Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity.
Human carbonic anhydrase II (hCAII) naturally catalyzes the reaction between two achiral molecules-water and carbon dioxide-to yield the achiral product carbonic acid through a zinc hydroxide intermediate. We have previously shown that a zinc hydride, instead of a hydroxide, can be generated in this...
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Online Access: | https://doi.org/10.1002/anie.202407111 https://pubmed.ncbi.nlm.nih.gov/38955771 |
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ftpubmed:38955771 2024-09-15T18:01:39+00:00 Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity. Chen, Reichi Kayrouz, Colby S McAmis, Eli Clark, Douglas S Hartwig, John F 2024 Jul 02 https://doi.org/10.1002/anie.202407111 https://pubmed.ncbi.nlm.nih.gov/38955771 eng eng Wiley https://doi.org/10.1002/anie.202407111 https://pubmed.ncbi.nlm.nih.gov/38955771 © 2024 Wiley-VCH GmbH. Angew Chem Int Ed Engl ISSN:1521-3773 biocatalysis enantioselectivity ketones metalloenzymes reduction Journal Article 2024 ftpubmed https://doi.org/10.1002/anie.202407111 2024-08-30T16:03:00Z Human carbonic anhydrase II (hCAII) naturally catalyzes the reaction between two achiral molecules-water and carbon dioxide-to yield the achiral product carbonic acid through a zinc hydroxide intermediate. We have previously shown that a zinc hydride, instead of a hydroxide, can be generated in this enzyme to create a catalyst for the reduction of aryl ketones. Dialkyl ketones are more challenging to reduce, and the enantioselective reduction of dialkyl ketones with two alkyl groups that are similar in size and electronic properties, is a particularly challenging transformation to achieve with high activity and selectivity. Here, we show that hCAII, as well as a double mutant of it, catalyzes the enantioselective reduction of dialkyl ketones with high yields and enantioselectivities, even when the two alkyl groups are similar in size. We also show that variants of hCAII catalyze the site-selective reduction of one ketone over the other in an unsymmetrical aliphatic diketone. Computational docking of a dialkyl ketone to variants of hCAII containing the zinc hydride provides insights into the origins of the reactivity of various substrates and the high enantioselectivity of the transformations and show how a confined environment can control the enantioselectivity of an abiological intermediate. Article in Journal/Newspaper Carbonic acid PubMed Central (PMC) Angewandte Chemie International Edition |
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PubMed Central (PMC) |
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topic |
biocatalysis enantioselectivity ketones metalloenzymes reduction |
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biocatalysis enantioselectivity ketones metalloenzymes reduction Chen, Reichi Kayrouz, Colby S McAmis, Eli Clark, Douglas S Hartwig, John F Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity. |
topic_facet |
biocatalysis enantioselectivity ketones metalloenzymes reduction |
description |
Human carbonic anhydrase II (hCAII) naturally catalyzes the reaction between two achiral molecules-water and carbon dioxide-to yield the achiral product carbonic acid through a zinc hydroxide intermediate. We have previously shown that a zinc hydride, instead of a hydroxide, can be generated in this enzyme to create a catalyst for the reduction of aryl ketones. Dialkyl ketones are more challenging to reduce, and the enantioselective reduction of dialkyl ketones with two alkyl groups that are similar in size and electronic properties, is a particularly challenging transformation to achieve with high activity and selectivity. Here, we show that hCAII, as well as a double mutant of it, catalyzes the enantioselective reduction of dialkyl ketones with high yields and enantioselectivities, even when the two alkyl groups are similar in size. We also show that variants of hCAII catalyze the site-selective reduction of one ketone over the other in an unsymmetrical aliphatic diketone. Computational docking of a dialkyl ketone to variants of hCAII containing the zinc hydride provides insights into the origins of the reactivity of various substrates and the high enantioselectivity of the transformations and show how a confined environment can control the enantioselectivity of an abiological intermediate. |
format |
Article in Journal/Newspaper |
author |
Chen, Reichi Kayrouz, Colby S McAmis, Eli Clark, Douglas S Hartwig, John F |
author_facet |
Chen, Reichi Kayrouz, Colby S McAmis, Eli Clark, Douglas S Hartwig, John F |
author_sort |
Chen, Reichi |
title |
Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity. |
title_short |
Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity. |
title_full |
Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity. |
title_fullStr |
Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity. |
title_full_unstemmed |
Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity. |
title_sort |
carbonic anhydrase variants catalyze the reduction of dialkyl ketones with high enantioselectivity. |
publisher |
Wiley |
publishDate |
2024 |
url |
https://doi.org/10.1002/anie.202407111 https://pubmed.ncbi.nlm.nih.gov/38955771 |
genre |
Carbonic acid |
genre_facet |
Carbonic acid |
op_source |
Angew Chem Int Ed Engl ISSN:1521-3773 |
op_relation |
https://doi.org/10.1002/anie.202407111 https://pubmed.ncbi.nlm.nih.gov/38955771 |
op_rights |
© 2024 Wiley-VCH GmbH. |
op_doi |
https://doi.org/10.1002/anie.202407111 |
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Angewandte Chemie International Edition |
_version_ |
1810438759759478784 |