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. 2024 Feb 19;15:1520. doi: 10.1038/s41467-024-45782-2

Fig. 5. NHR-49 agonists integrate bacterial and endogenous metabolism.

Fig. 5

A The Rhodobacter sphaeroides SAM-dependent methyltransferase, UfaM (FCMT-1 BLAST E-value 5e-72), catalyzes methyl transfer to VA to produce an 11-methyl-12-trans 18:1 FA68. B Proposed biosynthesis of bemeth#1 based on isotopically labeled D13-vaccenic acid (VA) feeding experiment (number of D atoms denoted in green next to each carbon). Methyl transfer results in the abstraction of one deuterium atom (highlighted with green arrow) and distal oxidation results in metabolites with a diagnostic number of deuterium atoms remaining. C EICs for m/z 215.1289 and 226.1982, corresponding to bemeth#3 and D11-bemeth#3, respectively, in extracts of hacl-1 cultures supplemented with D13-cis- or D13-trans-VA. Isotopically enriched bemeth#3 is observed when hacl-1 animals are supplemented with D13-cis- but not D13-trans-VA. Y-axis for m/z 226.1982 is scaled 5-fold to clearly show traces for labelled features. Isotope enrichment in low-abundance isomers confirmed the existence of several additional bemeth#3 isomers (bemeth#33 – bemeth#38, marked by arrowheads, see Supplementary Table 2). D Representative GFP fluorescence micrographs of Pfat-7::fat-7::GFP animals reared at 25 °C on HT115 E. coli expressing various RNAi and supplemented with either 75 μM bemeth#1 or 75 μM becyp#1, as indicated. The scale bar represents 0.1 mm. Five independent experiments were performed. E Top: Cyclopropyl lipids are synthesized by the E. coli cyclopropyl fatty acid synthase, CFA, which converts VA or palmitoleic acid to the corresponding cyclopropyl derivatives in membrane phospholipids. R represents remainder of phospholipid. Bottom: VA is the substrate for FCMT-1 methylation; four rounds of β-oxidation produce bemeth#1, a fat-7 agonist that requires NHR-13, −49, and −80. Degradation of bemeth#1 occurs via α-oxidation, which yields an α-methyl aldehyde compatible with β-oxidation. In parallel, lipolysis and β-oxidation of bacterial CPFAs by C. elegans produces a C11 β-cyclopropyl fatty acid, becyp#1, which signals via overlapping NHRs. becyp#1 is likely degraded by ACDH-11-dependent β-oxidation, which is predicted to yield an α-methyl aldehyde.