Widespread bacterial lysine degradation proceeding via glutarate and L-2-hydroxyglutarate

Sebastian Knorr, Malte Sinn, Dmitry Galetskiy, Rhys M. Williams, Changhao Wang, Nicolai Müller, Olga Mayans, David Schleheck and Jörg S. Hartig ()
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Sebastian Knorr: University of Konstanz
Malte Sinn: University of Konstanz
Dmitry Galetskiy: University of Konstanz
Rhys M. Williams: University of Konstanz
Changhao Wang: University of Konstanz
Nicolai Müller: University of Konstanz
Olga Mayans: Konstanz Research School Chemical Biology (KoRS-CB)
David Schleheck: Konstanz Research School Chemical Biology (KoRS-CB)
Jörg S. Hartig: University of Konstanz

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract Lysine degradation has remained elusive in many organisms including Escherichia coli. Here we report catabolism of lysine to succinate in E. coli involving glutarate and L-2-hydroxyglutarate as intermediates. We show that CsiD acts as an α-ketoglutarate-dependent dioxygenase catalysing hydroxylation of glutarate to L-2-hydroxyglutarate. CsiD is found widespread in bacteria. We present crystal structures of CsiD in complex with glutarate, succinate, and the inhibitor N-oxalyl-glycine, demonstrating strong discrimination between the structurally related ligands. We show that L-2-hydroxyglutarate is converted to α-ketoglutarate by LhgO acting as a membrane-bound, ubiquinone-linked dehydrogenase. Lysine enters the pathway via 5-aminovalerate by the promiscuous enzymes GabT and GabD. We demonstrate that repression of the pathway by CsiR is relieved upon glutarate binding. In conclusion, lysine degradation provides an important link in central metabolism. Our results imply the gut microbiome as a potential source of glutarate and L-2-hydroxyglutarate associated with human diseases such as cancer and organic acidurias.

Date: 2018
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DOI: 10.1038/s41467-018-07563-6

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