An HD domain phosphohydrolase active site tailored for oxetanocin-A biosynthesis
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...
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2017
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| Online Access: | http://hdl.handle.net/1721.1/109092 https://orcid.org/0000-0002-7437-6217 https://orcid.org/0000-0001-5486-2755 https://orcid.org/0000-0003-2117-3528 |
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| author | Zhong, Aoshu Liu, Hung-wen Rabb, Jennifer Drennan, Catherine L. Kang, Gyung Hoon |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Zhong, Aoshu Liu, Hung-wen Rabb, Jennifer Drennan, Catherine L. Kang, Gyung Hoon |
| author_sort | Zhong, Aoshu |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:53:20Z |
| format | Article |
| id | mit-1721.1/109092 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:53:20Z |
| publishDate | 2017 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1090922022-10-01T17:48:20Z An HD domain phosphohydrolase active site tailored for oxetanocin-A biosynthesis Zhong, Aoshu Liu, Hung-wen Rabb, Jennifer Drennan, Catherine L. Kang, Gyung Hoon Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemistry Rabb, Jennifer Drennan, Catherine L. Kang, Gyung Hoon 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. United States. National Institutes of Health (F32-GM108189) 2017-05-16T13:56:53Z 2017-05-16T13:56:53Z 2016-11 2016-08 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/109092 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 https://orcid.org/0000-0002-7437-6217 https://orcid.org/0000-0001-5486-2755 https://orcid.org/0000-0003-2117-3528 en_US http://dx.doi.org/10.1073/pnas.1613610113 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Zhong, Aoshu Liu, Hung-wen Rabb, Jennifer Drennan, Catherine L. Kang, Gyung Hoon An HD domain phosphohydrolase active site tailored for oxetanocin-A biosynthesis |
| title | An HD domain phosphohydrolase active site tailored for oxetanocin-A biosynthesis |
| title_full | An HD domain phosphohydrolase active site tailored for oxetanocin-A biosynthesis |
| title_fullStr | An HD domain phosphohydrolase active site tailored for oxetanocin-A biosynthesis |
| title_full_unstemmed | An HD domain phosphohydrolase active site tailored for oxetanocin-A biosynthesis |
| title_short | An HD domain phosphohydrolase active site tailored for oxetanocin-A biosynthesis |
| title_sort | hd domain phosphohydrolase active site tailored for oxetanocin a biosynthesis |
| url | http://hdl.handle.net/1721.1/109092 https://orcid.org/0000-0002-7437-6217 https://orcid.org/0000-0001-5486-2755 https://orcid.org/0000-0003-2117-3528 |
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