Abstract
Background Pest insects are increasingly resistant to phosphine gas, which is used globally to protect grain reserves. The enzyme dihydrolipoamide dehydrogenase (DLD) is a phosphine resistance factor and participates in four key steps of core metabolism, making it a potential central metabolic regulator.
Results Here we used microarray data and NMR-based metabolomics to characterize the phosphine response of wild-type C. elegans and the phosphine-resistant strain dld-1(wr4) which has a partial loss-of-function mutation in the gene for DLD. In addition, we have constructed CeCon, a C. elegans genome-scale metabolic model to facilitate integration of gene expression and metabolomics data.
Conclusions The resulting systems biology analysis is consistent with the hypothesis that adaptation to a hypometabolic state is the most prominent mechanism of phosphine resistance in this nematode strain. The involvement of DLD in regulating and creating hypometabolic adaptation has implications for other biological phenomena involving hypometabolism, such as reperfusion injury and metabolic resistance.
List of abbreviations
- ANOVA
- Analysis of variance
- BCAA
- branched-chain amino acid
- BCKDH
- branched-chain ketoacid dehydrogenase
- CeCon
- C. elegans reconstruction
- CPMG
- Carr-Purcell-Meiboom-Gill
- CSE
- cystathionine gamma lyase
- DLD
- dihydrolipoamide dehydrogenase
- DSS
- 2,2-dimethylsilapentane-5-sulfonic acid
- GCS
- glycine cleavage system
- GABA
- gamma amino butyric acid
- GO
- gene ontology
- GSM
- genome-scale metabolic model
- HMBC
- heteronuclear multiple bond correlation
- HSQC
- heteronuclear single quantum correlation
- IMB
- Institute for Molecular Bioscience
- KGDH
- alpha-ketoglutarate dehydrogenase
- LC50
- Medial lethal concentration
- MTC
- multiple testing correction
- MTHF
- 5,10-methylene tetrahydrofolate
- NMR
- nuclear magnetic resonance
- NOESY
- nuclear Overhauser effect spectroscopy
- PDH
- pyruvate dehydrogenase
- ROS
- reactive oxygen species
- SAM
- S-adenosyl methionine
- TCA
- tricarboxylic acid
- TOCSY
- total correlation spectroscopy
- wt
- wild-type