Martin McLaughlin was on a mission when he entered MIT as a freshman, back in the fall of 2011. If there was one thing that he was determined to do, it was to work along side Catherine Drennan, an MIT biology and chemistry professor, and Howard Hughes Medical Institute (HHMI) investigator that studies proteins through the usage of X-ray crystallography.
As part of a major research that involved MIT and Penn State University scientists, McLaughlin sought out to get a better understanding of one thing, and one thing only. He was interested in finding out where the sulfur in lipoic acid’s reaction was derived from.
Through McLaudghlin’s hard work, he was able to come up with an answer that was published in a paper today. LipA separates itself in order to prepare the reaction that leads to the creation of lipoic acid by removing the sulfur contained in an iron-sulfur cluster.
“The enzyme is actually cannibalizing its own cluster, pulling it out and putting in sulfur,” Drennan explains. “The definition of a catalyst is that it’s not being consumed. So this goes against all the fundamentals really, that the enzyme would just destroy itself.” Based on the results, that’s exactly what is proven.
Solving the mystery infers a process by which other enzymes would utilize sulfur in a similar situation discovering that this could possibly have a long-term use in both medicine and in agriculture. It is also valuable within biochemistry research.
“It just wasn’t understood how nature inserts sulfur into unactivated carbon centers,” says Squire Booker, a professor from Penn State with a focus of chemistry and of biochemistry and molecular biology. As an HHMI investigator, his group research played a major role in the contributing to the findings. Booker, who would go on to receive his PhD from MIT back in 1994 added: “We knew how the process takes place for incorporation of oxygen, for example. But we didn’t know how the sulfur goes in, and we didn’t know what the source of the sulfur was.”
The most recent paper, “Crystallographic snapshots of sulfur insertion by lipoyl synthase,” is in the process of being published today in the Proceedings of the National Academies of Science (PNAS). The authors that collaborated in making it all happen are McLaughlin; Nicholas D. Lanz, a Penn State graduate student; Peter J. Goldman, a former Drennan lab graduate student; Kyung-Hoon Lee, a researcher in Booker’s lab; Booker; and Drennan.
From arriving at MIT on a Thrusday to starting research on Monday
Amazingly, McLauglin’s body of work dates back to before he attended MIT. McLaughlin attended State College High School in State College, Pennsylvania, and had already found a deep interest in science, where he made the decision to volunteer his time at Penn State. It didn’t take long before McLaughlin got connected with Booker, who was more than happy to show the high school students the ropes on research.
“Squire said, ‘Sure, you can work in my lab,’” McLaughlin recounts. “So we met and he told me I’d be setting up crystallization trials in an anaerobic chamber. I had no idea what that meant.”
This means that McLaughlin would be using what, in biology terms, is known as “glove box”. This involves wearing gloves and and putting it inside an oxygen-free box in order to crystallize proteins. In order words, researches place the proteins in solutions that evaporate, and based on circumstances, the proteins will crystallize in such a way that would allow them to analyze just a little deeper.
“My job was to set up all of these crystallization experiments,” says McLaughlin. “I got lucky and got crystals for a few of those proteins, and one of them was lipoyl synthase.”
“Martin really was somebody very different,” Booker says. “He was aggressive, in a good way, incredibly motivated. He was so excited about science. Within a week, he said, ‘I’m going to need a key to the lab.’”
By the time he graduated from high school, McLaughlin had become proficient in doing the lab work, and had also gotten accepted to MIT. Booker and Drennan were already collaborating on the project, so Booker, acting as a catalyst, suggested that McLaughlin work on the sulfur problem with Drennan at MIT.
“Martin emailed me that he’s coming to MIT for undergrad, and asked if he could work in my research group,” Drennan recalls. “And I said ‘Absolutely.’ He said, ‘Well, okay, I might need a little time to settle into MIT.’ So I’m thinking sophomore year, or something. Then he said, ‘I arrive on Thursday, I unpack on Friday. Could I wait until the following Monday to start in the lab?’ Which is a week before classes start. He shows up in the lab apologizing for how long it took him to arrive.”
In the meantime, an important advance had been made by Nicholas Lanz, a Penn State graduate student, who found that in certain circumstances, molecules containing carbon form a bond with iron-sulfur clusters in such a way that an iron atom disappears — leaving an “extra” sulfur atom available for another reaction. In a sense, this showed that the conditions for the chemical cannibalization existed.
“For us, this was an important discovery, because it showed that the iron-sulfur cluster actually can be cannibalized in the reaction,” Booker says. “We saw it.”
Lanz handed McLaughlin a version of this very molecule that he created. McLaughlin then crystallized it and made it possible to analyze the structures and mechanisms proving that LipA used its sulfur atoms to contribute in the production of lipoic acid.
“Crystallography is a little unusual in that it’s very difficult to tell if you’re going to get any interesting results until you get them,” McLaughlin says. “You spend months or years working on getting a single crystal. I always hoped it would work, but I definitely wouldn’t say I knew it would work. It was an interesting enough system that I was willing to spend years on it, if that’s what was needed.”
McLaughlin, upon arriving at MIT, Drennan adds, her lab workers had been attempting to figure out how to derive high high-quality crystals for LipA for some years now. “My graduate students had all but given up, and then Martin arrived,” she says.
Not an area available for boring coversations
It was emphasized by the researchers that there remains many studies to be done as it pertains to LipA, including the fact that iron-sulfur clusters are reconstructed after being taken apart. With that being said, there appears to be be some potential applications derived from the understanding of the lipoic acid and its production.
“Lipoic acid is an incredibly important factor,” Booker says. “You can’t have aerobic life without lipoic acid.”
A factitious form of Lipoic acid is presently created and utilized as a medical supplement in some countries, to attack diabetes, among others. In addition, it’s possible to foresee the drugs that focus on that reaction so that more than one disease is addressed at the same time, including those like cancer and tuberculosis. (The molecule used was derived from tuberculosis bacterium, in fact.) Lipoic acid is considered as a livestock feed produced in a “costly multistep synthesis,” the researchers clarified on paper with the possibility to further simplify.
As of now, the researchers are comfortable enough to move forward. As for McLaughlin, who is currently pursuing his doctorate at the University of Illinois, focuses his luck on having been in the center of the LipA story.
“I’m so grateful to Squire and to Cathy,” McLaughlin says. “They let a high school and undergraduate student work on some of their coolest projects. Both of those labs are great places to become a scientist.” He would go on to add: “MIT is a very intellectually rich environment. It’s very difficult to have a boring conversation at MIT.”
This research was backed by the National Institutes of Health, the National Science Foundation, the Meryl and Stewart Robertson UROP Fund, the MIT Energy Initiative, and the DeFlorez Endowment Fund. It was also backed by the National Institute of General Medical Sciences, and the U.S. Department of Energy.
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Dizikes, Peter (2016, August 8). Research by MIT undergrad helps crack chemical mystery. MIT News. Retrieved from http://news.mit.edu/2016/chemical-mystery-enzyme-cannibalizes-0808