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Researchers from the Departments of Chemistry and Biology at the University of Constance have gained new fundamental knowledge about the degradation of amino acid lysine – carcinogenic oncometabolites as intermediates
In fact, they were looking for a specific enzyme. What they have found is so fundamental that their new discoveries could well be found in textbooks. The amino acid lysine, which is an important building block of proteins, is mentioned here. In bacteria and many other organisms, lysine generates energy during degradation. "We thought there was nothing left to discover in this area, and then we realized that a lot of bacteria had no information on the degradation of the bacteria until now." lysine, "says Professor Jörg Hartig, a biochemist in the chemistry department at the University of London. Constancy. This even applies to the body that is by far the most studied: the bacterium Escherichia coli, in short E. coli – model organism of microbiology in itself. The results of the collaborative work conducted by researchers from the Department of Chemistry and the Department of Biology of the University of Constance are available in the current issue of Nature Communications, November 29, 2018.
The degradation of lysine was hitherto unknown to many bacteria. The new route discovered by Jörg Hartig and his two PhD students Sebastian Knorr and Malte Sinn helped fill this gap. "It's a brand new trail that follows a route unknown to this day," says biochemist Hartig. To date, lysine has been considered as one of the two amino acids for which sugar can not be obtained directly through their degradation pathway. It was considered to be only ketogenic instead of glucogen. This means that the precursors of fatty acid metabolism are obtained during the degradation. Lipids can be synthesized from this, for example. However, synthesizing sugars from simple building blocks is very important for metabolism.
Important results were obtained by describing the different stages of degradation: Konstanz scientists, including biologists, professors Olga Mayans and David Schleheck, were able to identify glutarate and hydroxyglutarate as metabolic products, among others. The researchers mastered the structural characterization of the key enzyme glutarate hydroxylase by solving the crystal structure. They have also been able to show that the oxidation of hydroxyglutarate to α-ketoglutarate, a central metabolic product, is coupled to the respiratory chain. Above all, however: with succinate as a criterion of the metabolic pathway, they have been able to prove for the first time that lysine can be degraded in a glucogenic way. Jörg Hartig summarizes: "The path of degradation we have discovered is the first to degrade lysine into a glucogenic compound."
The hydroxyglutarate compound, which had not previously been described as a metabolic intermediate, can act as an oncometabolite in humans. This means that it can accumulate in some forms of cancer and promote tumor growth. Hydroxyglutarate could play a role in cancer early in the developmental stage is a topic of discussion. "If the detoxification of this compound is disrupted, it could then contribute to the development of cancer," says Malta Sinn. To date, scientists knew no specific role of this oncometabolite. It was considered a metabolic waste. "We discovered that at least in many bacteria, it was not just a waste, but a part of a path," Hartig said. This makes hydroxyglutarate an intermediate product.
In addition to their role in cancer, glutarate and hydroxyglutarate play important roles in some inherited neurodegenerative diseases. If the detoxification mechanisms of metabolic products are already defective in the genome, these substances accumulate as a result, resulting in neurological disorders early in childhood. Scientists can imagine that via organisms such as E. coli, capable of carrying out this pathway of degradation in the intestine, these metabolic products enter human cells and must be eliminated there. Sebastian Knorr points out that research is paying more and more attention to the interrelation between bacteria that colonize the intestine and humans. "Our results warrant a fresh look at such processes, and perhaps we will find more links."
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Highlights:
· Original publication: Sebastian Knorr, Malte Sinn, Dmitry Galetskiy, Rhys Williams, Changhao Wang, Nicolai Muller, Olga Mayans, David Schleheck and Jörg S. Hartig: widespread lysine degradation by glutarate and L-2-hydroxyglutarate . Nature Communications, DOI: 10.1038 / s41467-018-07563-6
· Fundamental information about the pathway of degradation of lysine amino acid
· Collaboration between the Department of Chemistry and the Department of Biology of the University of Constance
· Funding provided by the ERC Consolidator grant to Professor Jörg Hartig (funding period 2016-2021).
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Caption: Overview of the recently discovered lysine degradation pathway in E. coli
Copyright: Jörg Hartig
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