An HD domain phosphohydrolase active site tailored for oxetanocin-A biosynthesis
Name
Bridwell-Rabb-2016-An HD domain phosphohydrola.pdf
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Author(s)
Zhong, Aoshu
Liu, Hung-wen
Rabb, Jennifer
Drennan, Catherine L.
Kang, Gyung Hoon
Date Issued
November 2016
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Bridwell-Rabb, Jennifer; Kang, Gyunghoon; Zhong, Aoshu; Liu, Hung-wen and Drennan, Catherine L. “An HD Domain Phosphohydrolase Active Site Tailored for Oxetanocin-A Biosynthesis.” Proceedings of the National Academy of Sciences 113, no. 48 (November 2016): 13750–13755. © National Academy of Sciences
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Final published version
Abstract
HD domain phosphohydrolase enzymes are characterized by a conserved set of histidine and aspartate residues that coordinate an active site metallocenter. Despite the important roles these enzymes play in nucleotide metabolism and signal transduction, few have been both biochemically and structurally characterized. Here, we present X-ray crystal structures and biochemical characterization of the Bacillus megaterium HD domain phosphohydrolase OxsA, involved in the biosynthesis of the antitumor, antiviral, and antibacterial compound oxetanocin-A. These studies reveal a previously uncharacterized reaction for this family; OxsA catalyzes the conversion of a triphosphorylated compound into a nucleoside, releasing one molecule of inorganic phosphate at a time. Remarkably, this functionality is a result of the OxsA active site, which based on structural and kinetic analyses has been tailored to bind the small, four-membered ring of oxetanocin-A over larger substrates. Furthermore, our OxsA structures show an active site that switches from a dinuclear to a mononuclear metal center as phosphates are eliminated from substrate.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1073/pnas.1613610113
