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Review
. 2020 Jan 31;25(3):625.
doi: 10.3390/molecules25030625.

Linking Genes to Molecules in Eukaryotic Sources: An Endeavor to Expand Our Biosynthetic Repertoire

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Free PMC article
Review

Linking Genes to Molecules in Eukaryotic Sources: An Endeavor to Expand Our Biosynthetic Repertoire

Jack G Ganley et al. Molecules. .
Free PMC article

Abstract

The discovery of natural products continues to interest chemists and biologists for their utility in medicine as well as facilitating our understanding of signaling, pathogenesis, and evolution. Despite an attenuation in the discovery rate of new molecules, the current genomics and transcriptomics revolution has illuminated the untapped biosynthetic potential of many diverse organisms. Today, natural product discovery can be driven by biosynthetic gene cluster (BGC) analysis, which is capable of predicting enzymes that catalyze novel reactions and organisms that synthesize new chemical structures. This approach has been particularly effective in mining bacterial and fungal genomes where it has facilitated the discovery of new molecules, increased the understanding of metabolite assembly, and in some instances uncovered enzymes with intriguing synthetic utility. While relatively less is known about the biosynthetic potential of non-fungal eukaryotes, there is compelling evidence to suggest many encode biosynthetic enzymes that produce molecules with unique bioactivities. In this review, we highlight how the advances in genomics and transcriptomics have aided natural product discovery in sources from eukaryotic lineages. We summarize work that has successfully connected genes to previously identified molecules and how advancing these techniques can lead to genetics-guided discovery of novel chemical structures and reactions distributed throughout the tree of life. Ultimately, we discuss the advantage of increasing the known biosynthetic space to ease access to complex natural and non-natural small molecules.

Keywords: algae; animals; apicomplexans; biosynthetic gene clusters; eukaryotes; natural products.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Workflow from natural product discovery to enzyme utility in accessing complex molecules. The example shown illustrates the chronological order of research on platensimycin (PTM), from molecule discovery [29] to biosynthetic gene cluster (BGC) identification [30] to enzyme characterization [31]. This directly enabled the use of an enzyme from this pathway (PtmO6) in the synthesis of the complex natural products mitrekaurenone, pharboside aglycone, and fujenoic acid [32]. Pink dots represent carbons that are functionalized by PtmO6.
Figure 2
Figure 2
Analysis of the Minimum Information about a Biosynthetic Gene Cluster (MiBIG) repository [33]. The pie chart (center) shows the natural product source for all 2009 BGCs deposited on the MiBIG repository. All 1666 bacterial BGCs are further categorized by phylum (right) and Proteobacteria are further categorized by class. All 310 fungal BGCs are further categorized by phylum and class (left).
Figure 3
Figure 3
Natural products present in both cyanobacteria and marine eukaryotes. (A) Structure of the mycosporine-like amino acid (MAA) shinorine produced by Anabaena variabilis and Nostoc punctiforme. (B) Biosynthesis and BGC of shinorine from Anabaena variabilis and Nostoc punctiforme [59]. SH 7-P; Sedoheptulose 7-phosphate. (C) The MAA Porphyra-334 is produced in the dinoflagellate Symbiodinium SymA and the BGC was identified, while Symbiodinium SymC does not produce MAAs and no BGC is found within the genome [56]. (D) Structure of saxitoxin produced by Cylindrospermopsis raciborskii T3. (E) The BGC for saxitoxin (stx) and resolved biosynthetic steps [68,69].
Figure 4
Figure 4
Natural products and their biogenesis from marine eukaryotes. (A) Structure of DA from the diatom Pseudo-nitzchia multiseries. (B) The domoic acid (DA) BGC from Pseudo-nitzchia multiseries and the biosynthesis to isodomoic acid A [79]. l-NGG; N-geranyl-l-glutamic acid. (C) Structure of kainic acid (KA) from the seaweed Digenea simplex. (D) The KA BGC from Digenea simplex and the biosynthesis of KA. (E) Semisynthetic route to KA by Moore and colleagues [80].
Figure 5
Figure 5
Sacoglossan sea slug polyproionate biosynthesis. (A) Representative structures of four polypropionates from Elysia spp. (B) Polypropionate synthase in Elysia chlorotica (EcPKS1) and its domain architecture. (C) In vitro reconstitution of EcPKS1 with methylmalonyl-CoA and NADPH led to the triene pyrone and tetraene pyrone, likely precursors to sacoglossan polypropionates [96].
Figure 6
Figure 6
Polyene natural products and their role in pigmentation in birds. (A) Psittacofulvins isolated from the scarlet macaw. (B) WT feathers in Melopsittacus undulatus are green. The blue trait was mapped to a single-nucleotide polymorphism (SNP) located within the MuPKS. (C) Heterologous expression of MuPKS in yeast led to the production of the same polyene pigments found within WT feathers. Heterologous expression of the MuPKS with the blue trait SNP led to no pigment production [104].
Figure 7
Figure 7
Nemamide biosynthesis in Caenorhabditis elegans. (A) Domain architecture of the Caenorhabditis elegans N2 PKS (pks-1) on chromosome III and the NRPS (nrps-1) on chromosome X. (B) Differential metabolomics approach using both pks-1 and nrps-1 mutated worms against WT worms to identify the nemamide metabolites, which were subsequently isolated and structurally characterized [119].

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