Vol 7. Issue 11 / April 2, 2007

A Place Called Discovery

By Eric Sauter

This is an important year for David Goodin, an associate professor in the Scripps Research Department of Molecular Biology. Not only does 2007 mark his 20th anniversary at the institute (he arrived in 1987 fresh from postdoctoral studies at the University of British Columbia), this is the first full year of his National Institutes of Health (NIH) MERIT award, actually the renewal of a grant whose origins go way back to 1989.

Goodin's NIH MERIT award is a ten-year grant for exploring the possibilities of rationally engineering hemoprotein catalysts to better understand the immense chemical diversity of natural enzymes and to generate novel catalysts with pharmaceutical potential.

An NIH MERIT award is a certified big deal. The award, as the agency describes it, is "offered…to researchers who have demonstrated superior competence and outstanding productivity during their previous research endeavors. The award provides long-term stable support for research, freeing investigators from some of the administrative burdens associated with the traditional research grant process. Of the 22,536 research grants that were awarded by the NIH in 1999, only four percent were MERIT award grants."

The grant is also the reason that Goodin's research has taken a different turn, thanks mostly to a grant administrator at NIH who stuck a handwritten note on Goodin's renewal application.

 "When I filed the application in 2005 to renew the grant," Goodin explained, "I got a handwritten note back with it saying, 'What would you do if you took a different direction with your research?' That was an interesting question. I took it as constructive criticism and decided not to change my goals but to change my approach. That's when it was awarded a MERIT."

What is most striking about the award, and about his whole field of endeavor, is the fact that it is basically the same as when he arrived at Scripps Research in 1987.

"This has been a very long project," Goodin admitted, "to look more deeply at heme [pronounced heem as in hemoglobin] enzymes. That has surprised me because I didn't think it would last for this many years. It turned out to have some legs on it."

Diverse Potential

Goodin has been looking at these catalytic proteins for all of his adult life, a fascination that bit him early and held on. Heme enzymes—part of hemoglobin—are complex molecules that contain an iron ion in their structure and are essential to a number of critical catalytic actions that range from electron transfer to oxygen transfer.

The main fascination for Goodin is the potential they have for making a lot of important things happen.

"They are very diverse," he said. "This one chemical group can carry and release oxygen or help our metabolism maintain its energy balance. Another class is involved in oxidative chemical reactions—radical, nasty chemistry, reactive intermediates of oxygen that can be very dangerous. These enzymes control a whole spectrum of reactions and it has fascinated me to see how evolution has created these things."

His focus on the evolution of these enzymes falls into what he calls the third stage of his research, a stage Goodin is now using as a launch platform to move into a new direction.

"In the early days of our research, we took more of a classic biochemistry approach to study how these enzymes worked, using various mutagenesis tools to manipulate them in different ways to probe the basic mechanisms," he said. "That gave us insights into this class of enzymes, and how parts of the structure were used for various types of activity."

Now that he more or less understands the structure and basic mechanism, Goodin is interested in seeing what he can make from them. Or rather, seeing exactly what he can make them do—directed evolution. For many years, Goodin said, he resisted evolving proteins, but once he defined the structures of what he was interested in building it seemed like a natural progression: "We're looking at the diversity of nature and hoping that there might be something new that nature hasn't seen fit to create just yet."

The targets would be what everyone is looking for these days—drugs that can treat disease.

"Once we understand the basic structure and mechanisms, we should be able to bring different catalytic functions into this scaffold and create binding sites for small molecules that will make these enzymes perform as we want," he said. "If they were cars, I would say that we know how the engine works, so now we're learning how to adapt the car to do different jobs, haul different payloads around."

A Deep Vein of Knowledge

This is a little different than what Goodin did for the first 18 years of his research, which was basic research of the highest order. He would examine a crystal structure of an enzyme and see what changing a particular channel would do. He would study an enzyme to see which molecule it would oxidize, not to create a new drug but to see what the capability of the enzyme might be. The research was directed at testing how the enzyme worked, not building something that someone might use.

It was highly organized, carefully directed movement, but not towards a particular place—unless you consider discovery to be a single place. In a sense it was exactly how Goodin himself grew up.

Goodin was born in 1955 in Hobbs, New Mexico, a place with fewer than 30,000 people, a stone's throw from the Texas border in one direction and a few miles from Alamogordo in the other. His father was part of an oil exploration crew, so he and his family moved every calendar year, skidding around America's rugged western oil patch and living, he remembers, in at least 16 dusty little towns just like Hobbs in as many years. He has no friends left in those places, but he is left with a love of the desert and a sense of closeness to his own family. He and his wife, an author of biology textbooks, have two girls, 12 and 6, and he spends as much time with them as he can.

Perhaps in reaction to his peripatetic youth, he has found his own deep vein of knowledge in these enzymes, and looks to see just how far it will take him. What he cannot do, however, is predict exactly what they will do, even though he believes they can do a great deal.

"We've spent 18 years manipulating them and I'm still surprised just how much you can bang on them and they still produce the kind of chemical reactions we're looking for," he said.

The Meatball Test

One of the enzymes he's studying now is the cytochrome P450, part of diverse superfamily of hemoproteins found in bacteria and involved in a remarkable range of functions in organisms from bacteria to humans. Consequently, cytochrome P450 enzymes are able to recognize a lot of different molecules, and their structure makes them good candidates for small molecule modification, the heart of modern drug design.

Part of the modification process is introducing binding sites for small molecules at specific locations within the hemoprotein. This is done through cavity complementation, basically plucking out bits of amino acid side-chains, an approach that brought Goodin new insights into what determines the diversity of heme enzyme function, although with some limitations.

"If you pull a meatball out of a bowl of spaghetti, you don't know how big a hole it will leave," he said. "When we pulled out a piece of structure for a binding site we were surprised that the protein didn't collapse on itself. But the real crux of the matter is that there are limitations as to how much you can alter the structure and not affect catalytic function."

Goodin and his laboratory colleagues are now bent on developing a large library of mutants that bind to various targets. Once that information is harnessed, the scientists will use heme chemistry within these evolved enzymes to carry out specific reactions comparable to natural oxidation except with targets of the scientists' choosing. The targets that Goodin has in mind—steroids, macrolide antibiotics, and possibly some prostaglandin intermediates—might ultimately do some good in the world.

However, Goodin knows that if the researchers tweak the catalytic residues on the active binding site even a little—basically what evolution has managed to do over billions of years—that will change the catalytic process in ways that are unpredictable.

So, after having had a 20-year celebration in his laboratory, he is getting back to work, settling in, getting a second wind. Like a long distance runner well into the race, he knows the finish line is out there, he just doesn't know precisely where.

"I've been given a great opportunity, a lot of freedom, and I feel extremely lucky, so my plan is to spend the next year doing things with my own hands, in my own laboratory," he said "Are these targets something we can hit in every case? I don't know. I'm pretty certain I can do something interesting, but I can't predict what."


Send comments to: mikaono[at]scripps.edu






Associate Professor David Goodin explores the tremendous possibilities of rationally engineering hemoprotein catalysts.