For the first time, Stanford researchers figured out a sneaky way to make an enzyme do something it wouldn’t normally do — imitate another enzyme and digest alcohol properly. Their work suggests a possible preventative mechanism for alcohol-related cancers in an at-risk population and is a promising new route for drug discovery.
Daria Mochly-Rosen, PhD, professor in chemical and systems biology, and Che-Hong Chen, PhD, senior research scientist, conducted the study, which was published online yesterday in Proceedings of the National Academy of Sciences.
Enzymes are notoriously choosy, selectively responding to certain molecules that bind precisely in their active site, but the researchers were able to change the selectivity of an enzyme’s active site by “hijacking” it with a small molecule.
Making an enzyme act like another enzyme isn’t just cool. It can have important health consequences for people who have broken enzymes because of genetic mutations.
I wrote about this enzyme deficiency in a press release on the study:
When most people and animals consume alcohol, the body digests it rapidly, within a few hours. One of the byproducts of alcohol metabolism is a chemical called acetylaldehyde. According to the World Health Organization, acetylaldehyde is a Group-1 carcinogen, which means there is a direct link between exposure and cancer.
For most people, acetylaldehyde is not a major health risk — though it can contribute to hangover symptoms — because an enzyme called ALDH2 quickly converts it to a harmless acid. But for some, acetylaldehyde is a big problem.
These people lack a working version of ALDH2 because of a genetic mutation. ALDH2 deficiency is the most common genetic mutation in humans, affecting about 40 percent of East Asians — some 560 million people, or nearly 8 percent of the world’s population. Without a working enzyme, the body cannot clear the toxic acetylaldehyde quickly.
The ALDH2 enzyme is usually responsible for acetylaldehyde metabolism. Using mice with mutant ALDH2 enzymes, the researchers discovered that a small molecule could hijack another enzyme, making it less choosy and converting it into an efficient acetylaldehyde metabolizer.
How exactly a small molecule hijacks an enzyme can be explained by thinking about your shoes. Chen told me that hijacking an enzyme with a small molecule is like figuring out how to modify a pair of shoes that are too loose.
“You could stuff a piece of newspaper inside the shoes to make them fit better,” Chen said. “The piece of newspaper has to be there in order to create a better fit.”
Enzyme hijacking using small molecules is a creative way to address the problem of defective enzymes.
Kimberlee D’Ardenne is a writing intern in the medical school’s Office of Communication and Public Affairs.
Previously: Finally, a way to fix broken enzymes, SPARK program helps researchers cross the ‘valley of death’ between drug discovery and development and New painkiller could tackle pain, without risk of addiction
Photo of Daria Mochly-Rosen by Steve Gladfelter