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Massive enzyme footballs control sugar metabolism
18 July 2011
Institut Laue-Langevin (ILL)
Neutrons have shown how massive enzyme complexes inside cells might determine whether sugar is burnt for energy or stored as fat. These findings will improve understanding of diabetes and a range of metabolic diseases.
Scientists using neutrons at the Institut Laue-Langevin (ILL) have shown how pyruvate dehydrogenase complexes (PDCs) could control the rate of sugar metabolism by actively changing their own composition. The research is published in the Biochemical Journal.
PDCs are found within all cell types from bacteria to mammals and are known to help regulate the level of sugar in the blood to meet the continuously changing metabolic demands of the body. The complexes have a unique, football-shaped central scaffold, forming a hollow ball with 12 open pentagonal faces. They are composed of 60 subunits made up of two related proteins. The first is a scaffolding enzyme that acts as the structural heart of the complex, whilst the second has binding role with a third enzyme (attached to the outside of the central football) to generate rapid metabolism.
Whilst the structure of the complex is well understood , the exact composition was undetermined. Most previous purification studies had suggested a ratio of 48 scaffold enzyme units to 12 binding units.
The team at the ILL synthesised human PDC in bacteria and identified the location of the two enzymes through low angle neutron scattering. This revealed a new, unexpected ratio of 40:20 in favour of the scaffold enzyme. However experiments on PDCs from cow heart cells confirmed the expected figure of 48:12.
With further mathematical modelling the team have shown that their synthesised PDC could vary its composition, with any ratio from 60:0 to 40:20 possible. This flexibility may explain why the PDC complex is so quick to react to changes in blood sugar levels, says Dr Phil Callow, an instrument scientist at ILL. “Our models show how the structural organisation of PDC could be fine-tuned through changes in its overall composition to promote maximal metabolic efficiency.”
These findings could provide vital information for future treatments of diseases caused by unusual blood sugar levels such as diabetes and those directly related to mutations in the PDC such as Biliary cirrhosis, a progressive form of liver inflammation.
Professor Gordon Lindsay, University of Glasgow: “Using neutron scattering at ILL, we have shown the potential of these football structures to vary their composition to allow the most efficient utilisation of sugars by the body and enables precise control of sugar breakdown. The next step is to see if this occurs naturally across different tissues of the body and in different living organisms.”
Andrew Harrison, ILL’s Director for Science: “ILL has a proud history carrying out fundamental research that underpins medical breakthroughs and potential new treatments. The PDC complexes studied by Dr Callow and his colleagues are too large for most other techniques. By using neutrons and the wide range of instruments available at ILL, they have given the medical world a new perspective on diseases that affect millions of people across the world.”
The four images show the different arrangements of enzymes E2 (structural - green) and E3BP (metabolising - red) within the PDC structure. The PDC molecules can exist in any of these forms within the cell depending on the rate of metabolism required. Image 1, with the highest proportion of the E3BP enzyme, would promote the highest rate of metabolism and could play a key role in bringing blood sugar levels down to normal rates following a meal.