Many indus­trial chem­istry appli­ca­tions, such as drug or bio­fuel syn­thesis, require large energy inputs and often pro­duce toxic pol­lu­tants. But chem­istry and chem­ical biology pro­fessor Mary Jo Ondrechen said enzymes — pro­teins that increase the rate of chem­ical reac­tions in the body — could be used to effec­tively replace stan­dard indus­trial processes.

Enzy­matic reac­tions are cleaner, pro­duce fewer byprod­ucts and use less energy,” she explained. But attempts to repli­cate nat­ural enzymes for indus­trial appli­ca­tions are lim­ited by our incom­plete knowl­edge of these proteins.

Ondrechen and Penny J. Beuning, an assis­tant pro­fessor of chem­istry and chem­ical biology, have received a three-​​year, $565,000 grant from the National Sci­ence Foun­da­tion to develop a better under­standing of enzyme activity.

If you want to design pro­teins to cat­alyze a par­tic­ular reac­tion, it’s good to under­stand how they work,” said Ondrechen.

Enzymes, she explained, are made up of a string of amino acids coded by the gene sequence. Each amino acid has a dif­ferent role in the pro­tein: Some are struc­turally impor­tant while others are required for the enzyme’s cat­alytic properties.

There are cav­i­ties on the sur­face of a pro­tein where a mol­e­cule can come in and sit down,” Ondrechen said. “The enzyme does a reac­tion on it and the product goes away.”

The cur­rent body of research on enzyme activity mostly focuses on the amino acids in that cavity, which come into direct con­tact with the reac­tive mol­e­cule. But over the years, some research has sug­gested that amino acids far away from the active site also play a role in catalysis.

Ondrechen’s team, using a method she devel­oped 10 years ago, will be able to pre­dict which remote amino acids will impact reac­tivity. Beuning’s team will test these pre­dic­tions experimentally.

My lab is really inter­ested in speci­ficity of enzymes,” Beuning said. “We look enzymes and figure out how they rec­og­nize their substrates.”

To do this, her team takes a pro­tein engi­neering approach in which they manip­u­late the enzyme’s com­po­si­tion and observe how it affects its function.

Beuning’s exper­i­mental data can be used to train the com­pu­ta­tional method to make even better pre­dic­tions about which amino acids are impor­tant to catalysis.

There is a nice syn­ergy between our inter­ests,” she said. “We can take the com­pu­ta­tional work from Ondrechen’s lab, add the exper­i­mental work to it and then take the exper­i­mental results and say, ‘Did it work? Are there sub­tleties that we’re missing?’”

By building a library of enzymes known to have remote amino-​​acid activity, the group can even­tu­ally begin to answer fun­da­mental research ques­tions in the quest to improve indus­trial enzy­matic chem­istry techniques.