Metabolism enzyme reveals anti-ageing function

The structure of a key energy-releasing enzyme found in all animals is designed to minimise free radical production, an international team of researchers report in this week's Science​.

In what is claimed to be an amazing feat of structural biology, the team visualised the entire molecular structure of succinate dehydrogenase in the E. coli bacterium, allowing them to see for the first time how the protein's three-dimensional shape helps prevent the formation of large quantities of destructive free radicals.

Formed as a by-product during cellular respiration, free radicals can cause havoc in cells by reacting with DNA or the cell membrane, impairing their function. This process is linked to cellular ageing.

Professor Paul Fremont, director of Imperial College London's Centre for Structural Biology, said: "Professor Iwata's group have performed an extraordinary feat in obtaining the first three-dimensional insights of succinate dehydrogenase.​

"This fundamentally important and highly complex metabolic enzyme protects the bacterium from self inflicted damage and lies at the heart of the cell's energy powerhouse. It acts like a built in anti-pollution system, and has significant implications for understanding human ageing."​

Professor So Iwata of Imperial College London, senior author of the paper, added: "Solving the structure of succinate dehydrogenase opens up new leads in the quest to understand longevity and ageing. It now appears that a wide variety of genetic disorders, including muscle and neurodegenerative diseases, and tumour formation, are caused by defective forms of this enzyme - as a result of increased free radical formation."​

"The challenge now is to try and engineer succinate dehydrogenase to maximise its efficiency. The E. coli bacterium provides a flexible model to advance this research because the enzyme is very similar to the human version."​

Cellular respiration is the process of oxidizing food molecules, like glucose, to release energy for use in the body. Found deep inside most human cells in tiny power plants called mitochondria, succinate dehydrogenase plays a key part in this process when oxygen is present. Embedded in the inner membrane of the mitochondria, the enzyme is involved in a system that transfers energy using electrons.

Using the latest X-ray crystallography techniques, Imperial PhD student, Rob Horsfield solved the structure of succinate dehydrogenase. Researchers from the UK, Sweden, the United States and Japan were then able to probe the three-dimensional structure of the protein, to examinehow the enzyme releases energy by breaking down a derivative of glucose, succinate, to a smaller molecule fumarate.

To determine what factors influence free radical production, the team compared the structure of succinate dehydrogenase to a similar enzyme, fumarate reductase.

"Until now, it has been unclear why cells preferentially use succinate dehydrogenase in the presence of oxygen and fumarate reductase in its absence to perform the same job,"​ explained Professor Iwata.

He added that previous research has shown that fumarate reductase produces 120 times more superoxide than succinate dehydrogenase in the presence of oxygen. "Now, we can see why subtle differences between the two structures means that when energy is released from succinate it is not transferred to the next stage of respiration but leaks out, leading to superoxide production."​

Professor Iwata continued:

"Succinate dehydrogenase's structure is far more efficient at handing that energy onto the next stage of respiration. It seems likely that there has been evolutionary pressure for organisms to pick succinate dehydrogenase to limit the damage inflicted on cells by superoxide production."