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Massive enzyme footballs control sugar metabolism

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Massive enzyme footballs control sugar metabolism. 13.07.2011

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 [1], 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.”

Re.: Biochemical Journal, 13th July 2011

Contact: Robin Wilkinson +44 845 680 1869


Notes for editors

1.    The PDC complex is made up of two related types of protein subunits, termed E2 and E3BP. The E2 enzyme is the structural and mechanistic heart of the complex and has a unique lipoyl ‘swinging arm’ which has to interact with its two companion enzymes, E1 and E3, during the catalytic cycle. E2 is also responsible for tethering and positioning the E1 enzyme on the central scaffold whereas the second scaffold protein E3BP is primarily a structural protein that is responsible for integrating the E3 enzyme correctly into this large molecular machine.

2.    “Variation in the organisation and subunit composition of the mammalian pyruvate dehydrogenase complex E2/E3BP core assembly” by Vijayakrishnan et al. will be published in the Biochemical Journal (2011) Vol 437, part at on 13 July 2011.

3    About ILL – the Institut Laue-Langevin (ILL) is an international research centre based in Grenoble, France. It has led the world in neutron-scattering science and technology for almost 40 years, since experiments began in 1972. ILL operates one of the most intense neutron sources in the world, feeding beams of neutrons to a suite of 40 high-performance instruments that are constantly upgraded. Each year 1,200 researchers from over 40 countries visit ILL to conduct research into condensed matter physics, (green) chemistry, biology, nuclear physics, and materials science. The UK, along with France and Germany is an associate and major funder of the ILL.

4.      Formed in 2010, the College of Medical, Veterinary & Life Sciences at the University of Glasgow brings together internationally-renowned experts in order to advance research in medical, veterinary and life sciences. Its collaborative, interdisciplinary approach means it can study processes at every level of their biological organisation, from genes, to cells, organs, individuals, populations, and ecosystems. Its high quality research is used across the UK and internationally to improve human and animal health, quality of life and the competitiveness of the UK economy.

5.     The Biochemical Journal is published on behalf of the Biochemical Society by Portland Press Limited. Portland Press Limited is a not-for-profit publisher of journals, books and electronic resources in the cellular and molecular life sciences.  It also delivers association management solutions for publishers, learned societies and membership-based organizations.