Sunlight is the Earth's primary energy source and is exploited by an array of natural and man-made processes. Photosynthetic plants harness solar energy to convert carbon dioxide and water into biomass, and solar panels capture light and convert it to electricity. Sunlight is critical to life on Earth, and yet excessive exposure to sunlight can cause serious harm as it contains ultraviolet (UV) radiation, which damages the DNA of cells. In humans, this damage can lead to conditions such as cataracts and skin cancer.

The marine organisms and animals that live in the upper ocean and on reefs are subject to intense and unrelenting sunlight. In their effort to protect against potentially deadly UV radiation, many small and particularly vulnerable marine organisms, such as bacteria and algae, produce UV-protective sunscreens. While UV-protective compounds have also been found in larger organisms, including fish and their eggs, the presence of these sunscreens has always been attributed to the animal sequestering the compounds from their environment or partnering with a sunscreen-producing microorganism.

Now, Osborn, Almabruk, Holzwarth et al. have discovered a fish that is able to produce such a UV-protective compound completely on its own. After identifying the full set of genes—or pathway—responsible for generating the UV-protective compound, the same pathway was detected in a variety of diverse animals, including amphibians, reptiles, and birds. This opens up a new area of study, because besides providing UV protection, no one yet knows what other roles the molecule may have in these animals. Furthermore, introducing the complete pathway into yeast enabled these cells to produce the sunscreen. In the future, engineering a yeast population to produce large quantities of the natural sunscreen could lead to large-scale production of the UV-protective compound so it can be used in pharmaceuticals and cosmetics.

The sunscreen compounds, mycosporine-like amino acids (MAAs) and related gadusols, commonly found in bacteria, fungi, algae, and marine invertebrates (Shick and Dunlap, 2002; Miyamoto et al., 2014), have been proposed to fulfill a variety of functions, such as sunscreen, antioxidant, stress response, intracellular nitrogen reservoir, and/or optical filter (Gao and Garcia-Pichel, 2011; Bok et al., 2014). Although their formation had long been proposed to originate from the shikimate pathway, more recent bioinformatic and biochemical studies revealed that in cyanobacteria, MAAs are synthesized by desmethyl-4-deoxygadusol synthase (DDGS), a dehydroquinate synthase (DHQS) homolog (Wu et al., 2007; Balskus and Walsh, 2010; Singh et al., 2010; Asamizu et al., 2012). Interestingly, inactivation of the DDGS gene in Anabaena variabilis ATCC 29413 did not abolish the production of MAAs, suggesting that additional pathways exist for the biosynthesis of MAAs (Spence et al., 2012). DDGS converts sedoheptulose 7-phosphate (SH7P) to desmethyl-4-deoxygadusol via a unique sequence of dephosphorylation, aldol condensation, enolization, dehydration, reduction, and tautomerization reactions (Figure 1—figure supplement 1) (Balskus and Walsh, 2010; Asamizu et al., 2012). The product is subsequently converted by a methyltransferase to 4-deoxygadusol, the building block of MAAs.

4-Deoxygadusol has also been proposed to be the precursor of gadusol (Starcevic et al., 2010; Rosic and Dove, 2011), a related compound initially isolated from cod roe (Gadus morhua L.) (Plack et al., 1981), but also found in roes of other marine fish (Plack et al., 1981; Arbeloa et al., 2010), sea urchin eggs (Chioccara et al., 1986), cysts and nauplii of brine shrimp (Grant et al., 1985), mantis shrimp crystalline cones (Bok et al., 2014), and sponges (Bandaranayake et al., 1997). As genes responsible for the production of 4-deoxygadusol and MAAs are commonly found in bacteria (e.g., cyanobacteria), algae, and other marine microorganisms (Shick and Dunlap, 2002; Miyamoto et al., 2014), the accumulation of these compounds in marine animals has been proposed to be of dietary or symbiont origin (Arbeloa et al., 2010; Gao and Garcia-Pichel, 2011; Loew, 2014). On the other hand, a gene cluster like that in cyanobacteria apparently encoding a four-step DDGS-based pathway for converting SH7P to MAAs was discovered in the genomes of a coral (Acropora digitifera) and sea anemone (Nematostella vectensis), suggesting that these invertebrates can produce MAAs autonomously (Rosic and Dove, 2011; Shinzato et al., 2011).

DDGS is a member of the sugar phosphate cyclase (SPC) superfamily (Wu et al., 2007). In addition to DHQS, this superfamily includes four enzymes known for their roles in the biosynthesis of natural products with therapeutic application: 2-epi-5-epi-valiolone synthase (EEVS), 2-epi-valiolone synthase, aminoDHQS, and 2-deoxy-scyllo-inosose synthase (DOIS) (Wu et al., 2007; Mahmud, 2009; Asamizu et al., 2012; Kang et al., 2012). EEVS catalyzes the entry step to the biosynthesis of pseudosugar-containing natural products, such as the antidiabetic drug acarbose and the crop protectant validamycin A, and has so far only been identified and characterized in bacteria (Mahmud, 2009).

Recently, we surprisingly also found genes that encode EEVS-like proteins (annotated as ‘PREDICTED: pentafunctional AROM polypeptide-like’) in the genomes of fish, amphibians, reptiles, and birds (Figure 1A, Figure 1—figure supplement 2, Table 1, Figure 1—source data 1). This gene is located in a cluster with another functionally unknown gene (labeled as MT-Ox hereafter) and flanked by a suite of transcription factor genes encoding FRMD4B, MitF, MDFIC, and FoxP1 (Figure 1B). These transcription factors have been known to regulate the expression of genes with essential roles in cell differentiation, proliferation, and survival (Levy et al., 2006; Rice et al., 2012; Garner et al., 2014; Zhao et al., 2015). However, whether they have a direct functional relationship with the EEVS and MT-Ox genes remains an open question. Whereas humans and other mammals also have FRMD4B, MitF, MDFIC, and FoxP1 homologs, they lack the EEVS-like and the MT-Ox genes (Figure 1B). Therefore, the presence of the EEVS-like gene, previously only found in bacteria, in the genomes of fish, and other egg-laying vertebrates is puzzling and evolutionarily intriguing. Here, we report bioinformatics and functional studies of zebrafish (Danio rerio) EEVS-like and MT-Ox genes and the expression of this two-enzyme pathway in yeast, and discuss the evolutionary origin of this pathway in fish, amphibians, reptiles, and birds.

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Figure 1—source data 1

Amino acid sequences of the Sugar Phosphate Cyclases (SPCs).

https://doi.org/10.7554/eLife.05919.004

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To investigate the function of the vertebrate EEVS-like genes, the protein encoded by the zebrafish EEVS-like gene (LOC100003999) was expressed in Escherichia coli. Incubation of the recombinant protein with SH7P gave a product, which was confirmed by thin-layer chromatography (TLC) and GC-MS to be EEV (Figure 1C, Figure 1—figure supplements 3, 4), identifying the protein as an EEVS. The best-characterized bacterial EEVS is ValA from the validamycin pathway in Streptomyces hygroscopicus subsp. jinggangensis 5008 (Bai et al., 2006), and the crystal structure of ValA (Protein Data Bank [PDB] entry 4P53) (Kean et al., 2014), allowed identification of a fingerprint set of 14 active-site residues with characteristic variations that could differentiate the various SH7P cyclases. Further supporting the assignment of the LOC100003999-encoded protein as an EEVS, sequence comparisons show that all animal EEVS-like proteins are highly similar (60–72% identity) and also match the sequence of ValA at all 14 fingerprint sites (Figure 1D, Figure 1—figure supplements 5, 6). This firmly establishes the presence of EEVS activity in animals.

The second gene, MT-Ox (zgc:113054), is predicted to encode a protein that contains two domains: the N-terminal domain is similar to S-adenosylmethionine (SAM)–dependent methyltransferases, and the C-terminal domain is similar to NAD⁺-dependent oxidoreductases. Although its function in zebrafish is unknown, the transcription of this gene in larvae is upregulated by light, leading to a prediction of its involvement in circadian clock regulation (Weger et al., 2011). In contrast, we hypothesized that this bifunctional protein is involved in modifying EEV to yield an oxidized and methylated product (Figure 1C). To test this hypothesis, recombinant MT-Ox protein encoded by zgc:113054 was incubated with EEV in the presence of SAM and NAD⁺. Following incubation, a product with λmax of 294 nm (pH 7) and 270 (pH 2.5) was detected (Figure 2A–B). Further analysis of the product by (−)-ESI-MS (m/z 203 [M-H]⁻) and ¹H NMR confirmed its identity as gadusol (Figure 2—figure supplements 1, 2). We postulate that the conversion of EEV to gadusol by MT-Ox takes place via oxidation of the C-2 or C-3 OH, followed by enolization and methylation of the resulting C-2 OH (Figure 2—figure supplement 3). This new pathway to the UV-absorbing vinylogous acid functional group shared by gadusol and 4-deoxygadusol is distinct from that used in the biosynthesis of the MAAs (Balskus and Walsh, 2010; Spence et al., 2012), and the existence of multiple pathways for generating this scaffold is intriguing and may indicate that this is a privileged chemical scaffold in living organisms.

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In zebrafish, both of the LOC100003999 and zgc:113054 genes are expressed during embryonic development. qRT-PCR analysis of mRNA isolated from zebrafish embryos at 12, 24, 48, 72, 96, and 120 hpf showed maximal expression at 72 hpf (Figure 2C–D). To demonstrate de novo synthesis of gadusol in zebrafish, the embryos were collected at 72 hpf, lyophilized and extracted with methanol, and the extract was analyzed by HPLC and ESI-MS (Figure 2G). Our finding of gadusol in the extract unambiguously confirms the ability of zebrafish to synthesize gadusol and amends the current perception that gadusol found in fish and other vertebrates is necessarily of dietary or symbiont origin. However, as MAAs are synthesized via a different pathway and there is no evidence that fish have those biosynthetic enzymes, the accumulation of MAAs in fish would still appear to be of dietary origin (Mason et al., 1998; Zamzow, 2004).

To show that the recombinant LOC100003999 and zgc:113054 genes are sufficient for encoding gadusol synthesis, they were cloned into a yeast expression vector and transferred into a Saccharomyces cerevisiae strain, in which the transaldolase gene TAL1 had been deleted. Yeast possesses a robust pentose–phosphate pathway (Figure 2—figure supplement 4), and by removing the transaldolase enzyme, which normally metabolizes SH7P, and adding EEVS and MT-Ox, we expected to facilitate an effective shunt pathway from SH7P to gadusol. Analysis of the culture broth by HPLC, ESI-MS, and UV spectrophotometry revealed the presence of gadusol (Figure 2H) and its accumulation to ∼20 mg/l after 5 days (Figure 2E). The results not only demonstrate the ability of the engineered yeast to produce and secrete gadusol but also present a new avenue for large-scale production of the compound for possible commercial uses, for example, sunscreen and/or antioxidant (Plack et al., 1981; Schmid et al., 2006; Cardozo et al., 2007; Arbeloa et al., 2010).

To test the UV-protective activity of gadusol, a yeast rad1∆ mutant, which is sensitive to UVB, was suspended at approximately 10⁷ cells/mL in the concentrated supernatant from the gadusol-producing yeast strain or from an otherwise isogenic control strain that did not produce gadusol. The gadusol-containing supernatant suppressed the UVB-sensitivity of the rad1∆ mutant (Figure 2I), confirming the UVB-protective activity of gadusol. Analogous experiments with a wild-type strain (RAD1) at higher doses of UVB showed comparable results (Figure 2J), consistent with UVB protective activity.

As noted above, the SPCs EEVS, EVS, DDGS, aminoDHQS, and DOIS are all related to DHQS and are widespread in bacteria and fungi, but other than this report, are not known to exist in vertebrates or prevertebrates. We suggest that the vertebrate EEVS and MT-Ox genes were most plausibly acquired via horizontal gene transfer. Interestingly, searches identify the stramenopile Aureococcus anophagefferens and the microalgae Coccomyxa subellipsoidea, as the only non-vertebrate organisms in current databases that harbor a similar bifunctional MT-Ox gene, and both organisms have a predicted EEVS gene adjacent to that of MT-Ox. As algae are known to be active horizontal gene transfer agents (Ni et al., 2012), algae such as these become a plausible place both for the development of this alternate pathway for gadusol production and as a source of the genes found in vertebrates. Further supporting such a relationship, the A. anophagefferens EEVS protein is substantially more similar to the vertebrate EEVSs than it is to bacterial EEVSs (Figure 1A and Figure 1—figure supplement 2, denoted by the blue star).

Further bioinformatics studies also showed that the tunicates and lancelets lack the EEVS and MT-Ox genes, suggesting that the gene transfer occurred sometime during the evolution of primitive chordates to bony fishes (Figure 3). While the EEVS and MT-Ox genes are retained in modern ray-finned fish (with the exception of puffer fish), as well as in amphibians, reptiles, and birds, they were lost in mammals, including the egg-laying mammal platypus, indicating the lack of a direct link between gadusol and the mode of reproduction. The West African coelacanth genome (Amemiya et al., 2013) also appears to lack the EEVS and MT-Ox genes (Figure 3, Table 1). This rare ovoviviparous fish lives in caves 100–500 meters deep and feeds at night, and its lack of gadusol production ability may be directly related to its limited exposure to UV light and/or oxidative stress. Other than the well-documented presence of gadusol in fish eggs, where it can serve to protect the roe from UV damage (Arbeloa et al., 2010; Colleter et al., 2014), nothing is known of its role(s) in fish, reptiles, amphibians, and birds. Exploring its function in these organisms will increase our understanding of their physiology and ecology.

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Author details

1. Andrew R Osborn

   Department of Pharmaceutical Sciences, Oregon State University, Corvallis, United States

   Contribution

   ARO, Acquisition of data, Analysis and interpretation of data

   Contributed equally with

   Khaled H Almabruk and Garrett Holzwarth

   Competing interests

   The authors declare that no competing interests exist.

2. Khaled H Almabruk

   Department of Pharmaceutical Sciences, Oregon State University, Corvallis, United States

   Contribution

   KHA, Acquisition of data, Analysis and interpretation of data

   Contributed equally with

   Andrew R Osborn and Garrett Holzwarth

   Competing interests

   The authors declare that no competing interests exist.

3. Garrett Holzwarth

   1. Department of Food Science and Technology, Oregon State University, Corvallis, United States
   2. Department of Microbiology, Oregon State University, Corvallis, United States

   Contribution

   GH, Acquisition of data, Analysis and interpretation of data

   Contributed equally with

   Andrew R Osborn and Khaled H Almabruk

   Competing interests

   The authors declare that no competing interests exist.

4. Shumpei Asamizu

   Department of Pharmaceutical Sciences, Oregon State University, Corvallis, United States

   Present address

   Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo, Japan

   Contribution

   SA, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

5. Jane LaDu

   Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, United States

   Contribution

   JLD, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

6. Kelsey M Kean

   Department of Biochemistry and Biophysics, Oregon State University, Corvallis, United States

   Contribution

   KMK, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

7. P Andrew Karplus

   Department of Biochemistry and Biophysics, Oregon State University, Corvallis, United States

   Contribution

   PAK, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

8. Robert L Tanguay

   Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, United States

   Contribution

   RLT, Conception and design, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

9. Alan T Bakalinsky

   Department of Food Science and Technology, Oregon State University, Corvallis, United States

   Contribution

   ATB, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

10. Taifo Mahmud

    Department of Pharmaceutical Sciences, Oregon State University, Corvallis, United States

    Contribution

    TM, Conception and design, Analysis and interpretation of data, Drafting or revising the article

    For correspondence

    taifo.mahmud@oregonstate.edu

    Competing interests

    The authors declare that no competing interests exist.

    "This ORCID iD identifies the author of this article:" 0000-0001-9639-526X

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