Boal Group Teams up with Harvard to Study How Bacteria Produces a Compound Used to Treat Cancer

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Boal Group Teams up with Harvard to Study How Bacteria Produces a Compound Used to Treat Cancer

The Boal group (PSU Chemistry/BMB) teamed up with the Balskus lab at Harvard University to solve the first structure of a non-heme-iron-dependent N-N bond-forming enzyme, SznF, published online in Nature.

25 February 2019

 

Dr. Amie Boal, assistant professor of chemistry at Penn State, and members of her research group (BMMB Ph.D. graduate Andrew Mitchell and chemistry postdoctoral scholar Roman Rohac) recently teamed up with Dr. Emily Balskus of Harvard and her Ph.D. student, Tai Ng, to explore how a bacterium that lives in soil produces an important anticancer compound, streptozotocin. Streptozotocin contains an N-nitrosamine (-N-N=O) functional group that is responsible for its anticancer activity, and the collaborative team was particularly interested in studying formation of the nitrogen-nitrogen (N-N) bond in the drug. Although streptozotocin has been important in the treatment of cancer for many years, the Balskus group is the first to illustrate how the bacterium actually produces this important compound.Their discovery was recently published as a paper in Nature.

 

N-N bonds in nitrosamine compounds can be generated non-enzymatically via reaction between primary amines and nitrosating agents. In streptozotocin biosynthesis, the Balskus group found that a dedicated iron- and oxygen-dependent enzyme, SznF, was responsible for N-nitrosamine formation. SznF catalyzes an oxidative rearrangement of an arginine (Arg) amino acid precursor to generate the N-nitrosamine product. Dr. Boal says this finding is particularly exciting because it reveals a new, largely unprecedented way to perform this sort of reaction. It is now clear that the bacteria evolved a specific process to produce nitrosamine compounds that is very different from any other known routes.

 

The Boal group solved an x-ray crystal structure of SznF, showing that the protein contains two different active sites. Each domain contains its own non-heme-iron cofactor and performs a different step in conversion of the amino acid substrate to the N-nitrosamine product. First, two different N-hydroxylations are performed by a multinuclear iron center located in the middle of the protein. This chemistry is known in other systems but the structure of this part of SznF is unusual. The last step of the SznF reaction is an oxidative rearrangement to form the N-nitrosamine. This transformation is performed in a different domain with a mononuclear iron cofactor. The structures solved by the Boal group show that a hydroxylated-Arg intermediate coordinates this iron center, and this feature of the active site is likely critical for choreographing the complicated N-N bond formation chemistry.

 

Dr. Boal says that this work opens the door to new questions about how the N-N=O unit is made. “To a chemist,” she notes, “there’s a lot of interesting questions about how these reactions work because there’s such a big structural change in the molecule.” The discovery of SznF also suggests that scientists may have underestimated how compounds like streptozotocin might be used in nature.

 

The Balskus and Boal groups searched bacterial genomes that have been sequenced to identify other proteins similar to SznF. They have discovered that approximately 400 of these proteins exist, and the Balskus group noted that some are found in human pathogens such as Legionella pneumophila, the cause of Legionnaires disease. “Emily and Tai have proposed that human pathogens make these compounds as part of causing disease, an interesting and novel idea,” Dr. Boal notes. Further study of these enzymes will help scientists to understand how they function in nature and the impact they might have on human health.

 

Going forward, the collaborators will continue to study how the enzyme functions at the molecular level and to work towards a better understanding of the steps in the production of compounds like streptozotocin in pathogens.

 

You can read more about their discovery in Nature.

 

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