Metabolism enzyme visualised in living tissue

This week in Nature Chemical Biology: researchers from Leiden University and the AMC (Academic Medical Centre) have developed a method of visualising the GBA1 enzyme in living cells. Patients with Gaucher’s disease have a deficiency of this enzyme.

Better diagnostics

Gaucher patients are administered the missing enzyme as a treatment, but this treatment is extremely expensive. The new technology could lead to better diagnostics and, in the long term, to a more effective treatment as well. The influential scientific journal Nature Chemical Biology published the article about the new method on Sunday 31 October. NWO (Netherlands Organisation for Scientific Research) funded the research.

Mode of action of a retaining beta-glucosidase and GBA1 activity-based probes 6 and 7

Mode of action of a retaining beta-glucosidase and GBA1 activity-based probes 6 and 7

Storage of fat molecules

Gaucher is a rare hereditary metabolic disease – there are about 150 patients in the Netherlands. They have a serious deficiency of the glucocerebrosidase (GBA1) enzyme, which means that fat molecules accumulate in certain immune system cells – the macrophages – particularly in the liver, spleen and bone marrow. This can cause severe symptoms. Gaucher patients are administered the missing enzyme once a fortnight.

Fluorescent binding

Researchers led by Professor of Bio-organic Synthesis Herman Overkleeft (Leiden University) and Professor of Biochemistry Hans Aerts (AMC) have developed a fluorescent binding that attaches specifically to the GBA1 enzyme. The new method is much more sensitive than existing techniques for making the enzyme visible, and it can be used in living cells.

The right concentration in the right tissues?

The technique is currently only used on laboratory animals, but the researchers hope that it will soon be possible to use it on people. For the first time, researchers will then be able to see if the therapeutic enzyme does actually end up in the right concentration in the right tissues. Hans Aerts: ‘If a patient continues to suffer from bone problems despite treatment, it is sometimes decided to increase the dose. This is very expensive, and we do not know if this extra dose actually reaches the right place and therefore whether more of the enzyme does actually work better. If that is not the case, an increased dose is a waste of money.’

Comparing two preparations

There are two preparations for enzyme therapy. The new technique makes it possible to compare these two preparations for the first time. Aerts: ‘You could, for example, give one of the therapeutic enzymes a red label and the other a green one and then mix them. After a certain amount of time, it might become clear that enzyme one was active longer or that enzyme two penetrated certain tissues better because the enzyme shows red or green in those particular cells.’

Diabetes 2

Leiden colleague Herman Overkleeft: ‘Gaucher is an interesting disease for a chemist. It is easy to understand at the molecular level, easier than more complex diseases in which multiple factors play a role. By developing clever molecules you won’t just find solutions for Gaucher but will also find out more about more complex diseases in which the same molecules as those in Gaucher also play a role, such as diabetes 2.’

NWO Top Grant

The Leiden part of the research was carried out with a TOP grant from NWO (Netherlands Organisation for Scientific Research) for the discipline of Chemical Sciences. TOP grants are aimed at enabling research groups to set up new, innovative lines of research.

Last Modified: 03-11-2010