Posted on Aug 09, 2005, 9 a.m.
By Bill Freeman
The organisation of a key cellular energy-producing enzyme has been revealed by a team of scientists from the Medical Research Council (MRC) Dunn Human Nutrition Unit in Cambridge, UK. The discovery has potential implications for understanding human ageing and is published in the current issue of the journal Science.
‘Complex I' is the first of several protein complexes or enzymes in mitochondria and bacteria that work together in the ‘respiratory chain' to produce the energy that all cells need to function. Complex I generates almost half of that energy, but as a by-product, it also produces harmful ‘oxygen radicals'. These can damage DNA and may be one of the causes of ageing in humans. Malfunction in complex I also leads to many neurodegenerative diseases, including Parkinson's disease. Complex I is assembled from many protein molecules containing many active centres called “iron-sulphur clusters”, which transfer electrons within the enzyme to and from chemicals used in the respiratory chain. Complex I is one of the largest iron-sulphur cluster and protein assemblies and is sometimes called the “monster” by scientists. To understand how this complicated molecular machine works, we need to know how the clusters are arranged inside the protein.
Lead scientist, Dr Leonid Sazanov and his group isolated complex I from bacteria that grow in almost boiling water. Enzymes from these bacteria are very stable, making it is easier to crystallize them and work out their structure. The scientists identified seven clusters in complex I that are elegantly organised into an extended “wire” that connects the points of entry and exit of electrons from the respiratory chain into the enzyme. These clusters are sufficiently close to each other to allow electrons to be passed on quickly.
The scientists were surprised, however, to discover that an additional cluster is located too far away from the others to participate directly in the transfer of electrons along the main pathway. It is possible that its purpose is to take up excess electrons when necessary and that this may decrease the production of the harmful oxygen radicals.
Dr Sazanov said, “The location of this cluster in the enzyme was unexpected. It is important now to explore, by genetic modifications, how changes to this cluster might affect the rate of oxygen radical production. This might help us to learn more about longevity and aging.”
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