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Abstract Fatty acid desaturation is central to metazoan lipid metabolism and provides building blocks of membrane lipids and precursors of diverse signaling molecules. Nutritional conditions and associated microbiota regulate desaturase expression, but the underlying mechanisms have remained unclear. Here, we show that endogenous and microbiota-dependent small molecule signals promote lipid desaturation via the nuclear receptor NHR-49/PPARα inC. elegans. Untargeted metabolomics of a β-oxidation mutant,acdh-11, in which expression of the stearoyl-CoA desaturase FAT-7/SCD1 is constitutively increased, revealed accumulation of a β-cyclopropyl fatty acid, becyp#1, that potently activatesfat-7expression via NHR-49. Biosynthesis of becyp#1 is strictly dependent on expression of cyclopropane synthase by associated bacteria, e.g.,E. coli. Screening for structurally related endogenous metabolites revealed a β-methyl fatty acid, bemeth#1, which mimics the activity of microbiota-dependent becyp#1 but is derived from a methyltransferase,fcmt-1, that is conserved across Nematoda and likely originates from bacterial cyclopropane synthase via ancient horizontal gene transfer. Activation offat-7expression by these structurally similar metabolites is controlled by distinct mechanisms, as microbiota-dependent becyp#1 is metabolized by a dedicated β-oxidation pathway, while the endogenous bemeth#1 is metabolized via α-oxidation. Collectively, we demonstrate that evolutionarily related biosynthetic pathways in metazoan host and associated microbiota converge on NHR-49/PPARα to regulate fat desaturation.
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This content will become publicly available on August 11, 2026
Automated Iterative N─C and C─C Bond Formation
Small molecule solutions to many contemporary societal challenges await discovery, but the artisanal and manual process via which this class of chemical matter is typically accessed limits the discovery of new functions. Automated assembly of (N‐methyl iminodiacetic acid) MIDA or (tetramethyl N‐methyl iminodiacetic acid) TIDA boronate building blocks via iterative C─C bond formation, an approach we call “block chemistry”, alternatively enables generalized and automated preparation of many different types of small molecules in a modular fashion. But in its current form, this engine cannot also leverage nitrogen atoms as iteration handles. Here, we disclose a new iteration‐enabling group, CbzT (p‐TIDA boronate‐substituted carboxybenzyl), that reversibly attenuates the reactivity of nitrogen atoms and enables generalized catch‐and‐release purification. CbzT is leveraged to achieve the automated modular synthesis of Imatinib (Gleevec), an archetypical clinically approved kinase inhibitor, in which building blocks are iteratively linked by both N─C and C─C bonds. This work substantially expands the types of small molecules that can be iteratively assembled in an automated modular fashion. It also advances the concept of intentionally developing chemistry that machines can do.
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- Award ID(s):
- 2019897
- PAR ID:
- 10633852
- Publisher / Repository:
- Wiley
- Date Published:
- Journal Name:
- Angewandte Chemie International Edition
- Volume:
- 64
- Issue:
- 33
- ISSN:
- 1433-7851
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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