Rare Metabolic Diseases - New Treatment Approaches

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Academic Journal
Main Category: Pediatrics / Children's Health
Also Included In: Endocrinology
Article Date: 05 Jan 2012 - 10:00 PST


According to a study published in the December issue of Chemistry & Biology, a crucial interaction that could lead to a novel treatment for Fabry disease (a rare childhood metabolic disorder), has been discovered by an investigation team led by biochemist Scott Garman at the University of Massachusetts Amherst. In addition, the finding will researchers understand other protein-folding disorders, such as Parkinson's, Huntington's, and Alzheimer's diseases.

Fabry disease is caused by the lack of or faulty alpha-galactosidase (α-GAL) enzyme needed to metabolize lipids. When the enzyme functions normally, it breaks down an oily lipid known as GB3 in the lysosome (the cell's recycling center). Individuals with the disease have a mutation in the gene that controls α-GAL. This mutation causes insufficient breakdown of lipids, which leads to toxic lipid build-up in the eyes, blood vessels, kidneys, autonomic nervous system, and cardiovascular system.

The mutated gene causes damage by generating a misfolded protein, producing an unstable, poorly functioning α-GAL enzyme. These proteins only become active when folded into precise shapes. The only therapy currently approved for lysosomal storage disorders like Fabry, Gaucher, and Pompe diseases by the U.S. Food and Drug Administration (FDA) is enzyme replacement therapy (ERT). ERT purifies and replaces damaged α-GAL enzymes, however it is a complicated and expensive process that requires administration by a physician.

Rather than replacing the mutated enzyme, a novel treatment for Fabry disease called pharmacological chaperone (PC) therapy is currently in Phase III Clinical trials. Garman explains:

"It relies on using smaller, "chaperone" molecules to keep proteins on the right track toward proper folding, but their biochemical mechanism is not well understood."

Garman and his team reveal results of an exhaustive investigation at the atomic level of the biophysical and biochemical basis of two tiny molecules for possibly steadying the enzyme. According to Garman, their use in pharmacological chaperone therapy could in the future be considerably cheaper than ERT, and can be taken orally.

This study, which enhances understanding of an entire class of molecular chaperones, exhibits the centerpiece of Umass Amherst student Abigail Guce's doctoral thesis. Additional members of the study include graduate students Jerome Rogich and Nat Clark. The National Institutes of Health supported the investigation.

Garman explains:

"The interactions we looked at are exactly the things occurring in the clinical trial right now. The same concept is now being applied to other protein-folding diseases such as Parkinson's and Alzheimer's diseases. Many medical researchers are trying to keep proteins from misfolding by using small chaperone molecules. Our studies have definitely advanced the understanding of how to do that."

In the present report, Garman and team examined the capability of two tiny chaperone molecules, 1-deoxygalactononjirimycin (DGJ) and galactose to sustain the α-GAL enzyme, to help prevent it unraveling in various circumstances, such as different pH levels and high temperature.

The researchers discovered that every chaperone has extremely different affinities: galactose attaches loosely to the enzyme, while DGJ attaches firmly to the α-GAL enzyme, in addition DGJ and galactose differ in only two atomic positions.

Garman explains:

"Tight is better, because you can use less of the drug for treatment. We now can explain DGJ's high potency, its tight binding, down to individual atoms."

Like in the present study, prior investigations used X-ray crystallography to develop 3D images of all atoms in the enzyme in order to gain insight into how it conducts its metabolic mission. Furthermore, the Umass Amherst scientists discovered a different attachment location for tiny molecules on human α-GAL enzymes that had never been seen before.

Crystallography on the two chaperones attached to the enzyme revealed that only one interaction between DGJ and the enzyme was accountable for DGJ's high affinity for the enzyme. Furthermore, additional tests demonstrated the 11- and 12- atom chaperones ability to guard the large, 6,600-atom α-GAL from deterioration and unraveling.

For the first time the researchers forced the DGJ to attach loosely by creating a single alteration in one amino acid in the enzyme, suggesting that one atomic interaction is accountable for DGJ's high affinity.

Garman explained:

"It was surprising to find these two small molecules that look very much the same have very different affinities for this enzyme, and we now understand why. The iminosugar DGJ has high potency due to a single ionic interaction with α-GAL. Overall, our studies show that this small molecule keeps the enzyme from unfolding, or when it unfolds, the process happens more slowly, all of which you need in treating disease."

The next step for the investigators is to use the principles, experiments and assessments they created in this study on mutated enzymes in other human diseases to analyze novel treatments for them and related disorders.

Written by Grace Rattue
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

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