Microbial Biotechnology (2011) 4(1), 1–7 doi:10.1111/j.1751-7915.2010.00241.
Genomics update
Microbial sunscreens
Roland J. Siezen1,2,3,4*
1
Kluyver Centre for Genomics of Industrial
Fermentation, Delft, the Netherlands.
2
TI Food and Nutrition, 6700AN Wageningen, the
Netherlands.
3
NIZO food research, 6710BA Ede, the Netherlands.
4
Netherlands Bioinformatics Centre and Center for
Molecular and Biomolecular Informatics, Radboud
University Nijmegen Medical Centre, 6500HB Nijmegen,
the Netherlands.
Basking in the sun on an Australian beach, I began to feel
a burning sensation from excessive UV irradiation and
decided not to wait for the ozone layer to return. As first
aid I scraped some algae and cyanobacteria from the
blistering rocks and smeared them on my exposed skin.
Why? Because these organisms contain sunscreen com-
pounds to protect themselves from harmful doses of UV-B
(280–315 nm) and UV-A (315–400 nm) radiation. Cyano-
bacteria are prominent in many superficial habitats Fig. 1. Filaments of the cyanobacterium Lyngbya sp. with sheaths
exposed to high solar irradiance, including deserts, polar coloured by the yellow to red-brown UV protectant scytonemin (see
arrow); bar = 10 mm. Reprinted from Sinha and Hader (2008) with
regions and intertidal marine flats. On rocky marine sub- permission from Elsevier.
strates, many cyanobacteria form crusts or small cushions
in the high intertidal or supratidal zone. In response to
intense solar radiation, cyanobacteria and some other mining of microbial genomes to assess their potential for
microorganisms have evolved a variety of defence producing sunscreen compounds. A brief overview is
mechanisms including the biosynthesis of UV-absorbing/ given here to wet your appetite.
screening compounds such as mycosporine-like amino
acids (MAAs) and scytonemin. So far, scytonemin has
Mycosporines and MAAs
been found to be produced mainly by cyanobacteria
(Fig. 1), while mycosporine and MAAs are widespread Mycosporines and MAAs are colourless compounds
and are accumulated by a range of microorganisms, found intracellularly in many marine and freshwater
prokaryotic (cyanobacteria) as well as eukaryotic organisms (Sinha et al., 2007; Klisch and Hader, 2008;
(microalgae, yeasts and fungi), and a variety of marine Llewellyn and Airs, 2010). These natural products are
macroalgae, corals and other marine life forms. Excellent characterized by a cyclohexenone or cyclohexenimine
reviews on this topic can be found in Klisch and Hader chromophore core conjugated with amino acids or imino
(2008), Sinha and Hader (2008), Rastogi and Sinha alcohol substituents (Fig. 2). These are attached to the
(2009), Rastogi et al. (2010) and Singh et al. (2010a). core through imine linkages, leading to a combination of
The very recent elucidation of biosynthetic pathways resonance tautomers which facilitates absorption of UV
and identification of associated genes now allows data light. Differences in the absorption spectra of MAAs, with
maxima ranging from 310 to 360 nm (Fig. 3C), are due to
*For correspondence. E-mail [Link]@[Link]; Tel. variations in the attached side groups and nitrogen
(+31) 2436 19559; Fax (+31) 2436 19395. substituent. Figure 2A shows chemical structures of
© 2010 The Author
Journal compilation © 2010 Society for Applied Microbiology and Blackwell Publishing Ltd
2 Genomics update
Fig. 2. Chemical structures of representative (A) mycosporines and MAAs from fungi (mycosporine serinol) and cyanobacteria
(mycosporine-glycine, shinorine and porphyra-334); from Balskus and Walsh (2010), reprinted with permission from American Association for
the Advancement of Sciences; and (B) scytonemin and derivatives; reprinted from Sinha and Hader (2008) with permission from Elsevier.
representative MAAs, and many more structures are and an (NR)peptide synthetase homologue attach
described in Sinha and Hader (2008) and Rastogi and glycine and serine to generate mycosporine-glycine and
Sinha (2009) and in the database of mycosporine-like shinorine.
amino acids (Sinha et al., 2007). Cyanobacteria make Genome data mining subsequently identified this gene
primarily mycosporine-glycine, shinorine, porphyra-334 cluster in several cyanobacteria, fungi, dinoflagellates and
and palythinol, while fungi make mainly mycosporine- even in an actinobacterium (Table 1) (Balskus and Walsh,
glutaminol/glutamicol-glucoside and macroalgae make 2010; Singh et al., 2010b). In cyanobacteria, all gene
various other MAAs (Sinha et al., 2007). MAAs found in clusters contain the first three genes to generate the main
higher animals are derived from their algal diet (Newman intermediate mycosporine-glycine, while additional genes
et al., 2000). vary. Most clusters encode a conserved D-Ala D-Ala ligase
Recently, the initial steps in the biosynthesis of homologue, presumably also to couple amino acids to the
mycosporines and MAAs in Anabaena variabilis were mycosporine core, while others encode a (NR)peptide
elegantly elucidated (Balskus and Walsh, 2010). A cluster synthetase and/or conserved transporter, or combinations
of four genes (Fig. 3A) was found to be responsible for of these.
conversion of the common pentose phosphate pathway
intermediate sedoheptulose 7-phosphate into shinorine
Scytonemins
(Fig. 3B). In the first steps, a dehydroquinate synthase
(DHQS) homologue 2-epi-5-epi-valiolone synthase and Cyanobacteria produce the indole alkaloid scytonemin as
an O-methyltransferase convert the precursor into part of their response strategy for survival in environmen-
4-deoxygadusol, after which an ATP-grasp homologue tally stressed conditions, particularly in pulsed-irradiation
© 2010 The Author
Journal compilation © 2010 Society for Applied Microbiology and Blackwell Publishing Ltd, Microbial Biotechnology, 4, 1–7
Genomics update 3
Fig. 3. A. The shinorine biosynthesis gene
cluster from Anabaena variabilis.
B. Biosynthetic pathways for the assembly of
mycosporine and MAAs from sedoheptulose
7-phosphate.
C. Absorption spectra of some MAAs.
Adapted from Sinha et al. (2007), Balskus and
Walsh (2010) and Rastogi et al. (2010), with
kind permission from Springer
Science+Business Media.
conditions such as in hot and cold deserts. It is found as clic units with a conjugated double-bond distribution that
a yellow (oxidized) to red-brown (reduced), lipid-soluble allows strong absorption of UV-A radiation with a
pigment in the extracellular sheaths or other polysaccha- maximum absorption at 384 nm (Fig. 2).
ride structures (Fig. 1). Its structure consists of a dimeric The scytonemin biosynthesis pathway and associated
carbon skeleton composed of fused symmetric heterocy- genes have been partially elucidated in the cyanobacte-
© 2010 The Author
Journal compilation © 2010 Society for Applied Microbiology and Blackwell Publishing Ltd, Microbial Biotechnology, 4, 1–7
4 Genomics update
Table 1. Putative mycosporine/MAA gene clusters in cyanobacteria (adapted from Balskus and Walsh, 2010).
D-Ala D-Ala
DHQS O-methyl- ATP-grasp ligase (NR)peptide Genome accession
homologue transferase homologue homologue synthetase Transporter code
Cyanobacteria
Anabaena variabilis + + + + NC_007413
ATCC29413
Nostoc punctiforme + + + + NC_010628
ATCC29133/PCC73102
Nodularia spumigena + + + + NZ_AAVW00000000
CCY9414
Cyanothece sp. PCC7424 + + + + + NC_011729
Cyanothece sp. + + + + + NC_010546
PCC51142
Cyanothece sp. CCY0110 + + + + + NZ_AAXW00000000
Lyngbya sp. PCC8106 + + + + + NZ_AAVU00000000
Microcystis aeruginosa + + + +
PCC7806
Microcoleus + + + + NZ_ABRS00000000
chthonoplastes
PCC7420
Crocosphaera watsonii + + + + + NZ_AADV00000000
WH 8501
Trichodesmium + + + ++ ++ + NC_008312
erythraeum IMS101
Actinobacteria
Actinosynnema mirum + + + + NC_013093
DSM43827
+: one gene; ++: two genes; gene accession codes can be found in Balskus and Walsh (2010) supplemental material.
rium Nostoc punctiforme ATCC29133 (Soule et al., 2007; been discovered (Fig. 2B) suggesting that scytonemin
Balskus and Walsh, 2008; 2009; Soule et al., 2009a). An may be the parent for a whole family of related molecules
18-gene cluster responsible for biosynthesis was identi- with subtle changes in radiation absorption.
fied and shown to be specifically induced by UV-A radia-
tion (Fig. 4) (Soule et al., 2007; 2009a). Six consecutive
Combinations of sunscreen compounds
genes coined scyA–scyF with no previously known func-
tion are likely involved in assembly of scytonemin. In In Nosctoc flagelliforme, a terrestrial cyanobacterium from
this gene cluster there is a redundant set of genes arid environments exposed to intense solar radiation and
coding for shikimic acid and aromatic acid biosynthesis known by Chinese for centuries for its edible and medici-
enzymes, leading to the production of tryptophan and nal values, a combination was found of compounds
p-hydroxyphenylpyruvate, which are the likely precursors having complementary absorption of UV-B by MAAs and
of scytonemin (Fig. 4). A tentative scheme of biosynthesis UV-A by scytonemin, thereby providing protection over
steps and a working model for the cellular localization of the whole UV radiation range from 280 to 400 nm (Ferroni
gene products have been proposed (Soule et al., 2009b; et al., 2010). The fact that gene clusters for both scytone-
Rastogi et al., 2010). Genome data mining subsequently min and MAAs biosynthesis are present in the sequenced
identified highly similar gene clusters in the cyanobacteria genomes of Nostoc, Anabaena, Cyanothece, Nodularia
Anabaena, Lyngbya, Nodularia, Cyanothece and Chloro- and Lyngbya strains (Soule et al., 2009b; Balskus and
gleopsis, and two linked smaller gene clusters probably Walsh, 2010) (Table 1) suggests that it is common for
also involved in biosynthesis and regulation, based on cyanobacteria to produce both sunscreen compounds,
synteny and sequence conservation (Fig. 5) (Soule et al., giving full protection over a wide UV radiation range.
2009b). Scytonemin biosynthesis could not be induced by
UV-A in all these strains, suggesting that some gene
Future
clusters have become inactive, possibly due to long labo-
ratory cultivation (Soule et al., 2009b). The ability of MAAs to prevent UV-induced damage in vivo
Scytonemin production has not been observed in other in mice (de la Coba et al., 2009) and in human fibroblast
organisms, but aquatic animals presumably accumulate cells (Oyamada et al., 2008) has been demonstrated.
scytonemins via the food chain or from symbiotic bacterial MAAs like shinorine and porphyra-334 from macroalgae
partners, as they lack the shikimate pathway for synthe- are already used in commercial sunscreen products
sizing precursors. Some derivatives of scytonemin have Helioguard 365 and Helionori to protect against UV-A
© 2010 The Author
Journal compilation © 2010 Society for Applied Microbiology and Blackwell Publishing Ltd, Microbial Biotechnology, 4, 1–7
Genomics update 5
Fig. 4. A. Working model of scytonemin biosynthesis based on genomic analyses. UV-A is absorbed and activates the proposed gene cluster
to produce the corresponding protein products localized according to putative protein domains. UV-A is blocked by scytonemin accumulated in
the cyanobacterial sheath, which ultimately deactivates the transcription of the gene cluster and eliminates the need for the putative protein
products.
B. Proposed biosynthetic pathway for scytonemin and associated gene cluster in Nostoc punctiforme ATCC29133. Green genes are predicted
to be involved in the biosynthesis of (precursors of) aromatic amino acids, while most of the red genes (e.g. scyA–scyF) are predicted to be
involved in scytonemin biosynthesis. Continuous arrows signify gene products that are functionally characterized, whereas broken arrows
indicate the gene products that are still to be functionally characterized.
Adapted from Soule et al. (2009b) and Rastogi et al. (2010), with kind permission from Springer Science+Business Media.
© 2010 The Author
Journal compilation © 2010 Society for Applied Microbiology and Blackwell Publishing Ltd, Microbial Biotechnology, 4, 1–7
6 Genomics update
Fig. 5. Genomic region associated with scytonemin biosynthesis in several strains of cyanobacteria.
A. Genomic region in N. punctiforme ATCC29133, Anabaena PCC7120, Nodularia CCY9414 and Lyngbya PCC8106 (not drawn to scale).
Red, regulatory proteins; yellow, scytonemin core genes; pink, aromatic amino acid biosynthetic genes; black, orthologues to the five-gene
satellite cluster in N. punctiforme; white, genes without homologues among the strains studied; all other colours represent orthologues. Hash
marks delimit the two gene clusters in N. punctiforme and carats connect adjacent genes. Orthologues to the five-gene satellite cluster from
N. punctiforme are specified with a star.
B. Genomic region associated with scytonemin biosynthesis of Chlorogloeopsis CCMEE5094, vertically aligned to match N. punctiforme in (A).
An orthologue to the last gene in the N. punctiforme cluster has not been identified in Chlorogloeopsis and tyrP does not appear to be
integrated within the gene cluster, although it is present in the genome. Genes that are not continuously linked are shown by the insertion of
hash marks.
Reproduced from Soule et al. (2009b).
radiation. In addition to its UV-A absorbing properties, and the Netherlands Bioinformatics Centre, which are part of
scytonemin also has strong anti-proliferative and anti- the Netherlands Genomics Initiative/Netherlands Organiza-
inflammatory activities (Stevenson et al., 2002a,b). Given tion for Scientific Research.
the ever-increasing UV radiation on earth due to depletion
of the ozone layer, there is clearly a great need to discover References
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© 2010 The Author
Journal compilation © 2010 Society for Applied Microbiology and Blackwell Publishing Ltd, Microbial Biotechnology, 4, 1–7
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Journal compilation © 2010 Society for Applied Microbiology and Blackwell Publishing Ltd, Microbial Biotechnology, 4, 1–7
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