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Comparative Metabolomics Reveals Biogenesis of Ascarosides, a Modular Library of Small-Molecule Signals in C. elegans

von Reuss, Stephan H. and Bose, Neelanjan and Srinivasan, Jagan and Yim, Joshua J. and Judkins, Joshua C. and Sternberg, Paul W. and Schroeder, Frank C. (2012) Comparative Metabolomics Reveals Biogenesis of Ascarosides, a Modular Library of Small-Molecule Signals in C. elegans. Journal of the American Chemical Society, 134 (3). pp. 1817-1824. ISSN 0002-7863. PMCID PMC3269134. doi:10.1021/ja210202y. https://resolver.caltech.edu/CaltechAUTHORS:20120404-104142772

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Abstract

In the model organism Caenorhabditis elegans, a family of endogenous small molecules, the ascarosides function as key regulators of developmental timing and behavior that act upstream of conserved signaling pathways. The ascarosides are based on the dideoxysugar ascarylose, which is linked to fatty-acid-like side chains of varying lengths derived from peroxisomal β-oxidation. Despite the importance of ascarosides for many aspects of C. elegans biology, knowledge of their structures, biosynthesis, and homeostasis remains incomplete. We used an MS/MS-based screen to profile ascarosides in C. elegans wild-type and mutant metabolomes, which revealed a much greater structural diversity of ascaroside derivatives than previously reported. Comparison of the metabolomes from wild-type and a series of peroxisomal β-oxidation mutants showed that the enoyl CoA-hydratase MAOC-1 serves an important role in ascaroside biosynthesis and clarified the functions of two other enzymes, ACOX-1 and DHS-28. We show that, following peroxisomal β-oxidation, the ascarosides are selectively derivatized with moieties of varied biogenetic origin and that such modifications can dramatically affect biological activity, producing signaling molecules active at low femtomolar concentrations. Based on these results, the ascarosides appear as a modular library of small-molecule signals, integrating building blocks from three major metabolic pathways: carbohydrate metabolism, peroxisomal β-oxidation of fatty acids, and amino acid catabolism. Our screen further demonstrates that ascaroside biosynthesis is directly affected by nutritional status and that excretion of the final products is highly selective.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/ja210202yDOIArticle
http://pubs.acs.org/doi/abs/10.1021/ja210202yPublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269134/PubMed CentralArticle
ORCID:
AuthorORCID
Srinivasan, Jagan0000-0001-5449-7938
Sternberg, Paul W.0000-0002-7699-0173
Schroeder, Frank C.0000-0002-4420-0237
Additional Information:© 2012 American Chemical Society. Received: October 30, 2011. Publication Date (Web): January 5, 2012. We thank Arthur Edison (University of Florida, Gainesville) for helpful suggestions, the Caenorhabditis Genetics Center, Ho Yi Mak (Stowers Institute), and Shohei Mitani (Tokyo Women’s Medical University) for providing C. elegans mutant strains, and Maciej Kukula (BTI Mass Spectrometry Facility) and Wei Chen (Proteomics and Mass Spectrometry Core Facility, Cornell University) for assistance with HR-MS. This work was supported in part by the National Institutes of Health (GM088290, GM085285, and T32GM008500) and the Cornell/Rockefeller/Sloan-Kettering Training Program in Chemical Biology.
Funders:
Funding AgencyGrant Number
NIHGM088290
NIHGM085285
NIH Predoctoral FellowshipT32GM008500
Cornell/Rockefeller/Sloan-Kettering Training Program in Chemical BiologyUNSPECIFIED
Issue or Number:3
PubMed Central ID:PMC3269134
DOI:10.1021/ja210202y
Record Number:CaltechAUTHORS:20120404-104142772
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20120404-104142772
Official Citation:Comparative Metabolomics Reveals Biogenesis of Ascarosides, a Modular Library of Small-Molecule Signals in C. elegans Stephan H. von Reuss, Neelanjan Bose, Jagan Srinivasan, Joshua J. Yim, Joshua C. Judkins, Paul W. Sternberg, and Frank C. Schroeder Journal of the American Chemical Society 2012 134 (3), 1817-1824
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:29976
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:04 Apr 2012 18:01
Last Modified:09 Nov 2021 19:33

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