Discovery of an Antarctic Ascidian-Associated Uncultivated
            <i>Verrucomicrobia</i>
            with Antimelanoma Palmerolide Biosynthetic Potential

Murray, Alison E.; Lo, Chien‐Chi; Daligault, Hajnalka; Avalon, Nicole E.; Read, Robert W.; Davenport, Karen W.; Higham, Mary L.; Kunde, Yuliya A.; Dichosa, Armand E. K.; Baker, Bill J.; Chain, Patrick

doi:10.1128/msphere.00759-21

Cited by 11 publications

(16 citation statements)

References 77 publications

(112 reference statements)

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“…The Ca. Synoicihabitans palmerolidicus MAG (GenBank accession number JAGGDC000000000; NCBI BioProject accession number PRJNA662631) included candidate hybrid PKS-NRPS biosynthetic gene clusters that were present in multiple, non-identical copies (Murray et al, 2021). Detailed inspection of one of these clusters (specifically contig 9 which corresponds to pal BGC 4, the first to be interrogated here) has excellent congruence with the retrobiosynthetic predictions outlined above (Figure 1).…”

Section: Proposed Architecture Of the Putative Pal Biosynthetic Gene Cluster And Biosynthesis Of Palmerolide Amentioning

confidence: 61%

“…The D-arabinono-1,4-lactone oxidase (palH) is a FADdependent oxidoreductase that likely works in concert with the glycosyltransferase. An ATP-binding cassette (ABC) transporter is encoded between the core biosynthetic genes and the genes for the trans-acting enzymes (Murray et al, 2021). This transporter, which has homology to SryD and contains the key nucleotidebinding domain GGNGSGKST, may be responsible for the translocation of the macrolide out of the cell, since it is housed within the BGC, it is likely under the same regulatory control.…”

Section: Additional Trans-acting Domains and Domains Between Genes Responsible For Biosynthesismentioning

confidence: 99%

“…Careful assembly of the Ca. Synoicihabitans palmerolidicus MAG revealed the pal BGC was present in multiple copies (Figure 4 and Supplementary Figures S5-S7) (Murray et al, 2021), evidenced by their independent anchoring loci within the MAG and supported by a five-fold increase in depth of coverage relative to the rest of the genome. The structural complexity of the multicopy BGCs represents a biosynthetic system that is similar to that found in Ca.…”

Section: Multiple Copies Of the Pal Biosynthetic Gene Cluster Explain Structural Variants In The Palmerolide Familymentioning

confidence: 99%

“…Palmerolide B instead bears a sulfate group on the C-11 hydroxy group; proteins with homology to multiple types of sulfatases from the UniProtKB database (P51691, P15289, O69787, Q8ZQJ2) are found in the genome of Ca. Synoicihabitans palmerolidicus (Murray et al, 2021), but are not encoded within the BGCs. One of these transacting sulfatases likely modifies the molecule post-translationally.…”

Section: Multiple Copies Of the Pal Biosynthetic Gene Cluster Explain Structural Variants In The Palmerolide Familymentioning

confidence: 99%

“…Next, a persistent cohort of bacteria present across many individual ascidiansa core microbiomefor Synoicum adareanum was identified through analysis of occurrence of distinct amplicon sequence variants (ASV) from iTag sequencing of the Variable 3-4 regions of the bacterial 16S rRNA (Murray et al, 2020). This work ultimately led to the evaluation of the microbiome metagenome and the subsequent assembly of a nearly 4.3 Mbp metagenome assembled genome (MAG) of Candidatus Synoicihabitans palmerolidicus, a verrucomicrobium in the family Opitutaceae (Murray et al, 2021). Contained within the genome are five non-identical copies of a candidate pal BGC.…”

Section: Introductionmentioning

confidence: 99%

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Bioinformatic and Mechanistic Analysis of the Palmerolide PKS-NRPS Biosynthetic Pathway From the Microbiome of an Antarctic Ascidian

et al. 2021

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Complex interactions exist between microbiomes and their hosts. Increasingly, defensive metabolites that have been attributed to host biosynthetic capability are now being recognized as products of host-associated microbes. These unique metabolites often have bioactivity targets in human disease and can be purposed as pharmaceuticals. Polyketides are a complex family of natural products that often serve as defensive metabolites for competitive or pro-survival purposes for the producing organism, while demonstrating bioactivity in human diseases as cholesterol lowering agents, anti-infectives, and anti-tumor agents. Marine invertebrates and microbes are a rich source of polyketides. Palmerolide A, a polyketide isolated from the Antarctic ascidian Synoicum adareanum, is a vacuolar-ATPase inhibitor with potent bioactivity against melanoma cell lines. The biosynthetic gene clusters (BGCs) responsible for production of secondary metabolites are encoded in the genomes of the producers as discrete genomic elements. A candidate palmerolide BGC was identified from a S. adareanum microbiome-metagenome based on a high degree of congruence with a chemical structure-based retrobiosynthetic prediction. Protein family homology analysis, conserved domain searches, active site and motif identification were used to identify and propose the function of the ∼75 kbp trans-acyltransferase (AT) polyketide synthase-non-ribosomal synthase (PKS-NRPS) domains responsible for the stepwise synthesis of palmerolide A. Though PKS systems often act in a predictable co-linear sequence, this BGC includes multiple trans-acting enzymatic domains, a non-canonical condensation termination domain, a bacterial luciferase-like monooxygenase (LLM), and is found in multiple copies within the metagenome-assembled genome (MAG). Detailed inspection of the five highly similar pal BGC copies suggests the potential for biosynthesis of other members of the palmerolide chemical family. This is the first delineation of a biosynthetic gene cluster from an Antarctic microbial species, recently proposed as Candidatus Synoicihabitans palmerolidicus. These findings have relevance for fundamental knowledge of PKS combinatorial biosynthesis and could enhance drug development efforts of palmerolide A through heterologous gene expression.

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Section: Proposed Architecture Of the Putative Pal Biosynthetic Gene Cluster And Biosynthesis Of Palmerolide Amentioning

confidence: 61%

Section: Additional Trans-acting Domains and Domains Between Genes Responsible For Biosynthesismentioning

confidence: 99%

Section: Multiple Copies Of the Pal Biosynthetic Gene Cluster Explain Structural Variants In The Palmerolide Familymentioning

confidence: 99%

Section: Multiple Copies Of the Pal Biosynthetic Gene Cluster Explain Structural Variants In The Palmerolide Familymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bioinformatic and Mechanistic Analysis of the Palmerolide PKS-NRPS Biosynthetic Pathway From the Microbiome of an Antarctic Ascidian

et al. 2021

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Genome Mining Analysis Uncovers the Previously Unknown Biosynthetic Capacity for Secondary Metabolites in Verrucomicrobia

Di,

Li,

Wang

et al. 2024

Mar Biotechnol

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Integrated Metabolomic–Genomic Workflows Accelerate Microbial Natural Product Discovery

2022

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The pairing of analytical chemistry with genomic techniques represents a new wave in natural product chemistry. With an increase in the availability of sequencing and assembly of microbial genomes, interrogation into the biosynthetic capability of producers with valuable secondary metabolites is possible. However, without the development of robust, accessible, and medium to high throughput tools, the bottleneck in pairing metabolic potential and compound isolation will continue. Several innovative approaches have proven useful in the nascent stages of microbial genome-informed drug discovery. Here, we consider a number of these approaches which have led to prioritization of strain targets and have mitigated rediscovery rates. Likewise, we discuss integration of principles of comparative evolutionary studies and retrobiosynthetic predictions to better understand biosynthetic mechanistic details and link genome sequence to structure. Lastly, we discuss advances in engineering, chemistry, and molecular networking and other computational approaches that are accelerating progress in the field of omic-informed natural product drug discovery. Together, these strategies enhance the synergy between cutting edge omics, chemical characterization, and computational technologies that pitch the discovery of natural products with pharmaceutical and other potential applications to the crest of the wave where progress is ripe for rapid advances.

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Discovery of an Antarctic Ascidian-Associated Uncultivated Verrucomicrobia with Antimelanoma Palmerolide Biosynthetic Potential

Abstract: Palmerolide A has potential as a chemotherapeutic agent to target melanoma. We interrogated the microbiome of the Antarctic ascidian, Synoicum adareanum , using a cultivation-independent high-throughput sequencing and bioinformatic strategy.

Cited by 11 publications

References 77 publications

Bioinformatic and Mechanistic Analysis of the Palmerolide PKS-NRPS Biosynthetic Pathway From the Microbiome of an Antarctic Ascidian

Bioinformatic and Mechanistic Analysis of the Palmerolide PKS-NRPS Biosynthetic Pathway From the Microbiome of an Antarctic Ascidian

Genome Mining Analysis Uncovers the Previously Unknown Biosynthetic Capacity for Secondary Metabolites in Verrucomicrobia

Integrated Metabolomic–Genomic Workflows Accelerate Microbial Natural Product Discovery

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