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Proc Natl Acad Sci U S A

Title:		A shortcut to identifying small molecule signals that regulate behavior and development in Caenorhabditis elegans
Author(s):		Pungaliya C; Srinivasan J; Fox BW; Malik RU; Ludewig AH; Sternberg PW; Schroeder FC;
Address:		"Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA"
Journal Title:		Proc Natl Acad Sci U S A
Year:		2009
Volume:		20090403
Issue:		19
Page Number:		7708 - 7713
DOI:		10.1073/pnas.0811918106
ISSN/ISBN:		1091-6490 (Electronic) 0027-8424 (Print) 0027-8424 (Linking)
Abstract:		"Small molecule metabolites play important roles in Caenorhabditis elegans biology, but effective approaches for identifying their chemical structures are lacking. Recent studies revealed that a family of glycosides, the ascarosides, differentially regulate C. elegans development and behavior. Low concentrations of ascarosides attract males and thus appear to be part of the C. elegans sex pheromone, whereas higher concentrations induce developmental arrest at the dauer stage, an alternative, nonaging larval stage. The ascarosides act synergistically, which presented challenges for their identification via traditional activity-guided fractionation. As a result the chemical characterization of the dauer and male attracting pheromones remained incomplete. Here, we describe the identification of several additional pheromone components by using a recently developed NMR-spectroscopic approach, differential analysis by 2D NMR spectroscopy (DANS), which simplifies linking small molecule metabolites with their biological function. DANS-based comparison of wild-type C. elegans and a signaling-deficient mutant, daf-22, enabled identification of 3 known and 4 previously undescribed ascarosides, including a compound that features a p-aminobenzoic acid subunit. Biological testing of synthetic samples of these compounds revealed additional evidence for synergy and provided insights into structure-activity relationships. Using a combination of the three most active ascarosides allowed full reconstitution of the male-attracting activity of wild-type pheromone extract. Our results highlight the efficacy of DANS as a method for identifying small-molecule metabolites and placing them within a specific genetic context. This study further supports the hypothesis that ascarosides represent a structurally diverse set of nematode signaling molecules regulating major life history traits"
Keywords:		"Animals Biological Assay/methods Caenorhabditis elegans Female Magnetic Resonance Spectroscopy/*instrumentation/*methods Male Mass Spectrometry/methods Metabolomics Models, Biological Models, Chemical Mutation Sex Attractants/metabolism Signal Transductio;"
Notes:		"MedlinePungaliya, Chirag Srinivasan, Jagan Fox, Bennett W Malik, Rabia U Ludewig, Andreas H Sternberg, Paul W Schroeder, Frank C eng P41 GM079571/GM/NIGMS NIH HHS/ P41 GM079571-03/GM/NIGMS NIH HHS/ P41 GM079571-03S1/GM/NIGMS NIH HHS/ HHMI/Howard Hughes Medical Institute/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2009/04/07 Proc Natl Acad Sci U S A. 2009 May 12; 106(19):7708-13. doi: 10.1073/pnas.0811918106. Epub 2009 Apr 3"