epidermidis, and Escherichia coli.
The methanolic extract of Fischerella sp. showed activity against Mycobacterium
tuberculosis, Enterobacter aerogenes, Staphylococcus aureus, Pseudomonas aeruginosa,
Salmonella typhi and Escherichia coli in assays. Analyses of the extract established
the structure of the active principle as Hapalindole T39(2). The two exometabolites,
norharmane (9H-pyrido(3,4-b)indole) (3) and 4,4´-dihydroxybiphenyl (4) were extracted
from Nodularia harveyana and Nostoc insulare respectively. These exhibited antibacterial
and antifungal activities, although, so far, their function is not well understood. They may
have an allelopathic function which can be regarded as a chemical defence; a competition
with other organisms in the same habitat53.
Although many studies have emphasised the antibiotic activity of microalgae, almost
all of the assays were conducted, and the results may be vastly different.

5.2 Antivirals

Microalgae and cyanobacteria represent an inexhaustible source of compounds with

promising antiviral activity, but only a few have been identified so far. Figure 5 summarises
some of the antiviral compounds isolated from microalgae and cyanobacteria. One of the
products isolated is cyanovirin‑N (CV‑N) (7), a highly potent virucidal 11‑kDa protein,
originally purified from extracts of the cultured cyanobacterium, Nostoc ellipsosporum.
This irreversibly inactivates a broad spectrum of HIV strains. CV‑N binds with high
affinity to high mannose glycans on the viral envelop glycoprotein gp120, and interferes
with viral interactions with target cell receptors essential for viral entry and cell-to-
cell fusion. CV‑N is also active against a number of other enveloped viruses including
the herpes virus55. Structurally, CV‑N has a unique sequence of 101 amino acids. The
two halves (residues 1 – 50 and 51 – 101) share 32% of the sequence homology. This
protein contains four cysteins forming two intramolecular disulfide bonds. The disulfide
bonds and lack of sequence homology make the artificial production of this protein very
difficult. The protein displays an internal two-fold pseudo symmetric structure. The
154 T. Encarnação, A.A.C.C. Pais, M.G. Campos and H.D. Burrows
Figure 4 Chemical structures of some antibiotically active compounds, extracted from microalgae
and cyanobacteria.

structure of CV‑N has been solved by NMR and X‑ray crystallography and, surprisingly,
the results revealed a domain-swapped dimer in crystal form69. CV‑N it is in preclinical
development as a microbicide for the inhibition of sexual transmission of HIV by Cellegy
Pharmaceuticals, Inc.
A recently isolated cyanobacterial lectin isolated from Microcystis aeruginosa49,
microvirin (MVN) (8), inhibits the infection by a wide variety of HIV‑1 strains. As
with CV‑N, MVN binds to multiple glycans that are present on the envelope of HIV
and subsequently inhibits the viral entry process. However, in contrast to CV‑N, MVN
does not enhance viral replication in pretreated peripheral blood mononuclear cells and is
more than 50‑fold less cytotoxic than the former49.
Sulfated exopolysaccharides (EPS) are known to interfere with the absorption
and penetration of some enveloped viruses into host cells. The marine microalgae
Gyrodinium impudicum produce an extracellular sulfated polysaccharide p‑KG03 which
www.scienceprogress.co.uk Cyanobacteria and microalgae 155
Figure 5 Crystal structures of some antiviral compounds isolated from cyanobacteria. Images
downloaded from RCSB Protein Data Bank (PDB, www.rcsb.org)70.

exhibited extraordinary antiviral activity in vitro (EC50 = 26.9 μg mL – 1) against the

encephalomyocarditis virus (EMCV)43. The p‑KG03 comprises a homogenous mixture
of galactose units conjugated to uronic acid and sulfated group branches. The compound
p‑KG03 also exhibited anti-viral activity against the influenza virus type A (two H1N1
and one H3N2 isolates) and type B (two isolates). The EC50 values against influenza A
virus for p‑KG03 were comparable to those of TAMIFLU®42. Mechanism studies showed
that p‑KG03 inhibited the binding of the influenza virus to host cells, by capturing viral
particles, and prevented cellular internalisation of the virus and viral replication42.
Other compounds include the sulfated exopolysaccharides A1 and A2 which were
isolated and purified from the marine microalgae Cochlodinium polykrikoides. These EPS
inhibit the cytopathic effects of influenza virus types A and B in MDCK cells, and RSV
types A and B grown on Hep‑2 cells and also showed antiviral activity against HIV‑1 in
MT‑4 cells. In HMV‑2 cells A2 showed antiviral activity against the parainfluenza virus
type 2 and A1 against HSV‑1. A1 and A2 showed no cytotoxic effects for host cells at
156 T. Encarnação, A.A.C.C. Pais, M.G. Campos and H.D. Burrows
a concentration of 100 μg mL – 1 and inhibitory effects on blood coagulation process at
concentrations inhibitory to virus were not significant34.
Oscillatoria agardhii agglutinin (OAA) (9) is a novel cyanobacterial lectin that
showed potent anti-HIV activity. Its structure has not yet been completely elucidated.
Only its primary structure and carbohydrate binding data have been available. OAA is a
monomeric polypeptide, with 132 amino acids, that shows binding specificity for high
mannose N‑glycans. The overall structure of OAA is a compact β‑barrel-like domain,
comprising 10 β‑strands, thus creating a unique topology57.

5.3 Anticancer

In recent years, structures with potent cytotoxicity have been characterised. Most of these
structures have been found in the cyanobacteria genus Leptolyngbya. Considerable efforts
by the pharmaceutical industry to develop new and more effective drugs against cancer,
and the screening of molecules from marine organisms, has led to the discovery of a
family of secondary metabolites from cyanobacterium, the lipopeptides. These molecules
exhibit their biological activities on tumour cells and are used to induce apoptosis.
Figure 6 summarises some of the anticancer compounds isolated from microalgae
and cyanobacteria. The lipopeptide Somocystinamide A (11), isolated from Lyngbya
majuscule Schizothrix sp. mixed assemblage of marine cyanobacteria is reported to
possess exceptional biological properties. Nogle and Gerwick47 reported significant
cytotoxicity against mouse neuro‑2a neuroblastoma cells. This disulfide dimer potentially
stimulates apoptosis in tumour and angiogenic endothelial cells via both the intrinsic
and extrinsic pathways, but especially via caspase 8, which is an apoptosis-inducing
protein71. Apratoxin A (13) was also isolated from Lyngbya majuscule and exhibited
potent cytotoxicity in vitro, against cancer cell lines. However, the in vivo activity was
reduced against a colon tumour and ineffective against a mammary tumor46.
The dolastatins, in particular dolastatins 10 (15) and 15, are a family of peptides
originally isolated from the Indian Ocean sea hare Dollabela auricularia. Because of
the very small amounts of dolastatins isolated from this organism, it was speculated
that the sea hare acquires these compounds from its cyanobacterial diet. Subsequently,
dolastatins and their derivatives were isolated from the marine cyanobacterium Symploca
sp.62. Dolastatins are antiproliferative agents, active in inhibiting cancer cell growth and
inducing apoptosis (programmed cell death). Dolastatin 10 interacts with the microtubule
subunit protein, tubulin, which is an important component of the cell structure and
kinetics, interfering with the cell cycle and mitotic cell division ceases72.
Bisebromoamide (16), a cytotoxic peptide recently isolated from cyanobacterium
Lyngbya sp., exhibited cytotoxicity against HeLa cells, together with potent protein
kinase inhibition48.

5.4 Toxins

Some microalgae are known to produce toxins (Figure 7), in particular the cyanobacteria
and the dinoflagellates. They can form blooms all over the world, capable of producing a
wide range of toxins which are significantly hazardous to human and animal health. They
can cause oxygen depletion and alter the food web. Despite this, some of these toxins
have gained importance because of their potential use as pharmaceuticals68.
www.scienceprogress.co.uk Cyanobacteria and microalgae 157
Figure 6 Chemical structures of some marine cyanobacterial secondary metabolites exhibiting
anticancer activity.

Cyanotoxins are divided into three broad groups, according to their chemical
structure, namely cyclic peptides, including the hepatotoxin microcystis, the alkaloids,
which include the neurotoxin anatoxin a, and the lipopolysaccharides, including an
acylated glycolipid named lipid A. The lipopolysaccharides (LPS) are generally found
in the outer membrane of the cell, where they form complexes with proteins and
phospholipids64. A variety of health effects in humans such as fever, respiratory disease,
skin rashes and gastrointestinal, respiratory and allergic reactions are frequently attributed
to cyanobacterial lipopolysaccharides. However, these LPS, cited as toxins, are described
158 T. Encarnação, A.A.C.C. Pais, M.G. Campos and H.D. Burrows
Figure 7 Some of the microalgae toxin structures.

as weakly toxic compared to LPS from the Enterobacteriaceae. More research is needed
on this to identify the structure and understand the health implications of cyanobacterial
lipopolysaccharides73. Microcystins are a family of more than 50 structurally similar
potent hepatotoxins, mainly produced by Microcystis aeruginosa, but also by genera
Anabaena, Nostoc and Oscillatoria. Structurally, the microcystins are monocyclic
heptapeptides, containing both L- and D‑amino acids and 3 unique amino acids- β‑linked
D‑erythro-β-methylaspartic acid (MeAsp), (2S,3S,8S,9S)-3-amino-9-methoxy-2,6,8-
trimethyl-10-phenyldeca-4,6-dienoic acid (Adda) and N‑methyl dehydroalanine (MDha).
The amino acid Adda is fundamental for expression of biological activity, and changes
in stereochemistry about the conjugated double bond imply a loss of toxicity74. After
uptake into hepatocytes, the microcystins inhibit serine/threonine protein phosphatises 1
and 2A, and the consequent protein phosphorylation imbalance causes disruption of the
liver cytoskeleton leading to massive hepatic haemorrhage, and eventually death74. The
most common microcystin is microcystin‑LR (19), which is suspected of being a tumour
promoter in liver. Lyngbyatoxin‑a (18), identified in cyanobacteria Lyngbya majuscula,
www.scienceprogress.co.uk Cyanobacteria and microalgae 159
is a potent skin irritant that causes the dermatitis known as “Swimmer´s itch” and severe
oral and gastrointestinal inflammation75. This toxin is a potent activator of protein kinase
C (PKC), which is implicated in the regulation of various cellular responses, and was
found to be a potent tumour promoter41. Cyanobacterium Anabaena flos-aquae and some
species of dinoflagellates biosynthesise saxitoxins, known as paralytic shellfish poisons,
that pass through the marine food web via vector organisms, which accumulate the toxins
by feeding on paralytic shellfish poisons29. Saxitoxins are a broad group of neurotoxic
alkaloids which include non-sulfated (saxitoxins), singly sulfated (gonyautoxins), doubly
sulfated (C‑toxins), decarbamoyl variants and the recently discovered hydrophobic
analogs76. The mechanism of action of saxitoxin (17) involves a selective block of
the voltage gated Na+ channels by binding. Voltage-dependent sodium channels are
transmembrane proteins that produce the ionic current responsible for generating action
potentials and for the rapid conduction of electrical signals in excitable cells77. Several
groups of neurotoxins strongly alter channel function by binding to specific receptor
sites77. The inactivation is mediated by the short intracellular loop between the third
and the fourth domains77. Blockage of the ion sodium-ion channel in humans prevents
membrane depolarisation and inhibits subsequent impulse-generation in the peripheral
nerves and skeletal muscles, leading to a prolonged relaxed state and causing paralysis78.
In spite of its neurotoxicity to humans, 1 mg of the toxin being fatal29, saxitoxin has
therapeutic potential as potent blocker of nerve conduction that can produce prolonged
anaesthesia without myo and neurotoxic effects78.

6. Photosynthetic pigments

All photosynthetic organisms contain pigments to capture light energy. The three main
groups of pigments are chlorophylls, carotenoids and phycobilins. The chlorophyll
molecule consists of a tetrapyrrole porphyrin ring with an atom of magnesium in the
centre, and a long hydrocarbon side chain, Figure 8.
The various chlorophyll molecules designated a, b, c and d differ by substituent group
of the porphyrin ring and all of these molecules exhibit two absorption bands (400 – 475  nm
and 630 – 675 nm). Chlorophyll (23) is present in all oxygenic photoautotrophs, that is, in
all organisms performing oxygenic photosynthesis in the reaction centres of the pigment-
protein complexes. The pigment chlorophyll is used both to absorb light and to carry out
photochemistry, while the remaining pigments absorb at wavelengths other than that of
chlorophyll, and may have both light harvesting and other functions. Carotenoids absorb
light due to their highly conjugated network of single and double bonds (polyenes).
Carotenoids are a large group of organic chromophores with absorption band
between 400 and 550 nm. Their basic structure involves two rings linked to an 18‑carbon
chain by conjugated double bonds. They are usually hydrocarbons (carotenes such as
α‑carotene and β‑carotene (24)) or oxygenated hydrocarbons (xanthophylls such as
lutein, violaxanthin (27), zeaxanthin (25), etc.)4.
Plants and microalgae possess a variety of defence mechanisms against external
aggressions, such as excess light. Many of these mechanisms are also used to optimise
photosynthesis. An important relation has been found between the energy dissipation and
the presence of the xanthophyll zeaxanthin79,80. Zeaxanthin is produced by a mechanism
involving violaxanthin which is poorly understood80, and, through the xanthophyll cycle,
acts as protection agent for the chloroplasts. In this cycle, the excess energy is dissipated
160 T. Encarnação, A.A.C.C. Pais, M.G. Campos and H.D. Burrows
Figure 8 Some of the microalgae pigment structures.

as heat, thus acting as a switch, producing zeaxanthin where the energy dissipation is
required, followed by the removal of this pigment under low light intensity when energy
is required for photosynthesis.
The applications of zeaxanthin include food supplements. It has been shown that
zeaxanthin prevents age-related macular degeneration. This xanthophyll is distributed
in the macular centre, and can filter out blue light from the UV, whereby the intake
of zeaxanthin is related to a lower risk of age-related macular degeneration and with
improvement of visual performance81.
www.scienceprogress.co.uk Cyanobacteria and microalgae 161
 The mutant species strain zeal generated from Dunaliella salina accumulates large
amounts of zeaxanthin (6 mg zeaxanthin/g dry weight) and has been considered for
commercial exploitation82. Although many species of microalgae produce xanthophylls,
the species Haematococcus pluvialis is basically the only one produced on a large scale.
This species is well known for its accumulation of astaxanthin, which has high commercial
value due to its antioxidative properties and as a supplement in the aquaculture of
salmonids and other seafood82.

7. Fatty acids
The therapeutic importance of polyunsaturated fatty acids has been demonstrated in
various clinical studies. The central nervous system is highly rich in ω3 and ω6 long-
chain polyunsaturated fatty acids. Eicosapentaenoic acid (EPA) (28), a ω3 fatty acid,
plays an important role in the prevention and treatment of many diseases and disorders.
An adequate intake of ω3 is essential for optimal visual and neural development. There
is strong evidence that increased consumption of EPA and docosahexaenoic acid (DHA)
(29) may confer benefits in neurological and psychiatric disorders. The lower values of
DHA in the brain are associated with cognitive decline83.
Linoleic acid (LA) (31), an ω6, and the ω3 α‑linolenic acid (ALA‑α) and their
long-chain derivatives are important compounds of the cellular membranes of plants
and animals, and cannot be synthesised in vertebrates due to the absence of desaturase
enzymes Δ‑15 and Δ‑12. Consequently, the dietary intake of these fatty acids is extremely
important84. The fatty acid ALA derived from the diet is the precursor of EPA and DHA,
while LA fatty acid is a precursor of arachidonic acid, AA (30). Although the biosynthesis
of EPA and DHA from LA and ALA is possible, a greater efficiency of uptake in the
tissues is obtained when they are ingested.
Fatty acids are commercially found in dietary supplements, for pregnant and nursing
women, infant formulas, and in fish and animal feed. Microalgae are a recognised source of
these essential fatty acids, Figure 9. As primary producers in the food chain, they provide
a wide variety of polyunsaturated fatty acids that are essential for organisms higher up
the food chain. An oil rich in DHA and EPA, extracted from a strain of Schizochytrium,
has been commercially exploited as a nutraceutical formula and, recently, Aurora Algae
has announced a new product from Nannochloropsis85. This marine eustigmatophyte
is known for producing large amounts of EPA and it is possible to manipulate culture
conditions in order to provide a higher content of essential fatty acids – an optimum
nitrate concentration implies an increase in the abundance of EPA. The market price for
microalgae omega‑3 oil is around US$140 kg – 1, greater than the pricing for fish oil. The
global market for EPA and DHA omega‑3 oils in 2009 was over 85,000 tonnes, and was
estimated to reach 135,000 – 190,000 tonnes by 201585.

8. Biofuels and microalgae

Biofuel production has generated intensive global debate due to the global energy,
environmental and food supply crisis. Biofuels are usually produced from plant oils,
such as corn, soybean, sugar-cane, sugar-beet, sunflower and palm. Rises in global food
prices have been attributed to the use of arable land to produce biofuels. The decrease
in rice and wheat production, and a significant reduction in the market stockpile of
corn, have contributed to a potential food-crisis86. Photosynthetic microorganisms,
162 T. Encarnação, A.A.C.C. Pais, M.G. Campos and H.D. Burrows
Figure 9 Some of the structures of fatty acids extracted from microalgae.

such as cyanobacteria and microalgae, are renewable energy sources that also help to
reduce greenhouse gases, have low pollutant emission, the highest CO2 fixation and O2
production efficiencies, can be used to treat water waste and do not compete with the food
industry since they do not require arable land, and have fairly modest water requirements.
Microalgae cultures can be grown in photobioreactors that can be installed in regions
ranging from the desert to snow soils. They have growth rates higher than traditional
crops, with a complete life cycle that lasts a few days, and they can be easily genetically
manipulated. In addition to extracting lipid for producing biodiesel, other fractions of cell
can be used to produce pigments, nutraceuticals, etc. In terms of yield, there are some
algae that yield around 50% of their own weight of oil and it has been estimated that
they can produce around 125 tonnes ha – 1 of biodiesel86. Table 5 presents some indicative
values of oil production for different crops.
The lipid content can vary greatly between the species and with different growth
conditions. In general, microalgae possess a high content of lipid under depleted nitrogen
conditions. Neutral lipids, in particular, triacylglycerols (TAG) are the dominant type.
TAGs are considered to be preferred to phospholipids or glycolipids for biodiesel because
of their higher percentage of fatty acids and lack of phosphate87. For engine applications,
biodiesel must comply with some requirements such as cetane number, viscosity, flash
and solidification points87. The properties of the triglyceride and the biodiesel fuel are
determined by the amount of each fatty acid that is present in the molecules. Physical
characteristics of both, fatty acids and triglycerides, are determined essentially by chain
length and number of double bonds88.
Microalgae can produce different types of biofuels such as biodiesel, ethanol and
hydrogen. Production of hydrogen by cyanobacteria is a viable alternative energy source.
It is renewable, ecofriendly, carbon neutral and efficient89.
www.scienceprogress.co.uk Cyanobacteria and microalgae 163
 Table 5 Yield of various plant oils86
Crop Oil (L ha – 1)
Castor 1413
Sunflower 952
Safflower 779
Palm 5950
Soy 446
Canola/rapeseed 1000
Coconut 2689
Algae 80,000

Although the use of microalgae can be the most efficient biological producer of oil
on the planet and a versatile biomass source and may soon be one of the Earth´s most
important renewable fuel crops90, at the present, the microalgae and cyanobacteria-based
biofuels are still costly and therefore, unable to compete with petroleum-based fuels.

9. Microalgae and their application as biofertilisers

Nitrogen is an essential macronutrient upon which agricultural and global food supply
is dependent. This macronutrient is vital in the formation of biomolecules such as DNA,
proteins and amino acids. Although there is plenty of nitrogen in the atmosphere, water
and soil, most plants and microalgae are unable to assimilate the most available form
of nitrogen, dinitrogen (N2). In general, the microalgae and plants assimilate nitrates,
ammonia or organic nitrogen sources such as urea. Besides being costly, synthetic chemical
fertilisers, pesticides and herbicides, may have adverse effects on the environment, soil
fertility and productivity. Biofertilisers may help overcome these problems. Diazotrophic
heterocystous cyanobacteria are capable of assimilating N2 through the process of
nitrogen fixation, and have long being used as biofertiliser for rice. Anabaena azollae is
a heterocystous nitrogen-fixing cyanobacteria which lives in symbiotic association with
the water fern Azolla capable of fixing atmospheric nitrogen. The use of Azolla-Anabaena
azollae in agriculture has a long history in China and other countries in the Far East. The
earliest mention of the plant seems to be 2000 years ago in an ancient dictionary, and in
some Chinese poems in which the water plant is described91.
The dinitrogen fixation in cyanobacteria is carried out by the enzyme nitrogenase
found in specialised non-dividing cells known as heterocystis. In addition to enriching
the soil with nitrogen, the cyanobacteria improve soil texture, plant growth and crop
yield since they provide biologically active substances to plants, such as gibberellins,
auxin, cytokinins, vitamins, amino acids, polypeptides, substances with antibacterial and
antifungal activities and exopolysaccharides92. There have been a number of studies of the
effect of cyanobacterial biofertilisation. In a literature review of 634 field experiments,
inoculation of rise with cyanobacteria biofertizer was found to have induced an increase
of grain yield of 267 kg ha – 1 93.
Despite the success of rice production with diazotrophic heterocystous cyanobacteria,
its use is restricted to a very limited hectarage. This is mostly due to technological
obstacles of inoculums quality, establishment of protocols for use under field situations
and poor shelf-life93. However, potentially biofertilisation with cyanobacteria provides a
renewable non-costly, easily manageable biological nitrogen source that can contribute to
a sustainable agricultural development.
164 T. Encarnação, A.A.C.C. Pais, M.G. Campos and H.D. Burrows
 In addition to biologically fixing nitrogen, another very interesting application of
cyanobacteria in agriculture is their use in the degradation of pesticides and the release of
inhibitors of plant pathogen.

10. Conclusions

Microalgae and cyanobacteria are a promising natural resource. The possibilities of

commercial products derived from them are immense. However, at present, the products
offered in the marketplace are very few. The cost for obtaining some of the microalgae
products, and the difficulty to scale up others, are barriers to the commercial exploitation.
Also, culturally, apart from some specific cases, such as the use of spirulina in Chad as
part of their food for many generations, consumers are not yet used to this alternative.
However, the growing shortage of resources, coupled with improving extraction
and production techniques, are turning microalgae and cyanobacteria into an attractive
renewable source of bioactive compounds and other fine chemicals.

11. Acknowledgements

The authors acknowledge the Fundação para a Ciência e Tecnologia, FCT, for the financial
support through the PhD grant SFRH/BD/ 81385/2011 and the Centre of Chemistry,
Coimbra.

12. References
1. Norton, T.A., Melkonian, M. and Andersen, R.A. (1996) Algal biodiversity. Phycologia, 35, 308 – 326.
2. Sakshaug, E., Bricaud, A., Dandonneau, Y., Falkowski, P., Kiefer, D., Legendre, L., Morel, A., Parlsow, J. and
Takahashi, M. (1997) Parameters of photosynthesis: definitions, theory and interpretation of results. J. Plankton
Res., 19, 1637 – 1670.
3. Falkowski, P.G. (2002) The ocean´s invisible forest. Scient. Am., 287, 54 – 61.
4. Richmond, A. (2004) Handbook of microalgal cultures, biotechnology and applied Phycology. Blackwell, Iowa.
5. Encarnação, T., Burrows, H.D., Canelas, A.C. and Campos, M.G. (2012) Effect of N and P on the production of
carotenoids and chlorophyll by the microalgae Nannochloropsis sp. J. Agric. Sci. Technol., 2.
6. Chisti, Y. (2007) Biodiesel from microalgae. Biotech. Adv., 25, 294 – 206.
7. Nisbet, E.G. and Sleep, N.H. (2001) The habitat and nature of early life. Nature, 409, 1083 – 1091.
8. Payne, J.L. et al. (2011) The evolutionary consequences of oxygenic photosynthesis: a body size perspective.
Photosynth Res., 107, 37 – 57.
9. Macías, F.A., Galindo, J.L.G. and Galindo, J.C.G. (2007) Evolution and current status of ecological
phytochemistry. Phytochemistry, 68, 2917 – 2936.
10. Vishnivetskaya, T.A. (2009) Viable cyanobacteria and green algae from the Permafrost darkness. In: Permafrost
soils. Rosa Margesin Ed. Springer-Verlag, Berlin Heidelberg.
11. Beerling, D.J. (2012) Atmospheric carbon dioxide: a driver of photosynthetic eukaryote evolution for over a
billion years? Phil. Trans. R. Soc., 367, 477 – 482.
12. Rebolloso-Fuentes, M.M., Navarro-Pérez, A., García-Camacho, F., Ramos-Miras, J.J. and Guil-Guerrero, J.L.
(2001) J. Agric. Food Chem., 49, 2966 – 2972.
13. Man, J.M. de (1999) Principles of food chemistry. Aspen Publishing, New York.
14. Becker, E.W. (1994) In: Baddiley, J. et al. (eds), Microalgae: biotechnology and microbiology, pp. 178.
Cambridge University Press.
15. Peña, M.R. (2007) Cell growth and nutritive value of the tropical benthic diatom, Amphora sp., at varying levels
of nutrients and light intensity, and different culture locations. J. Appl. Phycol., 19, 647 – 655.
16. Zepka, L.Q., Jacob-Lopes, E., Goldbeck, R. and Queiroz, M.I. (2007) Production and biochemical profile of the
microalgae Aphanothece microscopica Nägeli submitted to different drying conditions. Chem. Eng. Process.,
47, 1305 – 1310.

www.scienceprogress.co.uk Cyanobacteria and microalgae 165

17. Matsudo, M.C., Bezerra, R.P., Sato, S., Perego, P., Converti, A. and Carvalho, J.C.M. (2009) Repeated fed-batch
cultivation of Arthrospira (Spirulina) platensis using urea as nitrogen source. Biochem. Eng. J. 43, 52 – 57.
18. Leema, J.T.M., Kirubagaran, R., Vinithkumar, N.V., Dheenan, P.S. and Karthikayulu, S. (2010) High value
pigment production from Arthrospira (Spirulina) platensis cultured in seawater. Bioresour. Technol., 101,
9221 – 9227.
19. Sydney, E.B., Sturm, W., Carvalho, J.C., Thomaz-Socclo, V., Larroche, C., Pandey, A. and Soccol, C.R. (2010)
Potential carbon dioxide fixation by industrially important microalgae. Bioresour. Technol., 101, 5892 – 5896.
20. Xu, F., Cai, Z., Cong, W. and Ouyang, F. (2004) Growth and fatty acid composition of Nannochloropsis sp.
Grown mixotrophically in fed-batch culture. Biotechnol. Lett., 26, 1319 – 1322.
21. Rebolloso Fuentes, M.M., Fernández, G.G.A., Pérez, J.A.S. and Guerrero, J.L.G. (2000) Biomass nutrient
profiles of the microalga Porphyridium cruentum. Food Chem., 70, 345 – 353.
22. Madigan, M.T., Martinko, J.M., Stahl, D.A. and Clark, D.P. (2012) Biology of microorganisms, 13 edn. Benjamin
Cummings Publishing, Guildford.
23. Falkowski, P.G. and Raven, J.A. (1997) Aquatic photosynthesis, p. 375. Blackwell Scientific Publishers, Oxford.
24. Singh, S., Kate, B. and Banerjee, U.C. (2005) Bioactive compounds from cyanobacteria and microalgae: an
overview. Crit. Rev. Biotechnol., 25, 73 – 95.
25. Florida Fish and Wildlife Conservation Commission (FWC) http://www.flickr.com/photos/myfwc/5884548128/.
26. Burja, A.M., Banaigs, B., Abou-Mansour, E., Burgess, J.G. and Wright, P.C. (2001) Marine cyanobacteria‑a
prolific source of natural products. Tetrahedron, 57, 9347 – 9377.
27. Casarett and Doull´s (2008) In: Klaassen, C.D. (ed.), Toxicology: the basic science of poisons, 7th edn. McGraw-
Hill, New York.
28. Kobayabshi, J. and Kubota, T. (2007) Bioactive macrolides and polyketides from marine dinoflagellates of the
Genus Amphidinium. J. Nat. Prod., 70, 451 – 460.
29. Wiese, M., D´Agostino, P.M., Mihali, T.K., Moffitt, M.C. and Neilan, B.A. (2010) Neurotoxic alkaloids:
saxitoxin and its analogs. Mar. Drugs, 8, 2185 – 2211.
30. Rao, A.R. (2006) Antioxidant activity of Botryococcus braunii extract elucidated models. J. Agric. Food. Chem.,
54, 4593 – 4599.
31. Rickards, R.W., Rothschild, J.M., Willis, A.C., Nola, M.C., Kirk, J., Kirk, K., Saliba, K.J. and Smith, G.D.
(1999) Calothrixins A and B, novel pentacyclic metabolites from Calothrix cyanobacteria with potent activity
against malaria parasites and human cancer cells. Tetrahedron, 55, 13513 – 13520.
32. Guzmán, S., Gato, A., Lamela, M., Freire-Garabal, M. and Calleja, J.M. (2003) Anti-inflammatory and
immunomodulatory activities of polysaccharide from Chlorella stigmatophora and Phaeodactylum tricornutum.
Phytother. Res., 17, 665 – 670.
33. Laguna, M.R., Villar, R., Calleja, J.M. and Cadavid, I. (1993) Effects of Chlorella stigmatophora on the central
nervous system. Planta Med., 59, 125 – 130.
34. Hasui, M., Matsuda, M., Okutani, K. and Shigeta, S. (1995) antiviral activities of sulfated polysaccharides from
a marine microalga (Cochlodinium polykrikoides) against human immunodeficiency virus and other enveloped
viruses. Int. J. Bio. Macromol., 17, 293 – 297.
35. Ohta, S., Ono, F., Shiomi, Y., Nakao, T., Aozasa, O., Nagate, T., Kitamura, K., Yamaguchi, S., Nishi, M.
and Miyata, H. (1998) Anti-Herpes Simplex Virus substances produced by the marine green alga Dunaliella
primolecta. J. Appl. Phycol., 10, 349 – 355.
36. Borowitzka, M.A. (1995) Microalgae as sources of pharmaceuticals and other biologically active compounds. J.
Appl. Phycol., 7, 3 – 15.
37. Villar, R., Laguna, M.R., Calleja, J.M. and Cadavid, I. (1992) Effects of Phaeodactylum tricornutum and
Dunaliella tertiolecta extracts on the central nervous system. Planta Med., 58, 405 – 409.
38. Mo, S., Krunic, A., Santarsiero, B.D., Franzblau, S.G. and Orjala, J. (2010) Hapalindole-related alkaloids from
the cultured cyanobacterium Fischerella ambígua. Phytochemistry, 71, 2116 – 2123.
39. Asthana, R.K., Srivastava, A., Singh, A.P., Deepali, Singh, S.P., Nath, G., Srivastava, R. and Srivastava, B.S.
(2006) Identification of an antimicrobial entity from the cyanobacterium Fischerella sp. isolated from bark of
Azadirachta indica (Neem) tree. J. Appl. Phycol., 18, 33 – 39.
40. Negri, A., Stirling, D., Quilliam, M., Blackburn, S., Bolch, C., Eaglesham, G., Thomas, K., Walter, J. and Willis,
R. (2003) Three novel hydroxybenzoate saxitoxin analogues isolated from the dinoflagellate Gymnodinium
catenatum. Chem. Res. Toxicol., 16, 1029 – 1033.
41. Bhakuni, D.S. and Rawat, D.S. (2005) Bioactive marine natural products. Anamaya Publishers, New Delhi.

166 T. Encarnação, A.A.C.C. Pais, M.G. Campos and H.D. Burrows

42. Kim, M., Yim, J.H., Kim, S., Kim, H.S., Lee, W.G., Kim, S.J., Kang, P. and Lee, C. (2012) In vitro inhibition
of influenza A virus infection by marine microalga-derived sulfated polysaccharide p‑KG03. Antiviral Res., 93,
253 – 259.
43. Yim, J.H., Kim, S.J., Ahn, S.H., Lee, C.K., Rhie, K.T. and Lee, H.K. (2004) Antiviral effects of sulfated
exopolysaccharide from the marine microalga Gyrodinium impudicum Strain KG03. Mar. Biotechnol., 6, 17 – 25.
44. Lorenz, R.T. and Cysewski, G.R. (2000) Commercial potential for Haematococcus microalgae as a natural
source of astaxanthin. Trends Biotechnol., 18, 160 – 167.
45. Laguna, M.R., Villar, R., Cadavid, I. and Calleja, J.M. (1993) Effects of extracts of Tetraselmis suecica and
Isochrysis galbana on the central nervous system. Planta Med., 59, 207 – 214.
46. Luesch, H., Yoshida, Y., Moore, R.E., Paul, V.J. and Corbett, T.H. (2001) Total structure determination of
apratoxin A, a potent novel cytotoxin from the marine cyanobacterium Lyngbya majuscule. J. Am. Chem. Soc.,
123, 5418 – 5423.
47. Nogle, L.M. and Gerwick, W.H. (2002) Somocystinamide A, a novel cytotoxic disulfide dimer from a Fijian
marine cyanobacterial mixed assemblage. Org. Lett., 4, 1095 – 1098.
48. Teruya, T., Sasaki, H., Fukazawa, H. and Suenaga, K. (2009) Bisebromoamide, a potent cytotoxic peptide from the
marine cyanobacterium Lyngbya sp.: isolation, stereostructure, and biological activity. Org. Lett., 11, 5062 – 5065.
49. Huskens, D., Férir, G., Vermeire, K., Kehr, J., Balzarini, J., Dittmann, E. and Schols, D. (2010) Microvirin, a novel
alpha(1,2)-mannose-specific lectin isolated from Microcystis aeruginosa, has anti-HIV‑1 activity comparable
with that of Cyanovirin‑N but a much higher safety profile. J. Biol. Chem., 285, 24845 – 24854.
50. Zafrir, E. and Carmeli, S. (2010) Micropeptins from an Israeli fishpond water bloom of the cyanobacterium
Microcystis sp. J. Nat. Prod., 73, 352 – 358.
51. Patil, V., Källqvist, T., Olsen, E., Vogt, G. and Gislerød, H.R. (2007) Fatty acid composition of 12 microalgae for
possible use in aquaculture feed. Aquacult. Int., 15, 1 – 9.
52. Lukiw, W.J. and Bazan, N.G. (2012) Docosahexaenoic acid and the aging brain. J. Nutr., 138, 2510 – 2514.
53. Volk, R. and Furkert, F.H. (2006) Antialgal, antibacterial and antifungal activity of two metabolites produced and
excreted by cyanobacteria during growth. Microbiol Res, 161, 180 – 186.
54. Jaki, B., Orjala, J. and Sticher, O. (1999) A Novel Extracellular Diterpenoid with Antibacterial Activity from the
Cyanobacterium Nostoc commune. J. Nat. Prod., 62, 502 – 503.
55. Tiwari, V., Shuklaa, S.Y. and Shuklaa, D. (2009) A sugar binding protein cyanovirin‑N blocks herpes simplex
virus type‑1 entry and cell fusion. Antiviral Res.,84, 67 – 75.
56. Pankaj, P.P., Mallick, N., Biswas, S. and Varma, M.C. (2010) In vitro Antimalarial activity of C‑phycocyanin from
Nostoc Muscorum. The Bioscan, 1, 69 – 78.
57. Koharudin, L.M.I., Furey, W. and Gronenborn, A.M. (2010) Novel fold and carbohydrate specificity of the potent
anti-HIV cyanobacterial lectin from Oscillatoria agardhii. J. Biol. Chem., 286, 1588 – 1597.
58. Villar, R., Laguna, M.R., Calleja, J.M. and Cadavid, I. (1992) Effects of Phaeodactylum tricornutum and
Dunaliella tertiolecta extracts on the central nervous system. Planta Med., 58, 405 – 409.
59. Villar, R., Laguna, M.R., Calleja, J.M. and Cadavid, I. (1992) Effects of Skeletonema costatum extracts on the
central nervous system. Planta Med., 58, 398 – 404.
60. Shih, S., Tsai, K., Li, Y., Chueh, C. and Chan, E. (2003) Inhibition of Enterovirus 71‑induced apoptosis by
allophycocyanin isolated from a blue-green alga Spirulina platensis. J Med Virol, 70, 119 – 125.
61. Taori, K., Liu, Y., Paul, V.J. and Luesch, H. (2009) Combinatorial strategies by marine cyanobacteria: symplostatin
4, an antimitotic natural Dolastatin 10/15 hybrid that synergizes with the coproduced HDAC inhibitor largazole.
ChemBioChem, 10, 1634 – 1639.
62. Luesch, H., Moore, R.E., Paul, V.J., Mooberry, S.L. and Corbett, T.H. (2001) Isolation of Dolastatin 10 from
the marine cyanobacterium Symploca Species VP642 and total stereochemistry and biological evaluation of its
analogue Symplostatin 1. J. Nat. Prod., 64, 907 – 910.
63. Wink, M. (2003) Evolution of secondary metabolites from an ecological and molecular phylogenetic perspective.
Phytochemistry, 64, 3 – 19.
64. http://www.who.int/bulletin/volumes/89/2/11-030211/en/ (last accessed August 2013).
65. Boucher, H.W., Talbot, G.H., Bradley, J.S., Edwards, J.E., Gilbert, D., Rice, L.B., Scheld, M., Spellberg, B. and
Bartlett, J. (2009) Bad bugs, no drugs: No ESKAPE! An update from the Infectious Diseases Society of America.
Clin. Infect. Dis., 48, 1 – 12.
66. http://www.emea.europa.eu/pdfs/human/antimicrobial_resistance/EMEA-576176-2009.pdf (last accessed July
2013).
67. Hannon, M., Gimpel, J., Tran, M., Rasala, B. and Mayfield, S. (2010) Biofuels from algae: challenges and
potential. Future Sci., 1, 763 – 784.

www.scienceprogress.co.uk Cyanobacteria and microalgae 167

68. Cohen, Z. (1999) Chemicals from microalgae. Taylor & Francis Ltd, Oxford.
69. Xiong, S., Fan, J. and Kitazato, K. (2010) The antiviral protein cyanovirin‑N: the current state of its production
and applications. Appl. Microbiol. Biotechnol., 86, 805 – 812.
70. Protein Data Bank. Cyanovirin‑N (1LSE,) Barrientos, L.G., Louis, J.M., Botos, I., Mori, T., Han, Z., O’Keefe,
B.R., Boyd, M.R., Wlodawer, A. and Gronenborn, A.M. (2002) Structure, 10, 673 – 686; Microvirin (2Y1S)
Shahzad-Ul-Hussan, S., Gustchina, E., Ghirlando, R., Clore, G.M. and Bewley, C.A. (2011) J. Biol. Chem., 286,
20788; Oscillatoria Agardhii Agglutinin (3S60) Koharudin, L.M. and Gronenborn, A.M. (2011) Structure, 19,
1170 – 1181; Allophycocyanin (1ALL) Brejc, K., Ficner, R., Huber, R. and Steinbacher, S. (1995) J. Mol. Biol.,
249, 424 – 440.
71. Wrasidlo, W., Mielgo, A., Torres, V.A., Barbero, S., Stoletov, K., Suyama, T.L., Klemke, R.L., Gerwick, W.H.,
Carson, D.A. and Stupack, D.G. (2007) The marine lipopeptide somocystinamide A triggers apoptosis via
caspase 8. Appl. Biol. Sci., 105, 2313 – 2318.
72. Zheng, L., Wang, Y., Sheng, J., Wang, F., Zheng, Y. and Lin, X., Sun, M. (2011) Antitumor peptides from marine
organisms. Mar. Drugs, 9, 1840 – 1859.
73. Stewart, I., Schluter, P.J. and Shaw, G.R. (2006) Cyanobacterial lipopolysaccharides and human health – a
review. Environ. Health, 5, 1 – 23.
74. Dawson, R.M. (1997) The toxicology of microcystins. Toxicon, 36, 953 – 962.
75. http://www.who.int/water_sanitation_health/resourcesquality/toxcyanchap3.pdf (last accessed July 2013).
76. Wu, L., Nishiyama, K., Hollyfield, J.G. and Wang, Q. (2002) Localisation of Nav1.5 sodium channel protein in
the mouse brain. Neuroreport, 13, 2547 – 2551.
77. Cestèle, S. and Catterall, W.A. (2000) Molecular mechanisms of neurotoxin action on voltage-gated sodium
channels. Biochimie, 82, 883 – 892.
78. Faber, S. (2012) Saxitoxin and the induction of paralytic shellfish poisoning. J. Young Investigators, 23, 1 – 7.
79. Aspinall-O’Dea, M., Pascal, A., Robert, B., Ruban, A. and Horton, P. (2002) In vitro reconstitution of the
activated zeaxanthin state associated with energy dissipation in plants. Plant Biol., 99, 16331 – 16335.
80. McDonald, M. (2003) Photobiology of higher plants. Wiley, London.
81. Wu, J., Hong, S., Wang, Y., Hsu, S. and Chang, C. (2012) Microalgae cultivation and purification of carotenoids
using supercritical anti-solvent recrystallisation of CO2 + acetone solution. J. Supercrit. Fluids, 66, 333 – 341.
82. Eonseon, J., Polle, J.E.W., Lee, H.K., Hyun, S.M. and Chang, M. (2003) Xanthophylls in microalgae: from
biosynthesis to biotechnological mass production and application. J. Microbiol. Biotechnol., 13, 165 – 174.
83. Yokoyama, M. and Origasa, H. (2003) Effects of eicosapentaenoic acid on cardiovascular events in Japanese
patients with hypercholesterolemia: rationale, design, and baseline characteristics of the Japan EPA Lipid
Intervention Study (JELIS). Am. Heart. J., 146, 613 – 620.
84. James, M.J., Gibson, R.A. and Cleland, L.G. (2000) Dietary polyunsaturated fatty acids and inflammatory
mediator production. Am. J. Clin. Nutr., 71, 343S – 8S.
85. Borowitzka, M.A. (2013) High-value products from microalgae – their development and commercialisation. J.
Appl. Phycol., 25, 743 – 756.
86. Rhodes, C.J. (2009) Oil from algae; salvation from peak oil? Science Prog., 92, 39 – 90.
87. Pruvost, J., Vooren, G.V., Cogne, G. and Legrand, J. (2009) Investigation of biomass and lipids production with
Neochloris oleoabundans in photobioreactor. Bioresource Technol., 100, 5988 – 5995.
88. Ramos, M.J., Fernández, C.M., Casas, A., Rodríguez, L. and Pérez, A. (2009) Influence of fatty acid composition
of raw materials on biodiesel properties. Bioresource Technol., 100, 261 – 268.
89. Sharma, N.K., Tiwari, S.P., Tripathi, K. and Rai, A.K. (2011) Sustainability and cyanobacteria (blue-green
algae): facts and challenges. J. Appl. Phycol., 23, 1059 – 1081.
90. Gouveia, L. and Oliveira, A.C. (2009) Microalgae as a raw material for biofuels production. J. Ind. Microbiol.
Biotechnol., 36, 269 – 274.
91. Shi, D. and Hall, D.O. (1988) The Azolla-Anabaena Association: historical perspective, symbiosis and energy
metabolism. Botan. Rev., 54, 353 – 386.
92. Osman, M.E.H., El‑Sheekh, M.M., El‑Naggar, A.H. and Gheda, S.F. (2010) Effect of two species of cyanobacteria
as biofertilisers on some metabolic activities, growth, and yield of pea plant. Biol. Fertil. Soils, 46, 861 – 875.
93. Jha, M.N. and Prasad, A.N. (2006) Efficacy of new inexpensive cyanobacterial biofertiliser including its shelf-
life. World J. Microb. Biot., 22, 73 – 79.

168 T. Encarnação, A.A.C.C. Pais, M.G. Campos and H.D. Burrows