Combinatorial Assembly of Modular Glucosides via Carboxylesterases Regulates C. elegans Starvation Survival
Abstract
The recently discovered modular glucosides (MOGLs) form a large metabolite library derived from combinatorial assembly of moieties from amino acid, neurotransmitter, and lipid metabolism in the model organism C. elegans. Combining CRISPR-Cas9 genome editing, comparative metabolomics, and synthesis, we show that the carboxylesterase homologue Cel-CEST-1.2 is responsible for specific 2-O-acylation of diverse glucose scaffolds with a wide variety of building blocks, resulting in more than 150 different MOGLs. We further show that this biosynthetic role is conserved for the closest homologue of Cel-CEST-1.2 in the related nematode species C. briggsae, Cbr-CEST-2. Expression of Cel-cest-1.2 and MOGL biosynthesis are strongly induced by starvation conditions in C. elegans, one of the premier model systems for mechanisms connecting nutrition and physiology. Cel-cest-1.2-deletion results in early death of adult animals under starvation conditions, providing first insights into the biological functions of MOGLs.
Additional Information
© 2021 American Chemical Society. Received 7 June 2021. Published online 30 August 2021. We thank WormBase for sequences and life stage expression levels data, and D. Kiemle for assistance with NMR spectroscopy, Integrated DNA technologies for CRISPR reagents, and Tsui-Fen Chou for Cas9 protein. This research was supported in part by the National Institutes of Health (R35GM131877 and U2CES030167 to F.C.S. and R24OD023041 to P.W.S.) and a National Science Foundation Graduate Research Fellowship (DGE 174301 to S.M.C.). F.C.S. is a Faculty Scholar of the Howard Hughes Medical Institute. Author Contributions: All authors have given approval to the final version of the manuscript. The authors declare no competing financial interest.Attached Files
Accepted Version - nihms-1752617.pdf
Supplemental Material - ja1c05908_si_001.pdf
Supplemental Material - ja1c05908_si_002.xlsx
Supplemental Material - ja1c05908_si_003.xlsx
Files
Additional details
- PMCID
- PMC8594405
- Eprint ID
- 110642
- Resolver ID
- CaltechAUTHORS:20210831-200226355
- NIH
- R35GM131877
- NIH
- U2CES030167
- NIH
- R24OD023041
- NSF Graduate Research Fellowship
- DGE-174301
- Howard Hughes Medical Institute (HHMI)
- Created
-
2021-08-31Created from EPrint's datestamp field
- Updated
-
2023-07-07Created from EPrint's last_modified field
- Caltech groups
- Division of Biology and Biological Engineering (BBE)