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This is a switch for me. When I first presented my work on these enzymes at an HHMI meeting, a friend came up to me afterward and said, “I can't believe you talked about enzyme mechanisms. As a student, you used to say it was so boring.”
It's true. My focus was thermodynamics. I was actively uninterested in chemistry back then. But it turns out to be the heart of the matter. Even though I was dragged into it by the necessities of my work, now I'm fascinated by it. Why does this enzyme do this baroque chemistry, how does it do it, and how is it being exploited by the cell?
I spend time talking to different people as well. Now I tend to gravitate to enzymologists at meetings. This bouncing of ideas off people who have thought about enzyme chemistry for years has proven invaluable. Like anything in science, if there's something you need to learn, you go and learn it. A good scientist is a lifelong student.
HHMI: HOW ARE YOU APPLYING YOUR NEW DEXTERITY IN CHEMISTRY AND ENZYMOLOGY?
CW: In my lab, we are learning about Sir2's chemistry in particular by visualizing structures of enzymes bound to a variety of substrates and intermediates, and by trying to trap the enzyme in the crystal at different stages of the reaction. Also, we are using proteomics approaches to identify new substrates and to characterize the substrate requirements for the reaction. That, together with standard enzymology of normal and mutant proteins, allows us to put together a picture of how sirtuins work.
HHMI: What is the payoff?
CW: Besides just understanding the fundamental nature of this fascinating chemistry, there are implications for human health. One sirtuin, SirT1, seems to regulate the p53 tumor-suppressor pathway. Sirtuins have also been implicated in the insulin-signaling pathway in diabetes. In lower organisms such as yeast, losing a copy of Sir2 shortens life span and getting extra copies of the enzyme makes them live significantly longer. Restricting calories extends life span in many organisms, including mammals (though it's never been proven in humans), and Sir2 may mediate that process. Much remains to be learned about Sir2's potential role in longevity. We're constantly finding out new things about them. Giving chemistry a fresh look is a big help.
Interview by Steve Benowitz
Cynthia Wolberger is Professor of Biophysics and Biophysical Chemistry at the Johns Hopkins University School of Medicine.