Mechanistic studies of an unprecedented enzyme-catalysed 1,2-phosphono-migration reaction
(S)-2-hydroxypropylphosphonate ((S)-2-HPP) epoxidase (HppE) is a mononuclear non-haem-iron-dependent enzyme1, 2, 3 responsible for the final step in the biosynthesis of the clinically useful antibiotic fosfomycin4. Enzymes of this class typically catalyse oxygenation reactions that proceed via the f...
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2013
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| Online Access: | http://hdl.handle.net/1721.1/82019 https://orcid.org/0000-0001-5486-2755 |
| _version_ | 1811094764844482560 |
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| author | Chang, Wei-chen Dey, Mishtu Liu, Pinghua Mansoorabadi, Steven O. Moon, Sung-Ju Zhao, Zongbao K. Liu, Hung-wen Drennan, Catherine L |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Chang, Wei-chen Dey, Mishtu Liu, Pinghua Mansoorabadi, Steven O. Moon, Sung-Ju Zhao, Zongbao K. Liu, Hung-wen Drennan, Catherine L |
| author_sort | Chang, Wei-chen |
| collection | MIT |
| description | (S)-2-hydroxypropylphosphonate ((S)-2-HPP) epoxidase (HppE) is a mononuclear non-haem-iron-dependent enzyme1, 2, 3 responsible for the final step in the biosynthesis of the clinically useful antibiotic fosfomycin4. Enzymes of this class typically catalyse oxygenation reactions that proceed via the formation of substrate radical intermediates. By contrast, HppE catalyses an unusual dehydrogenation reaction while converting the secondary alcohol of (S)-2-HPP to the epoxide ring of fosfomycin1, 5. Here we show that HppE also catalyses a biologically unprecedented 1,2-phosphono migration with the alternative substrate (R)-1-HPP. This transformation probably involves an intermediary carbocation, based on observations with additional substrate analogues, such as (1R)-1-hydroxyl-2-aminopropylphosphonate, and model reactions for both radical- and carbocation-mediated migration. The ability of HppE to catalyse distinct reactions depending on the regio- and stereochemical properties of the substrate is given a structural basis using X-ray crystallography. These results provide compelling evidence for the formation of a substrate-derived cation intermediate in the catalytic cycle of a mononuclear non-haem-iron-dependent enzyme. The underlying chemistry of this unusual phosphono migration may represent a new paradigm for the in vivo construction of phosphonate-containing natural products that can be exploited for the preparation of new phosphonate derivatives. |
| first_indexed | 2024-09-23T16:04:43Z |
| format | Article |
| id | mit-1721.1/82019 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:04:43Z |
| publishDate | 2013 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/820192022-10-02T06:11:51Z Mechanistic studies of an unprecedented enzyme-catalysed 1,2-phosphono-migration reaction Chang, Wei-chen Dey, Mishtu Liu, Pinghua Mansoorabadi, Steven O. Moon, Sung-Ju Zhao, Zongbao K. Liu, Hung-wen Drennan, Catherine L Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemistry Dey, Mishtu Drennan, Catherine L. (S)-2-hydroxypropylphosphonate ((S)-2-HPP) epoxidase (HppE) is a mononuclear non-haem-iron-dependent enzyme1, 2, 3 responsible for the final step in the biosynthesis of the clinically useful antibiotic fosfomycin4. Enzymes of this class typically catalyse oxygenation reactions that proceed via the formation of substrate radical intermediates. By contrast, HppE catalyses an unusual dehydrogenation reaction while converting the secondary alcohol of (S)-2-HPP to the epoxide ring of fosfomycin1, 5. Here we show that HppE also catalyses a biologically unprecedented 1,2-phosphono migration with the alternative substrate (R)-1-HPP. This transformation probably involves an intermediary carbocation, based on observations with additional substrate analogues, such as (1R)-1-hydroxyl-2-aminopropylphosphonate, and model reactions for both radical- and carbocation-mediated migration. The ability of HppE to catalyse distinct reactions depending on the regio- and stereochemical properties of the substrate is given a structural basis using X-ray crystallography. These results provide compelling evidence for the formation of a substrate-derived cation intermediate in the catalytic cycle of a mononuclear non-haem-iron-dependent enzyme. The underlying chemistry of this unusual phosphono migration may represent a new paradigm for the in vivo construction of phosphonate-containing natural products that can be exploited for the preparation of new phosphonate derivatives. Howard Hughes Medical Institute (Investigator) National Institutes of Health (U.S.) (NIH grant GM040541) Robert A. Welch Foundation (F-1511) 2013-11-07T17:27:24Z 2013-11-07T17:27:24Z 2013-04 Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 http://hdl.handle.net/1721.1/82019 Chang, Wei-chen, Mishtu Dey, Pinghua Liu, Steven O. Mansoorabadi, Sung-Ju Moon, Zongbao K. Zhao, Catherine L. Drennan, and Hung-wen Liu. “Mechanistic studies of an unprecedented enzyme-catalysed 1,2-phosphono-migration reaction.” Nature 496, no. 7443 (April 3, 2013): 114-118. https://orcid.org/0000-0001-5486-2755 en_US http://dx.doi.org/10.1038/nature11998 Nature 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 Nature Publishing Group PMC |
| spellingShingle | Chang, Wei-chen Dey, Mishtu Liu, Pinghua Mansoorabadi, Steven O. Moon, Sung-Ju Zhao, Zongbao K. Liu, Hung-wen Drennan, Catherine L Mechanistic studies of an unprecedented enzyme-catalysed 1,2-phosphono-migration reaction |
| title | Mechanistic studies of an unprecedented enzyme-catalysed 1,2-phosphono-migration reaction |
| title_full | Mechanistic studies of an unprecedented enzyme-catalysed 1,2-phosphono-migration reaction |
| title_fullStr | Mechanistic studies of an unprecedented enzyme-catalysed 1,2-phosphono-migration reaction |
| title_full_unstemmed | Mechanistic studies of an unprecedented enzyme-catalysed 1,2-phosphono-migration reaction |
| title_short | Mechanistic studies of an unprecedented enzyme-catalysed 1,2-phosphono-migration reaction |
| title_sort | mechanistic studies of an unprecedented enzyme catalysed 1 2 phosphono migration reaction |
| url | http://hdl.handle.net/1721.1/82019 https://orcid.org/0000-0001-5486-2755 |
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