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Molecular Model
Structural biologists chart path for potential chaperone therapy to treat group of genetic diseases
Surface representations of four human sulfatase proteins

"For the first time, we’ve been able to show the three-dimensional structure of this molecule and we can now correlate clinical observations with that molecular structure. These are more than incremental steps. This will forever change the way we think about this particular disease."
- Scott Garman

Considered separately, inherited metabolic disorders such as Tay-Sachs disease and MPS 4A (mucopolysaccharidosis 4A) are exceedingly rare, complex and difficult to study. But taken as a group, the collection of more than 50 lysosomal storage diseases become more common, affecting approximately 1 in 7,000 births, and lessons learned about any one can be applied to the others.

Now a team of structural biologists led by Scott Garman at UMass Amherst has again moved the field forward by revealing the structure of GALNS (human galactosamine-6-sulfatase) the lysosomal enzyme that is defective in patients with MPS 4A. The discovery is reported in the Journal of Molecular Biology.

Garman’s group has a history of significant advances in understanding basic mechanisms of these rare diseases, having previously determined the structures of the enzymes that lead to Fabry and Schindler/Kanzaki diseases.

Children born with MPS 4A have severe bone and growth problems. The cushioning properties of cartilage and the strength of bone come in part from the polymers chondroitin sulfate and keratan sulfate. Known overall as substrate for the enzyme, these are broken down at the end of their normal lifespan by enzymes including GALNS. In patients with MPS 4A, the GALNS enzyme is defective, so chondroitin sulfate and keratan sulfate build up.

Scott Garman, Biochemistry and Molecular Biology
Garman says, “For the first time, we’ve been able to show the three-dimensional structure of this molecule and we can now correlate clinical observations with that molecular structure. These are more than incremental steps. This will forever change the way we think about this particular disease.” This work was funded by the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health.

Lysosomes are the cell’s recycling centers, where hundreds of specialized enzymes break down a large variety of macromolecules at the ends of their useful lifespans. A baby born with a single genetic defect in a single lysosomal enzyme can have partial or total loss of enzyme activity, allowing harmful substrate to build up in cells. Depending on the substrate’s function and toxicity, disease symptoms can range from mild to severe.

At present there are no cures for lysosomal storage disorders, but some treatments are available. One is an expensive and time-consuming method known as enzyme replacement therapy (ERT), where commercially produced enzyme is injected into patients to help their cells digest substrate. The GALNS molecule is currently in phase III clinical trials for ERT treatment of MPS 4A patients.

Another potential therapy known as small molecule or pharmacological chaperone therapy could follow from the UMass Amherst team’s recent discovery of the GALNS enzyme’s molecular structure.

“It’s a future direction,” says Garman. “Knowing the crystal structure of GALNS shows us for the first time how each of the 130 defects in the protein in different patients leads to disease. We’d love to identify a small molecule to help treat MPS 4A, and knowing the structure is going to help medical researchers do that.”

First author Yadilette Rivera-Colón is Garman’s doctoral student who did much of the experimental work reported in the paper. She says, “Even though it’s interesting enough on its own for us to discover and understand the basic molecular structure of this enzyme, the fact that what we’re doing might help someone who has the disease is really important. Being able to open the door to new molecular medicine is very exciting.”

Originally trained as a nurse at the University of Puerto Rico Cayey, Rivera-Colón came to UMass Amherst as a chemistry research intern for a summer, was immediately captivated and knew that she wanted to pursue original research molecular biology. 

The two researchers say a next step will be to see if they can identify small molecules that help stabilize the GALNS enzyme as candidates for pharmacological chaperone therapy. Garman says, “We now understand how the protein works, and next we’re trying to understand how the protein breaks in people with disease. Because the protein can break in a number of different ways, different treatments might be possible, depending on the individual defect.”

In earlier studies as in the current work, the UMass Amherst team used their special expertise in X-ray crystallography to create three-dimensional images of all atoms in the protein, to understand how it carries out its metabolic mission.

Jan Lathrop
Image credit: Scott C. Garman

Description: Surface representations of four human sulfatase proteins, including GALNS, and Arylsulfatase A, B, and C respectively. The polypeptides are colored from blue to red from the N- to C-terminus of the proteins, with a calcium ion shown in magenta. The active sites of the enzymes are pulled out in the inset and colored according to their electrostatics. Each protein has a specific active site shape and charge corresponding to the enzymatic job it needs to do in the cell.