Unlocking the function of enzymes
Fitting a key into a lock may seem like a simple task, but researchers at Texas A&M University are using a method that involves testing thousands of keys to unlock the functions of enzymes, and their findings could open the door for new targets for drug designs.
Texas A&M researcher Frank Raushel is part of a team of scientists who modified a technique called 鈥渕olecular docking鈥� to predict which molecule, called a substrate, triggers an enzyme into action, enabling them to decipher an enzyme鈥檚 function based on its structure alone.
The team鈥檚 paper was published in the journal Nature.
Most biological processes depend on enzymes, which are proteins that speed up chemical reactions, but the function of many enzymes remains a mystery.
鈥淭here are thousands of molecules that could be substrates [for a specific enzyme], and it would take too long to physically test them all,鈥� Raushel said. 鈥淪o we decided there was a need for a new method to determine the function of enzymes.鈥�
The team started with the three-dimensional X-ray structure of an enzyme and then used a computer to try to fit different smaller molecules into the active site of the enzyme like pieces in a puzzle.
鈥淓ach enzyme has a specific size and shape,鈥� Raushel said, 鈥渁nd you can use a computer to take small molecules and fit them into the active site of an enzyme one by one and score them on how well they fit. It鈥檚 more or less like fitting a key into a lock, but a lot more difficult since both the enzyme and the substrate are conformationally flexible.鈥�
After the computer scores the molecules on how well they fit the enzyme, it ranks their order, and the researchers can then use the prioritized list to decide which molecules to physically test.
鈥淎s far as we know, this is the first time anybody has used molecular docking to predict the function of an enzyme,鈥� Raushel said. 鈥淎nd it was verified by both experiment and X-ray crystallography.鈥�
Other methods researchers use to try to determine an enzyme鈥檚 function or substrate specificity include physically testing thousands of possible molecules, gathering information from the nearby genes, and comparing the structure of the enzyme to that of other enzymes with known functions. 鈥淚 think that in the end, we鈥檒l have to use all of these methods together,鈥� Raushel said. 鈥淥ne single method just won鈥檛 suffice.鈥�
Raushel and his team plan to continue using their molecular docking method to find the function of other enzymes.
鈥淲e鈥檙e looking at other X-ray structures of proteins that have unknown functions, and we鈥檙e working to fill the gap,鈥� Raushel said. 鈥淲e鈥檙e trying to see how general this method is going to be or if we were just lucky in this particular case.鈥�
Raushel and Texas A&M post-doctoral associate Ricardo Marti-Arbona work in conjunction with Brian Shoichet at the University of California, San Francisco, and Steven Almo from the Albert Einstein College of Medicine in New York.
Raushel hopes that over the next five years, the team can start to use its findings to locate potential targets for new drugs.
鈥淯nderstanding the substrate specificity of certain enzymes could allow researchers to differentiate enzymes that catalyze one reaction in pathogenic organisms and a slightly different reaction in human systems,鈥� Raushel said. 鈥淭his would allow scientists to design [drugs] that would specifically target a pathogenic organism while not affecting the human enzyme.鈥�
Source: Texas A&M University
