Insights into the Molecular Mechanism of Formaldehyde Inhibition of [FeFe]-Hydrogenases
[FeFe]-hydrogenases are efficient H converting biocatalysts that are inhibited by formaldehyde (HCHO). The molecular mechanism of this inhibition has so far not been experimentally solved. Here, we obtained high-resolution crystal structures of the HCHO-treated [FeFe]-hydrogenase CpI from , showing...
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| Veröffentlicht in: | Journal of the American Chemical Society 2023-12, Vol.145 (48), p.26068-26074 |
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| container_title | Journal of the American Chemical Society |
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| creator | Duan, Jifu Veliju, Astrit Lampret, Oliver Liu, Lingling Yadav, Shanika Apfel, Ulf-Peter Armstrong, Fraser A Hemschemeier, Anja Hofmann, Eckhard |
| description | [FeFe]-hydrogenases are efficient H
converting biocatalysts that are inhibited by formaldehyde (HCHO). The molecular mechanism of this inhibition has so far not been experimentally solved. Here, we obtained high-resolution crystal structures of the HCHO-treated [FeFe]-hydrogenase CpI from
, showing HCHO reacts with the secondary amine base of the catalytic cofactor and the cysteine C299 of the proton transfer pathway which both are very important for catalytic turnover. Kinetic assays via protein film electrochemistry show the CpI variant C299D is significantly less inhibited by HCHO, corroborating the structural results. By combining our data from protein crystallography, site-directed mutagenesis and protein film electrochemistry, a reaction mechanism involving the cofactor's amine base, the thiol group of C299 and HCHO can be deduced. In addition to the specific case of [FeFe]-hydrogenases, our study provides additional insights into the reactions between HCHO and protein molecules. |
| doi_str_mv | 10.1021/jacs.3c07800 |
| format | Article |
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converting biocatalysts that are inhibited by formaldehyde (HCHO). The molecular mechanism of this inhibition has so far not been experimentally solved. Here, we obtained high-resolution crystal structures of the HCHO-treated [FeFe]-hydrogenase CpI from
, showing HCHO reacts with the secondary amine base of the catalytic cofactor and the cysteine C299 of the proton transfer pathway which both are very important for catalytic turnover. Kinetic assays via protein film electrochemistry show the CpI variant C299D is significantly less inhibited by HCHO, corroborating the structural results. By combining our data from protein crystallography, site-directed mutagenesis and protein film electrochemistry, a reaction mechanism involving the cofactor's amine base, the thiol group of C299 and HCHO can be deduced. In addition to the specific case of [FeFe]-hydrogenases, our study provides additional insights into the reactions between HCHO and protein molecules.</description><identifier>ISSN: 0002-7863</identifier><identifier>ISSN: 1520-5126</identifier><identifier>EISSN: 1520-5126</identifier><identifier>DOI: 10.1021/jacs.3c07800</identifier><identifier>PMID: 37983562</identifier><language>eng</language><publisher>United States</publisher><subject>Amines ; Catalysis ; Clostridium pasteurianum ; crystallography ; cysteine ; electrochemistry ; formaldehyde ; Formaldehyde - pharmacology ; Hydrogen - chemistry ; Hydrogenase - chemistry ; Iron-Sulfur Proteins - chemistry ; Protons ; reaction mechanisms ; secondary amines ; site-directed mutagenesis ; thiols</subject><ispartof>Journal of the American Chemical Society, 2023-12, Vol.145 (48), p.26068-26074</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c281t-9f6659c91545a863fc8e997665d4a9baf38f094f218cbc032b9ce7c0cf40b2bf3</cites><orcidid>0000-0003-1155-2241 ; 0000-0003-4874-372X ; 0000-0001-8041-2491 ; 0000-0002-5158-2253 ; 0000-0002-1577-2420</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,2752,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37983562$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Duan, Jifu</creatorcontrib><creatorcontrib>Veliju, Astrit</creatorcontrib><creatorcontrib>Lampret, Oliver</creatorcontrib><creatorcontrib>Liu, Lingling</creatorcontrib><creatorcontrib>Yadav, Shanika</creatorcontrib><creatorcontrib>Apfel, Ulf-Peter</creatorcontrib><creatorcontrib>Armstrong, Fraser A</creatorcontrib><creatorcontrib>Hemschemeier, Anja</creatorcontrib><creatorcontrib>Hofmann, Eckhard</creatorcontrib><title>Insights into the Molecular Mechanism of Formaldehyde Inhibition of [FeFe]-Hydrogenases</title><title>Journal of the American Chemical Society</title><addtitle>J Am Chem Soc</addtitle><description>[FeFe]-hydrogenases are efficient H
converting biocatalysts that are inhibited by formaldehyde (HCHO). The molecular mechanism of this inhibition has so far not been experimentally solved. Here, we obtained high-resolution crystal structures of the HCHO-treated [FeFe]-hydrogenase CpI from
, showing HCHO reacts with the secondary amine base of the catalytic cofactor and the cysteine C299 of the proton transfer pathway which both are very important for catalytic turnover. Kinetic assays via protein film electrochemistry show the CpI variant C299D is significantly less inhibited by HCHO, corroborating the structural results. By combining our data from protein crystallography, site-directed mutagenesis and protein film electrochemistry, a reaction mechanism involving the cofactor's amine base, the thiol group of C299 and HCHO can be deduced. In addition to the specific case of [FeFe]-hydrogenases, our study provides additional insights into the reactions between HCHO and protein molecules.</description><subject>Amines</subject><subject>Catalysis</subject><subject>Clostridium pasteurianum</subject><subject>crystallography</subject><subject>cysteine</subject><subject>electrochemistry</subject><subject>formaldehyde</subject><subject>Formaldehyde - pharmacology</subject><subject>Hydrogen - chemistry</subject><subject>Hydrogenase - chemistry</subject><subject>Iron-Sulfur Proteins - chemistry</subject><subject>Protons</subject><subject>reaction mechanisms</subject><subject>secondary amines</subject><subject>site-directed mutagenesis</subject><subject>thiols</subject><issn>0002-7863</issn><issn>1520-5126</issn><issn>1520-5126</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkD1PwzAQhi0EoqWwMaOMDKT4I3HsEVWUVmrFAmJAKHKcc-MqiYudDP33pGphZTrd3aNXrx6EbgmeEkzJ41bpMGUaZwLjMzQmKcVxSig_R2OMMY0zwdkIXYWwHdaECnKJRiyTgqWcjtHHsg12U3Uhsm3noq6CaO1q0H2tfLQGXanWhiZyJpo736i6hGpfQrRsK1vYzrr28Pqcwxy-4sW-9G4DrQoQrtGFUXWAm9OcoPf589tsEa9eX5azp1WshyZdLA3nqdSSpEmqhqJGC5AyG45lomShDBMGy8RQInShMaOF1JBprE2CC1oYNkH3x9ydd989hC5vbNBQ16oF14ec4QQnXKSM_4tSISnlkopkQB-OqPYuBA8m33nbKL_PCc4P1vOD9fxkfcDvTsl90UD5B_9qZj9SLH3C</recordid><startdate>20231206</startdate><enddate>20231206</enddate><creator>Duan, Jifu</creator><creator>Veliju, Astrit</creator><creator>Lampret, Oliver</creator><creator>Liu, Lingling</creator><creator>Yadav, Shanika</creator><creator>Apfel, Ulf-Peter</creator><creator>Armstrong, Fraser A</creator><creator>Hemschemeier, Anja</creator><creator>Hofmann, Eckhard</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><orcidid>https://orcid.org/0000-0003-1155-2241</orcidid><orcidid>https://orcid.org/0000-0003-4874-372X</orcidid><orcidid>https://orcid.org/0000-0001-8041-2491</orcidid><orcidid>https://orcid.org/0000-0002-5158-2253</orcidid><orcidid>https://orcid.org/0000-0002-1577-2420</orcidid></search><sort><creationdate>20231206</creationdate><title>Insights into the Molecular Mechanism of Formaldehyde Inhibition of [FeFe]-Hydrogenases</title><author>Duan, Jifu ; 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converting biocatalysts that are inhibited by formaldehyde (HCHO). The molecular mechanism of this inhibition has so far not been experimentally solved. Here, we obtained high-resolution crystal structures of the HCHO-treated [FeFe]-hydrogenase CpI from
, showing HCHO reacts with the secondary amine base of the catalytic cofactor and the cysteine C299 of the proton transfer pathway which both are very important for catalytic turnover. Kinetic assays via protein film electrochemistry show the CpI variant C299D is significantly less inhibited by HCHO, corroborating the structural results. By combining our data from protein crystallography, site-directed mutagenesis and protein film electrochemistry, a reaction mechanism involving the cofactor's amine base, the thiol group of C299 and HCHO can be deduced. In addition to the specific case of [FeFe]-hydrogenases, our study provides additional insights into the reactions between HCHO and protein molecules.</abstract><cop>United States</cop><pmid>37983562</pmid><doi>10.1021/jacs.3c07800</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0003-1155-2241</orcidid><orcidid>https://orcid.org/0000-0003-4874-372X</orcidid><orcidid>https://orcid.org/0000-0001-8041-2491</orcidid><orcidid>https://orcid.org/0000-0002-5158-2253</orcidid><orcidid>https://orcid.org/0000-0002-1577-2420</orcidid></addata></record> |
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| subjects | Amines Catalysis Clostridium pasteurianum crystallography cysteine electrochemistry formaldehyde Formaldehyde - pharmacology Hydrogen - chemistry Hydrogenase - chemistry Iron-Sulfur Proteins - chemistry Protons reaction mechanisms secondary amines site-directed mutagenesis thiols |
| title | Insights into the Molecular Mechanism of Formaldehyde Inhibition of [FeFe]-Hydrogenases |
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