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

Avalon, Nicole E.; Murray, Alison E.; Daligault, Hajnalka Erzsebet; Lo, Chien-Chi; Davenport, Karen Walston; Dichosa, Armand Earl Ko; Chain, Patrick Sam Guy; Baker, Bill J.

doi:10.3389/fchem.2021.802574

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

Journal Article · Fri Dec 24 00:00:00 EST 2021 · Frontiers in Chemistry

DOI:https://doi.org/10.3389/fchem.2021.802574· OSTI ID:1968219

Avalon, Nicole E. ^[1]; Murray, Alison E. ^[2];

^[3];

^[3]; Baker, Bill J. ^[1]

Univ. of South Florida, Tampa, FL (United States)
Desert Research Inst. (DRI), Reno, NV (United States)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

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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Research Organization:: Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: 89233218CNA000001; CA205932; ANT-0838776; PLR-1341339; ANT-0632389

OSTI ID:: 1968219

Report Number(s):: LA-UR-23-23080

Journal Information:: Frontiers in Chemistry, Vol. 9; ISSN 2296-2646

Publisher:: Frontiers Research FoundationCopyright Statement

Country of Publication:: United States

Language:: English

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A Bidomain Nonribosomal Peptide Synthetase Encoded by FUM14 Catalyzes the Formation of Tricarballylic Esters in the Biosynthesis of Fumonisins Zaleta-Rivera, Kathia; Xu, Chunping; Yu, Fengan Biochemistry, Vol. 45, Issue 8 https://doi.org/10.1021/bi052085s	journal	February 2006

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
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marine natural products
macrolide
biosynthetic gene clusters
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