Sweet lysine degradation

November 29, 2018

The researchers from the Departments of Chemistry and Biology at the University of Konstanz have gained fundamental new insights into the degradation of the amino acid lysine - carcinogenic oncometabolites as intermediate products

In fact, they were looking for a specific enzyme. What they found is something so fundamental that their new findings might well find their way into textbooks. Referred to here is the amino acid lysine, which is an important building block in proteins. In bacteria and many other organisms, lysine generates energy during degradation. "We thought that there was nothing more to discover in this field. Then it occurred to us that for many bacteria so far nothing is known about how lysine is degraded," says Professor Jörg Hartig, biochemist at the Department of Chemistry of the University of Konstanz. This even applied for the organism which is by far the most thoroughly studied: The bacterium Escherichia coli, in short E. coli - microbiology's model organism per se. The results of the collaborative work conducted by researchers in the Department of Chemistry and the Department of Biology at the University of Konstanz can be found in the current issue of Nature Communications, 29th November 2018.

Lysine degradation was so far unknown in many bacteria. The new pathway discovered by Jörg Hartig and his two doctoral researchers Sebastian Knorr and Malte Sinn has closed this knowledge gap. "It's a completely new pathway that follows a route so far unknown," says biochemist Hartig. To date, lysine was considered to be one of two amino acids where sugar cannot be obtained directly out of their degradation pathway. It was considered to be solely ketogenic instead of glucogenic. This means that precursors for fatty acid metabolism are obtained during degradation. Lipids can be synthesized from this, for example. However, the synthesis of sugars from simple building blocks is very important for metabolism.

Important findings were obtained while describing the various degradation stages: The Konstanz scientists, including biologists Professor Olga Mayans and Dr David Schleheck, were able to identify glutarate and hydroxyglutarate as metabolic products, amongst others. The researchers mastered the structural characterization of the key enzyme glutarate hydroxylase by solving the crystal structure. They were also able to show that the oxidation of hydroxyglutarate to the central metabolic product α-ketoglutarate is coupled with the respiratory chain. Above all, however: With succinate as the endpoint of the metabolic pathway, they were able to prove for the first time that lysine can be degraded in a glucogenic manner. Jörg Hartig summarizes: "The degradation pathway we've discovered is the very first one to degrade lysine to a glucogenic compound."

The compound hydroxyglutarate, which had not been described previously as a metabolic intermediate, can act as an oncometabolite in humans. This means that it can accumulate in some forms of cancer and promote tumour growth. That hydroxyglutarate might play a role in cancer already at the development stage is a topic of discussion. "If the detoxification of this compound is disrupted, then this could contribute to the development of cancer," says Malte Sinn. To date, scientists were not aware of any specific role for this oncometabolite. It was regarded as metabolic waste. "We've found out that at least in many bacteria it's not simply waste but part of a pathway," says Hartig. This makes hydroxyglutarate an intermediate product.

Apart from their role in cancer, glutarate and hydroxyglutarate play important roles in certain hereditary neurodegenerative diseases. If detoxification mechanisms for metabolic products are already defective in the genome, these substances ac-cumulate as a consequence, leading to neurological disorders already in childhood. The scientists can imagine that via organisms such as E. coli, which are able to carry out this degradation pathway in the bowel, these metabolic products enter human cells and must be disposed of there. Sebastian Knorr points out that research is paying more and more attention to the interrelationship between bacteria that colonize the bowel and humans. "Our results justify taking another fresh look at such processes. Perhaps we'll find more links."
-end-
Key facts:

· Original publication: Sebastian Knorr, Malte Sinn, Dmitry Galetskiy, Rhys M. Williams, Changhao Wang, Nicolai Müller, Olga Mayans, David Schleheck, & Jörg S. Hartig: Widespread bacterial lysine degradation proceeding via glutarate and L-2-hydroxyglutarate. Nature Communications, DOI: 10.1038/s41467-018-07563-6

· Fundamental insights into the degradation pathway of the amino acid lysine

· Collaboration between the Department of Chemistry and the Department of Biology at the University of Konstanz

· Funding provided by the ERC Consolidator Grant awarded to Professor Jörg Hartig (funding period from 2016 to 2021)

Note to editors: You can download a photo here:

https://cms.uni-konstanz.de/fileadmin/pi/fileserver/2018/Bilder/Sue%C3%9Fer_Lysin_Abbau_2.jpg

Caption: Overview of the newly discovered lysine degradation pathway in the bacterium E. coli

Copyright: Jörg Hartig

University of Konstanz

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.