3-D model of cancer-promoting enzyme developed

PIK3CA EnzymeWashington, Jan 5: Researchers at the Johns Hopkins Medical Institutions have made a three-dimensional picture of an enzyme often mutated in cancers that may promote the disease after mutation.

The enzyme known as PIK3CA is often mutated in many cancers comprising colon, brain, stomach, breast and lung cancers, making the enzyme more vigorous thus encouraging the cells to divide rapidly than normal, giving rise to cancer.

Dr Victor Velculescu, Associate professor at the Johns Hopkins Kimmel Cancer Centre said that the picture would help in understanding the cancer development clearly.

"Now that we have a better picture of the protein and how it is altered in cancer, we can envision development of mutation-specific inhibitors for cancer therapy," says Velculescu,

The researchers tried to study the enzyme action after mutations.

"We tried to guess how the enzyme’s activity was affect ed by the mutations based on their locations along the length of the protein," said L. Mario Amzel, Ph. D., professor and director of biophysics and biophysical chemistry at Hopkins.

"But without a 3-D structure, it’s hard to do. It’s like having a puzzle but missing critical pieces."

The team made a 3-D structure of the protein crystals derived by separating PIK3CA from another protein to binds to using X ray techniques.

They then examined the X-ray pattern through computers and built a 3-D model of the enzyme.

The researchers then mapped all the common mutations associated with cancer.

The researchers originally believed that the mutations obstructed the way PIK3CA interacted with other proteins and parts of the cell in some way therefore it must be on the outside surface of the enzyme.

According to Sandra Gabelli, Ph. D., an instructor of biophysics and biophysical chemistry at Hopkins, However, their results show that nearly all the mutations map to regions within the enzyme, however the results were contradictory.

The found that nearly all the mutations map to regions within the enzyme.

"Somehow, these internal mutations must cause the protein to subtly change how it works and interacts with itself," said Amzel.

"It’s an interesting problem to solve, trying to figure out what slight shape and structural changes can make an enzyme work better-usually we’re trying to figure out why things stop working," she added.

The team is presently studying the structure of mutated PIK3CA for comparing mutated to unmutated and comprehending how it leads to cancer progression.

Another goal is to find drugs that can specifically interfere with PIK3CA and turn it down, to develop cancer-fighting therapies.

The findings appear in the Dec. 14 issue of Science.(ANI)