Bioinformatic and Mechanistic Analysis of the Palmerolide PKS-NRPS Biosynthetic Pathway From the Microbiome of an Antarctic Ascidian
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...
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ftosti:oai:osti.gov:1968219 2023-07-30T03:57:33+02:00 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. 2023-04-12 application/pdf http://www.osti.gov/servlets/purl/1968219 https://www.osti.gov/biblio/1968219 https://doi.org/10.3389/fchem.2021.802574 unknown http://www.osti.gov/servlets/purl/1968219 https://www.osti.gov/biblio/1968219 https://doi.org/10.3389/fchem.2021.802574 doi:10.3389/fchem.2021.802574 37 INORGANIC ORGANIC PHYSICAL AND ANALYTICAL CHEMISTRY 2023 ftosti https://doi.org/10.3389/fchem.2021.802574 2023-07-11T10:26:19Z 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 ... Other/Unknown Material Antarc* Antarctic SciTec Connect (Office of Scientific and Technical Information - OSTI, U.S. Department of Energy) Antarctic The Antarctic Frontiers in Chemistry 9 |
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SciTec Connect (Office of Scientific and Technical Information - OSTI, U.S. Department of Energy) |
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37 INORGANIC ORGANIC PHYSICAL AND ANALYTICAL CHEMISTRY |
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37 INORGANIC ORGANIC PHYSICAL AND ANALYTICAL CHEMISTRY 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. Bioinformatic and Mechanistic Analysis of the Palmerolide PKS-NRPS Biosynthetic Pathway From the Microbiome of an Antarctic Ascidian |
topic_facet |
37 INORGANIC ORGANIC PHYSICAL AND ANALYTICAL CHEMISTRY |
description |
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 ... |
author |
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. |
author_facet |
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. |
author_sort |
Avalon, Nicole E. |
title |
Bioinformatic and Mechanistic Analysis of the Palmerolide PKS-NRPS Biosynthetic Pathway From the Microbiome of an Antarctic Ascidian |
title_short |
Bioinformatic and Mechanistic Analysis of the Palmerolide PKS-NRPS Biosynthetic Pathway From the Microbiome of an Antarctic Ascidian |
title_full |
Bioinformatic and Mechanistic Analysis of the Palmerolide PKS-NRPS Biosynthetic Pathway From the Microbiome of an Antarctic Ascidian |
title_fullStr |
Bioinformatic and Mechanistic Analysis of the Palmerolide PKS-NRPS Biosynthetic Pathway From the Microbiome of an Antarctic Ascidian |
title_full_unstemmed |
Bioinformatic and Mechanistic Analysis of the Palmerolide PKS-NRPS Biosynthetic Pathway From the Microbiome of an Antarctic Ascidian |
title_sort |
bioinformatic and mechanistic analysis of the palmerolide pks-nrps biosynthetic pathway from the microbiome of an antarctic ascidian |
publishDate |
2023 |
url |
http://www.osti.gov/servlets/purl/1968219 https://www.osti.gov/biblio/1968219 https://doi.org/10.3389/fchem.2021.802574 |
geographic |
Antarctic The Antarctic |
geographic_facet |
Antarctic The Antarctic |
genre |
Antarc* Antarctic |
genre_facet |
Antarc* Antarctic |
op_relation |
http://www.osti.gov/servlets/purl/1968219 https://www.osti.gov/biblio/1968219 https://doi.org/10.3389/fchem.2021.802574 doi:10.3389/fchem.2021.802574 |
op_doi |
https://doi.org/10.3389/fchem.2021.802574 |
container_title |
Frontiers in Chemistry |
container_volume |
9 |
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1772817980629975040 |