The key to understanding Sir2's biology, says Wolberger, an HHMI investigator at the Johns Hopkins University, is its unusual chemistry. To dig deeper, she dusted off her college notebooks and made some new friends.
HHMI: WHAT IS IT ABOUT SIR2 THAT CAUGHT YOUR ATTENTION AND INSPIRED YOU TO EXPAND YOUR KNOWLEDGE OF CHEMISTRY?
CW: My lab has always concentrated on gene regulation, especially on proteins that bind DNA and control transcription. I was thinking of further aspects of transcriptional regulation that might be amenable to the tools of structural biology—my field—when I encountered sirtuins.
I focused on the Sir proteins because they can shut down whole regions of a chromosome and turn off all genes located there. Sir2 in particular stands out because it makes life more difficult for itself. Instead of taking a more direct route to cleaving the appropriate molecules, it uses a more complex, energy-costly method. I wanted to explore the unusual chemistry of this process. When nature doesn't settle on the most efficient pathway to carry out a particular task, there must be a reason. Understanding Sir2's unique chemistry will be key to understanding its function and regulation. And the fact that it is universal—all organisms have at least one, if not several, sirtuins—means that its chemistry is important to all forms of life.
HHMI: IN WHAT WAYS ARE YOU LEARNING THE CHEMISTRY YOU NEED?
CW: Having had only the courses that most people took in college and graduate school—maybe fewer, as my background is in physics and biophysics—I'm basically playing catch-up. So I've been getting an education in chemistry and enzyme mechanisms in a number of ways, including by doing it. I asked my students to recommend some textbooks on enzyme mechanisms. I keep them here on my desk.
Photo: Paul Fetters
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