Category Archives: Biochemistry

Want renewable energy? There’s an enzyme for that.

It’s all about those enzymes.

Enzymes are nature’s magicians. They perform incredibly complicated feats of chemistry in milliseconds. They change light and food into energy, carbon dioxide into oxygen, one cell into two. They are responsible for catalyzing — speeding up — every biological process. If researchers could replicate the power, speed and efficiency of nature’s enzymes, it could mean true renewable energy, not to mention new drugs and greener industrial materials.

There has been some progress in engineering enzymes — think ethanol and other biofuel fuels — but enzymes designed in a lab still can’t compete with those evolved in nature. This is partly because researchers haven’t had a clear, step-by-step understanding of how enzymes do their magic.

Now, we do.

For the first time, Brandeis University researchers have observed and recorded each step of how the enzyme adenylate kinase (ADK), catalyzes the transfer of energy in our cells. Dorothee Kern, professor of biochemistry and Howard Hughes Medical Institute Investigator, published the findings in a recent issue of Nature Structural and Molecular Biology.

Adenylate kinase
Adenylate kinase

ADK plays an important role in cellular energy homeostasis, maintaining the right nucleotide (chemical energy storage molecules) levels in cells. Kern and her team, which included professor Michael Hagan, outlined the minimum five-step process of catalysis, during which the sophisticated ADK enzyme binds the target nucleotides, closes around them, catalyzes the chemical reaction, reopens and releases the final product. The whole process takes milliseconds with the enzyme. Without it, it would take about 8,000 years for this process to happen naturally.

The team also observed what each part of the enzyme does during the process — revealing an efficient team of players, including magnesium, each responsible for multiple parts of catalysis.

“We found that you really can’t get much more efficient than ADK,” Kern says. “It really is an amazing accelerator.”

Kern’s work is a first step to designing better, faster, stronger enzymes but there is still a long way to go.

“The first step is seeing how it works in nature,” Kern says. “Then, we can figure out how to make it better.”

This work was supported by the Howard Hughes Medical Institute, the Office of Basic Energy Sciences, Catalysis Science Program, Department of Energy and the National Institutes of Health.

Evolution may hold the key to rational drug design

This is the story of Abl and Src — two nearly identical protein kinases whose evolution may hold the key to unlocking new, highly specific cancer drugs.

Abl and Src are bad guys — oncogenes with a predilection to cause cancer in humans, mainly chronic myeloid leukemia (CML) and colon cancer. These two proteins are separated by 146 amino acids, and one big difference — Abl is susceptible to the cancer drug Gleevec, while Src is not.


From left, Src and Abl proteins
From left, Src and Abl proteins

Dorothee Kern, professor of biochemistry and Howard Hughes Medical Institute investigator, unraveled the journey of these two proteins over one billion years of evolution, pinpointing the exact evolutionary shifts that caused Gleevec to bind well with one and poorly with the other. This new approach to researching enzymes and their binding sites may have a major impact on the development of rational drugs to fight cancer.

Dorothee Kern
Dorothee Kern

The findings were published in the journal Science and coauthored by Doug Theobald, professor of biochemistry, with Christopher Wilson, Roman Agafonov, Marc Hoemberger, Steffen Kutter, Jackson Halpin, Vanessa Buosi, Adelajda Zorba, Renee Otten and David Waterman.

When Gleevec hit the market in 2001, it was hailed as the magic bullet against cancer.

That’s because most cancer drugs fight a scorched-earth campaign — killing as many healthy cells as cancerous ones. But Gleevec is specifically attracted only to Abl, the enzyme in cancerous cells responsible for growth and reproduction. Gleevec binds with Abl, deactivating it and stopping the spread of cancer in its tracks.


Developing more drugs to work like Gleevec — known as rational drug design —could create therapies that target specific enzymes in many types of cancer. Unfortunately, scientists haven’t known why Gleevec is so picky, binding with Abl but not with its close cousin Src.

To solve this puzzle, Kern and her team turned back the evolutionary clock one billion years to find Abl and Src’s common ancestor, a primitive protein in yeast they dubbed ANC-AS. They mapped out the family tree, searching for changes in amino acids and molecular mechanisms.

“Src and Abl differ by 146 amino acids and we were looking for the handful that dictate Gleevec specificity,” says Kern. “It was like finding a needle in a haystack and could only be done by our evolutionary approach.”

As ANC-AS evolved in more complex organisms, it began to specialize and branch into proteins with different regulation, roles and catalysis processes — creating Abl and Src. By following this progression, while testing the proteins’ affinity to Gleevec along the way, Kern and her team were able to whittle down the different amino acids from 146 to 15 responsible for Gleevec specificity.

These 15 amino acids play a role in Abl’s conformational equilibrium — a process in which the protein transitions between two structures. The main difference between Abl and Src, when it comes to binding with Gleevec, is the relative times the proteins spend in each configuration, resulting in a major difference in their binding energies.

By understanding how and why Gleveec works on Abl — and doesn’t work on Src — researchers have a jumping off point to design other drugs with a high affinity and specificity, and a strong binding on cancerous proteins.

“Understanding the molecular basis for Gleevec specificity is opened the door wider to designing good drugs,” says Kern. “Our results pave the way for a different approach to rational drug design.”

This research was supported by HHMI, the Office of Basic Energy Science, the U.S. Department of Energy Catalysis Science Program and grants from the National Institutes of Health.