Pitt Researchers Discover Mechanism behind Halogenation Process in New Enzyme
PITTSBURGH—Building upon its earlier discovery of a new halogenation enzyme, WelO5, a Pitt-led team of researchers has uncovered the molecular basis for the biohalogenation, creating a new “toolbox” for biochemists working with protein biocatalysis for important applications in pharmaceutical and agricultural industries.
The selective replacement of aliphatic carbon-hydrogen (CH) bonds—one of the most common molecular bonds in organic matter—with carbon-halogen bonds readily changes the physiochemical properties of the parental molecules, important for drug discoveries. WelO5 is the only known biocatalyst capable of this transformation on small molecules.
Lead researcher Xinyu Liu, an assistant professor of chemistry within Pitt’s Kenneth P. Dietrich School of Arts and Sciences, along with postdoctoral fellows Qin Zhu, Matthew Hillwig, and colleagues from Penn State, found that the key structural feature of WelO5 was a serine protein ligand that repositions an oxygen ligand to facilitate the halogen transfer.
Using x-ray crystallography conducted by Andrew Mitchell and Amie Boal at Penn State, Liu and coworkers biochemically validated the role of this unique serine residue in WelO5 in facilitating selective halogen transfer.
“This paper demonstrates the structural, biochemical basis of a unique family of metalloenzyme that can selectively modify chemically inert carbon-hydrogen bonds in drug-like small molecules,” said Liu. “By disclosing this principle, we can use this as a guide to rationally engineer other proteins in that family.”
The paper, “Structural basis for halogenation by iron- and 2-oxo-glutarate-dependent enzyme WelO5” was published online June 27 by Nature Chemical Biology. The project was supported by a National Institutes of Health grant, the Searle Scholars Program, and Pitt’s Department of Chemistry.
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6/30/16/klf/jm
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