Category Archives: Chemistry

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.

To find alien life, look for the weird

Life is a lot like Supreme Court Justice Potter Stewart’s famous definition of pornography — hard to define, but you know it when you see it. At least, that’s what scientists hope when they search the cosmos for life, or the remnants of life. But how do scientists know what to look for on planets where life could have evolved under drastically different circumstances than it did here on Earth? Would they really know it when they saw it?

There would be chemical clues, says Judith Herzfeld, professor of biophysical chemistry. Even if an organism itself didn’t look like any we’ve seen before, its appearance and its impact on its environment would be distinct from that of lifeless material, she says.

There’s a famous experiment that shows how life can change the surrounding environment. About 60 years ago, University of Chicago chemists Stanley Miller and Harold Urey built an apparatus that recreated pre-life conditions on the Earth’s surface. The experiment combined water and the gases in Earth’s primitive atmosphere — hydrogen, water vapor, methane and ammonia — with an electric spark to simulate lightning.  In the experiment the simple molecules were electrically stimulated to produce more complex molecules, like amino acids and sugars that we closely identify with life.

courtesy/ wikipedia

“Life has a remarkable tendency to throw things out of whack,” says Herzfeld, who won a NASA grant a few years ago to study a curious aspect of the Urey-Miller experiment.

In the original experiment, hydrogen cyanide and some amorphous gunk that could be precursors to biological polymers, chains of molecules, were also produced. Chemists suspected a relationship between the two, as hydrogen cyanide — a deadly gas, formerly used in gas chambers — is known to spontaneously form polymers. Herzfeld and graduate student Irena Mamajanov studied the structure of these polymers and discovered three forms that were nothing like scientists had imagined.

But what does this have to do with finding life on other planets?

First, it means that life can emerge from unlikely places. Second, how life changed Earth’s environment can provide clues for finding life on other planets. Before life, our atmosphere (well, it wasn’t really ours then) was composed primarily of methane, ammonia, hydrogen and water vapor. Once life took hold, the new organisms consumed methane and caused oxygen and carbon dioxide to accumulate.

“What would really point to life is if the balance of the chemistry somewhere doesn’t make sense with all the ordinary factors on the planet, like overall composition, temperature or radiation,” Herzfeld says.  “We are looking for something distinctive.”

Of course, whatever life on other planets looks like, it will likely need water, Herzfeld says.

“It’s hard to imagine life without water because it’s just such an unusual molecule,” she says. “Liquid water buffers temperature really well, it has a way of helping proteins fold and cell membranes form, it readily dissolves ions. Each water molecule can participate in hydrogen bonds with four neighbors, so it can do pretty amazing stuff.”

maven_mars_sunrise copy
NASA’s Maven — Mars Atmosphere and Volatile EvolutioN — is investigating the upper reaches of Mars’ atmosphere to see how much of its ancient water was lost to space. Credit: NASA

So, what are the chances of finding a planet with liquid water and chemistry that doesn’t make a lot of sense?

“The universe is a big place,” Herzfeld says. “There’s a good chance there is something really interesting out there. If we find it, we’ll probably argue about what it means for a while. But, then again, we argue about what is life on Earth, too.”

To learn how Brandeis alumna Valerie Scott is developing devices to chemically analyze soil and rock samples on celestial bodies, perhaps to find life, check out our profile on BrandeisNow.



Sickly sweet: How HIV uses sugar against us

It’s National Chemistry Week and this year’s theme is the chemistry of candy. What do all candies have in common? Sugar. Lots and lots of sugar.

But when it comes to chemistry, what is sugar — besides delicious?

Sugar is the sweet name we give to strands of carbohydrates built with carbon, hydrogen and oxygen. The sugar we know and love most is sucrose, a carbohydrate strand composed of two simple sugars, glucose and fructose. These simple sugars are energy sources, absorbed directly into the blood stream during digestion — and the main culprits in a sugar high.

But sugars do more than give us a buzz, excess pounds and cavities. Complex sugars, called oligosaccharides, are a vital part of our cellular landscape, coordinating cell-to-cell interactions and stabilizing protein structures. Our immune system uses sugar in signaling structures. Sugars and lipids combine to differentiate blood types.

We are chock full of sugar — making it the perfect camouflage for a deadly virus.

In 2012, 1.6 million people died of AIDS-related illnesses worldwide. There are treatments but still no cure or vaccine for HIV, in part because of the arsenal of weapons the virus deploys to infiltrate and destroy the immune system. Sugar is one of those lethal weapons.

HIV H9 T Cell
HIV H9 T Cell

One particular HIV protein, called gp120, is covered in sugars, allowing it to slip through our immune defenses just like any other harmless protein. Now, Brandeis researchers are turning that sugary weapon against HIV, researching a vaccine that can target gp120.

Some immune systems are better than others at fighting HIV; they have broadly neutralizing antibodies, such as 2G12, which bind to gp120 and block it from being able to infect cells.

Carbohydrate found on gp120

Isaac Krauss, assistant professor of chemistry, and his lab are researching an HIV vaccine that would boost 2G12 antibodies by designing clusters of carbohydrates that closely mimic the sugars on the outside of gp120. By using a technique of directed evolution, Krauss and his team have created several antigenic mimics, meaning they bind well with the 2G12 antibodies. Their next step is to test whether they are immunogenic, meaning if they can elicit an immune response.

If successful, these harmless mimics would spur the production of 2G12 antibodies, which would be able to identify the actual HIV virus and neutralize it.

And that would be very sweet.


Special thanks to graduate student Jenn Bailey, who sweetly contributed to this story. 

Novel microscope illuminates molecular architecture



Working with biochemistry professor Jeff Gelles, Brandeis research scientists Larry Friedman and Johnson Chung built a novel light microscope that uses multiple laser colors to examine the behavior of individual protein, DNA and RNA molecules. The researchers tag molecules with fluorescent colors, enabling the microscope to reveal the workings of the molecular machines that control the architecture of cells and regulate genes.