Medicinal Chemistry & Chemical Biology, Contributed Talk (15min)

Comparative metabolomics reveals the gene function of kat-1 in C. elegans

M. Scheidt1, S. Bandi1, S. von Reuss1*
1University of Neuchâtel, Institute of Chemistry, Laboratory of Bioanalytical Chemistry, Avenue des Bellevaux 51, 2000 Neuchâtel

In the model organism Caenorhabditis elegans mutation of the mitochondrial 3-ketoacyl-CoA thiolase (kat-1) has been reported to affect lifespan [1]. Although kat-1 has been assumed to be implicated in mitochondrial β-oxidation of fatty acids, its precise function has remained enigmatic. Comparative analysis of the C. elegans wildtype (N2) and kat-1 mutant exometabolomes revealed some yet unidentified compounds (see Figure 1).

Figure 1: Comparative metabolomics of exometabolomes of a kat-1 mutant (above) and a N2 control (below). The markers indicate some of the metabolic changes found in HPLC-MS traces of the exometabolome.

Large scale cultivation, followed by fractionation, and NMR spectroscopy enabled the identification of several modular tiglyl-glucosides. Their upregulation in kat-1 suggested a potential function in branched chain amino acid metabolism. Feeding experiments with the C. elegans kat-1 mutant using L-[U-13C5]-valine, L- [U-13C6,14N]-leucine, and L-[U-13C6,14N]-isoleucine enriched E. coli Δile Δleu Δval highlighted diverse metabolites derived from the catabolism of L-isoleucine that are strongly upregulated in the kat-1 mutant. Taken together, these results indicate that kat-1 functions as a mitochondrial 2-methylacetoacetyl-CoA thiolase. Consequently, C. elegans kat-1 might represent a suitable model system to study mitochondrial acetoacetyl-CoA thiolase (T2) deficiency, a rare disease in humans [2].

[1] Alina Berdichevsky, Simona Nedelcu, Konstantinos Boulias, Nicholas A. Bishop, Leonard Guarente, H. Robert Horvitz, Proceedings of the National Academy of Sciences of the United States of America, 2010, 107, 18927-18932.
[2] Elsayed Abdelkreem, Rajesh K. Harijan, Seiji Yamaguchi, Rikkert K. Wierenga, Toshiyuki Fukao, Human Mutation, 2019, 40, 1641-1663.