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, 10 (6), e0128742
eCollection

Occurrence of Isopenicillin-N-Synthase Homologs in Bioluminescent Ctenophores and Implications for Coelenterazine Biosynthesis

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Occurrence of Isopenicillin-N-Synthase Homologs in Bioluminescent Ctenophores and Implications for Coelenterazine Biosynthesis

Warren R Francis et al. PLoS One.

Abstract

The biosynthesis of the luciferin coelenterazine has remained a mystery for decades. While not all organisms that use coelenterazine appear to make it themselves, it is thought that ctenophores are a likely producer. Here we analyze the transcriptome data of 24 species of ctenophores, two of which have published genomes. The natural precursors of coelenterazine have been shown to be the amino acids L-tyrosine and L-phenylalanine, with the most likely biosynthetic pathway involving cyclization and further modification of the tripeptide Phe-Tyr-Tyr ("FYY"). Therefore, we searched the ctenophore transcriptome data for genes with the short peptide "FYY" as part of their coding sequence. We recovered a group of candidate genes for coelenterazine biosynthesis in the luminous species which encode a set of highly conserved non-heme iron oxidases similar to isopenicillin-N-synthase. These genes were absent in the transcriptomes and genome of the two non-luminous species. Pairwise identities and substitution rates reveal an unusually high degree of identity even between the most unrelated species. Additionally, two related groups of non-heme iron oxidases were found across all ctenophores, including those which are non-luminous, arguing against the involvement of these two gene groups in luminescence. Important residues for iron-binding are conserved across all proteins in the three groups, suggesting this function is still present. Given the known functions of other members of this protein superfamily are involved in heterocycle formation, we consider these genes to be top candidates for laboratory characterization or gene knockouts in the investigation of coelenterazine biosynthesis.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Structure of coelenterazine.
Structure of coelenterazine showing the incorporation of the amino acids phenylalanine and tyrosine.
Fig 2
Fig 2. Survey of conserved genes across ctenophore transcriptomes.
Dashed line indicates the maximum number of genes in this set, 248. The dotted line indicates the number of genes found in the Mnemiopsis leidyi genome. Most of the transcriptomes recovered a comparable number of genes as the genome. Species abbreviations are as follows: Bfos, Bathocyroe fosteri; Bchu, Bathyctena chuni; Baby, Beroe abyssicola; Bfor, Beroe forskalii; Binf, Bolinopsis infundibulum; Cfug, Charistephane fugiens; Dgla, Dryodora glandiformis; Edun, Euplokamis dunlapae; Hrub, Haeckelia rubra; Hcal, Hormiphora californensis; Llac, Lampea lactea; Lcru, Lampocteis cruentiventer; Mlei, Mnemiopsis leidyi; Omac, Ocyropsis maculata; Tinc, Thalassocalyce inconstans; spB, Undescribed ctenophore B; spC, Undescribed ctenophore C; spN1, Undescribed ctenophore N1; spN2, Undescribed ctenophore N2; spT, Undescribed ctenophore T; spV, Undescribed ctenophore V; Vpar, Velamen parallelum
Fig 3
Fig 3. Multiple sequence alignment of Mnemiopsis proteins.
ML032920-35201 is the putative full-length protein that connects ML032920a and ML35201a. MLRB263549-p indicates it is a partial sequence, as exons are missing in the scaffolds. The consensus sequence is indicated below, where identical residues are shown by ‘*’ and similar residues are shown by ‘.’. Black boxes indicate the highly conserved residues putatively involved in iron and 2-oxoglutarate binding.
Fig 4
Fig 4. Multiple sequence alignment of all FYY proteins.
Alignment of all FYY proteins across ctenophores. Partial sequences were excluded to show the high degree of identity, though they were used for subsequent analysis. The iron-binding residues are indicated by the black box above the consensus line. Species abbreviations are as follows: Bfos, Bathocyroe fosteri; Bchu, Bathyctena chuni; Baby, Beroe abyssicola; Bfor, Beroe forskalii; Binf, Bolinopsis infundibulum; Dgla, Dryodora glandiformis; Edun, Euplokamis dunlapae; Hrub, Haeckelia rubra; Llac, Lampea lactea; Lcru, Lampocteis cruentiventer; ML, Mnemiopsis leidyi; Omac, Ocyropsis maculata; Tinc, Thalassocalyce inconstans; spB, Undescribed ctenophore B; spC, Undescribed ctenophore C; spN1, Undescribed ctenophore N1; spN2, Undescribed ctenophore N2; spT, Undescribed ctenophore T; spV, Undescribed ctenophore V; Vpar, Velamen parallelum
Fig 5
Fig 5. Maximum-likelihood tree of all putative ctenophore non-heme oxygenase protein sequences.
Maximum-likelihood tree of all ctenophore non-heme oxygenase proteins including both FYY-containing (blue branches) and two non-FYY groups (green and purple branches). Outgroups from top BLAST hits (gold branches) and model enzymes (brown and red branches) show long branches compared to the FYY proteins. Sequence names are grayed out to emphasize branch lengths and clustering of the proteins. Scale bar indicates substitutions per site. Partial or incomplete sequences are indicated by -p as in Fig 4. Species abbreviations are as follows: Anid, Aspergillus nidulans; Bfos, Bathocyroe fosteri; Bchu, Bathyctena chuni; Baby, Beroe abyssicola; Bfor, Beroe forskalii; Binf, Bolinopsis infundibulum; Cfug, Charistephane fugiens; Cgig, Crassostrea gigas; Dgla, Dryodora glandiformis; Edun, Euplokamis dunlapae; Hrub, Haeckelia rubra; Hcal, Hormiphora californensis; Llac, Lampea lactea; Lcru, Lampocteis cruentiventer; ML, Mnemiopsis leidyi; Odio, Oikopleura dioica; Omac, Ocyropsis maculata; Otri, Oxytricha trifallax; Pbac, Pleurobrachia bachei; Scla, Streptomyces clavuligerus; Tinc, Thalassocalyce inconstans; spB, Undescribed ctenophore B; spC, Undescribed ctenophore C; spN1, Undescribed ctenophore N1; spN2, Undescribed ctenophore N2; spT, Undescribed ctenophore T; spV, Undescribed ctenophore V; Vpar, Velamen parallelum
Fig 6
Fig 6. Maximum-likelihood tree of putative ctenophore photoprotein-like proteins.
Maximum-likelihood tree of recovered ctenophore photoprotein-like genes and a set of verified cnidarian and ctenophore photoproteins from Schnitzler et al. (2012) [23]. Bootstrap values above 90 are shown. Abbreviations are as in Fig 5 with a few changes and additions: Ac, Aequorea coerulescens; Aque, Amphimedon queenslandica; Am, Aequorea macrodactyla; Ap, Aequorea parva; Av, Aequorea victoria; Ba, Beroe abyssicola; Bi, Bolinopsis infundibulum; Cg, Clytia gregaria; Mc, Mitrocoma cellularia; Nvec, Nematostella vectensis; Og, Obelia geniculata; Ol, Obelia longissima

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