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Unusual catalytic strategy by non-heme Fe()/2-oxoglutarate-dependent aspartyl hydroxylase AspH
Biocatalytic C-H oxidation reactions are of important synthetic utility, provide a sustainable route for selective synthesis of important organic molecules, and are an integral part of fundamental cell processes. The multidomain non-heme Fe( ii )/2-oxoglutarate (2OG) dependent oxygenase AspH catalyz...
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Published in: | Chemical science (Cambridge) 2024-03, Vol.15 (1), p.3466-3484 |
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description | Biocatalytic C-H oxidation reactions are of important synthetic utility, provide a sustainable route for selective synthesis of important organic molecules, and are an integral part of fundamental cell processes. The multidomain non-heme Fe(
ii
)/2-oxoglutarate (2OG) dependent oxygenase AspH catalyzes stereoselective (3
R
)-hydroxylation of aspartyl- and asparaginyl-residues. Unusually, compared to other 2OG hydroxylases, crystallography has shown that AspH lacks the carboxylate residue of the characteristic two-His-one-Asp/Glu Fe-binding triad. Instead, AspH has a water molecule that coordinates Fe(
ii
) in the coordination position usually occupied by the Asp/Glu carboxylate. Molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) studies reveal that the iron coordinating water is stabilized by hydrogen bonding with a second coordination sphere (SCS) carboxylate residue Asp721, an arrangement that helps maintain the six coordinated Fe(
ii
) distorted octahedral coordination geometry and enable catalysis. AspH catalysis follows a dioxygen activation-hydrogen atom transfer (HAT)-rebound hydroxylation mechanism, unusually exhibiting higher activation energy for rebound hydroxylation than for HAT, indicating that the rebound step may be rate-limiting. The HAT step, along with substrate positioning modulated by the non-covalent interactions with SCS residues (Arg688, Arg686, Lys666, Asp721, and Gln664), are essential in determining stereoselectivity, which likely proceeds with retention of configuration. The tetratricopeptide repeat (TPR) domain of AspH influences substrate binding and manifests dynamic motions during catalysis, an observation of interest with respect to other 2OG oxygenases with TPR domains. The results provide unique insights into how non-heme Fe(
ii
) oxygenases can effectively catalyze stereoselective hydroxylation using only two enzyme-derived Fe-ligating residues, potentially guiding enzyme engineering for stereoselective biocatalysis, thus advancing the development of non-heme Fe(
ii
) based biomimetic C-H oxidation catalysts, and supporting the proposal that the 2OG oxygenase superfamily may be larger than once perceived.
The second coordination sphere, Asp721, participates in a hydrogen bond with an iron-coordinated water molecule, thus compensating for the missing facial triad carboxylate in AspH and enabling stereoselective C-H oxidation. |
doi_str_mv | 10.1039/d3sc05974j |
format | article |
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ii
)/2-oxoglutarate (2OG) dependent oxygenase AspH catalyzes stereoselective (3
R
)-hydroxylation of aspartyl- and asparaginyl-residues. Unusually, compared to other 2OG hydroxylases, crystallography has shown that AspH lacks the carboxylate residue of the characteristic two-His-one-Asp/Glu Fe-binding triad. Instead, AspH has a water molecule that coordinates Fe(
ii
) in the coordination position usually occupied by the Asp/Glu carboxylate. Molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) studies reveal that the iron coordinating water is stabilized by hydrogen bonding with a second coordination sphere (SCS) carboxylate residue Asp721, an arrangement that helps maintain the six coordinated Fe(
ii
) distorted octahedral coordination geometry and enable catalysis. AspH catalysis follows a dioxygen activation-hydrogen atom transfer (HAT)-rebound hydroxylation mechanism, unusually exhibiting higher activation energy for rebound hydroxylation than for HAT, indicating that the rebound step may be rate-limiting. The HAT step, along with substrate positioning modulated by the non-covalent interactions with SCS residues (Arg688, Arg686, Lys666, Asp721, and Gln664), are essential in determining stereoselectivity, which likely proceeds with retention of configuration. The tetratricopeptide repeat (TPR) domain of AspH influences substrate binding and manifests dynamic motions during catalysis, an observation of interest with respect to other 2OG oxygenases with TPR domains. The results provide unique insights into how non-heme Fe(
ii
) oxygenases can effectively catalyze stereoselective hydroxylation using only two enzyme-derived Fe-ligating residues, potentially guiding enzyme engineering for stereoselective biocatalysis, thus advancing the development of non-heme Fe(
ii
) based biomimetic C-H oxidation catalysts, and supporting the proposal that the 2OG oxygenase superfamily may be larger than once perceived.
The second coordination sphere, Asp721, participates in a hydrogen bond with an iron-coordinated water molecule, thus compensating for the missing facial triad carboxylate in AspH and enabling stereoselective C-H oxidation.</description><identifier>ISSN: 2041-6520</identifier><identifier>EISSN: 2041-6539</identifier><identifier>DOI: 10.1039/d3sc05974j</identifier><identifier>PMID: 38455014</identifier><language>eng</language><publisher>England: Royal Society of Chemistry</publisher><subject>Binding ; Biomimetics ; Catalysis ; Chemical synthesis ; Chemistry ; Coordination ; Crystallography ; Enzymes ; Hydrogen atoms ; Hydrogen bonding ; Hydroxylation ; Iron ; Molecular dynamics ; Organic chemistry ; Oxidation ; Quantum mechanics ; Residues ; Route selection ; Stereoselectivity ; Substrates ; Water chemistry</subject><ispartof>Chemical science (Cambridge), 2024-03, Vol.15 (1), p.3466-3484</ispartof><rights>This journal is © The Royal Society of Chemistry.</rights><rights>Copyright Royal Society of Chemistry 2024</rights><rights>This journal is © The Royal Society of Chemistry 2024 The Royal Society of Chemistry</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c388t-c69b1095105ff4c1e0250b2cf13bd040ab720882edae5135757b7aa17a7979b73</cites><orcidid>0000-0003-3422-4531 ; 0000-0001-8629-4377 ; 0000-0002-0290-6565 ; 0000-0002-0562-2832</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10915816/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10915816/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38455014$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Krishnan, Anandhu</creatorcontrib><creatorcontrib>Waheed, Sodiq O</creatorcontrib><creatorcontrib>Varghese, Ann</creatorcontrib><creatorcontrib>Cherilakkudy, Fathima Hameed</creatorcontrib><creatorcontrib>Schofield, Christopher J</creatorcontrib><creatorcontrib>Karabencheva-Christova, Tatyana G</creatorcontrib><title>Unusual catalytic strategy by non-heme Fe()/2-oxoglutarate-dependent aspartyl hydroxylase AspH</title><title>Chemical science (Cambridge)</title><addtitle>Chem Sci</addtitle><description>Biocatalytic C-H oxidation reactions are of important synthetic utility, provide a sustainable route for selective synthesis of important organic molecules, and are an integral part of fundamental cell processes. The multidomain non-heme Fe(
ii
)/2-oxoglutarate (2OG) dependent oxygenase AspH catalyzes stereoselective (3
R
)-hydroxylation of aspartyl- and asparaginyl-residues. Unusually, compared to other 2OG hydroxylases, crystallography has shown that AspH lacks the carboxylate residue of the characteristic two-His-one-Asp/Glu Fe-binding triad. Instead, AspH has a water molecule that coordinates Fe(
ii
) in the coordination position usually occupied by the Asp/Glu carboxylate. Molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) studies reveal that the iron coordinating water is stabilized by hydrogen bonding with a second coordination sphere (SCS) carboxylate residue Asp721, an arrangement that helps maintain the six coordinated Fe(
ii
) distorted octahedral coordination geometry and enable catalysis. AspH catalysis follows a dioxygen activation-hydrogen atom transfer (HAT)-rebound hydroxylation mechanism, unusually exhibiting higher activation energy for rebound hydroxylation than for HAT, indicating that the rebound step may be rate-limiting. The HAT step, along with substrate positioning modulated by the non-covalent interactions with SCS residues (Arg688, Arg686, Lys666, Asp721, and Gln664), are essential in determining stereoselectivity, which likely proceeds with retention of configuration. The tetratricopeptide repeat (TPR) domain of AspH influences substrate binding and manifests dynamic motions during catalysis, an observation of interest with respect to other 2OG oxygenases with TPR domains. The results provide unique insights into how non-heme Fe(
ii
) oxygenases can effectively catalyze stereoselective hydroxylation using only two enzyme-derived Fe-ligating residues, potentially guiding enzyme engineering for stereoselective biocatalysis, thus advancing the development of non-heme Fe(
ii
) based biomimetic C-H oxidation catalysts, and supporting the proposal that the 2OG oxygenase superfamily may be larger than once perceived.
The second coordination sphere, Asp721, participates in a hydrogen bond with an iron-coordinated water molecule, thus compensating for the missing facial triad carboxylate in AspH and enabling stereoselective C-H oxidation.</description><subject>Binding</subject><subject>Biomimetics</subject><subject>Catalysis</subject><subject>Chemical synthesis</subject><subject>Chemistry</subject><subject>Coordination</subject><subject>Crystallography</subject><subject>Enzymes</subject><subject>Hydrogen atoms</subject><subject>Hydrogen bonding</subject><subject>Hydroxylation</subject><subject>Iron</subject><subject>Molecular dynamics</subject><subject>Organic chemistry</subject><subject>Oxidation</subject><subject>Quantum mechanics</subject><subject>Residues</subject><subject>Route selection</subject><subject>Stereoselectivity</subject><subject>Substrates</subject><subject>Water chemistry</subject><issn>2041-6520</issn><issn>2041-6539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNpdkc1P3DAQxS3UChDl0jtVpF5opYA_4nVyQmhbvoTEoeVaa-JMdrPyxsF2EPnva7qwtJ3LjDQ_vXmjR8hHRk8YFdVpI4KhslLFaofsc1qwfCZF9W47c7pHDkNY0VRCMMnVLtkTZSElZcU--XXfj2EEmxmIYKfYmSxEDxEXU1ZPWe_6fIlrzC7w-Mspz92TW9gxwjORNzhg32AfMwgD-DjZbDk13j1NFgJm52G4-kDet2ADHr70A3J_8f3n_Cq_vbu8np_f5kaUZczNrKoZrSSjsm0Lw5BySWtuWibqhhYUasVpWXJsACUTUklVKwCmQFWqqpU4IGcb3WGs19iYZMqD1YPv1uAn7aDT_276bqkX7lGnq0yWbJYUjl8UvHsYMUS97oJBa6FHNwbNK1koRZUqEvr5P3TlRt-n_xIllCzL5DVRXzeU8S4Ej-3WDaP6OTr9TfyY_4nuJsGf_va_RV-DSsDRBvDBbLdv2YvfEiCeLg</recordid><startdate>20240306</startdate><enddate>20240306</enddate><creator>Krishnan, Anandhu</creator><creator>Waheed, Sodiq O</creator><creator>Varghese, Ann</creator><creator>Cherilakkudy, Fathima Hameed</creator><creator>Schofield, Christopher J</creator><creator>Karabencheva-Christova, Tatyana G</creator><general>Royal Society of Chemistry</general><general>The Royal Society of Chemistry</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SR</scope><scope>8BQ</scope><scope>8FD</scope><scope>JG9</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3422-4531</orcidid><orcidid>https://orcid.org/0000-0001-8629-4377</orcidid><orcidid>https://orcid.org/0000-0002-0290-6565</orcidid><orcidid>https://orcid.org/0000-0002-0562-2832</orcidid></search><sort><creationdate>20240306</creationdate><title>Unusual catalytic strategy by non-heme Fe()/2-oxoglutarate-dependent aspartyl hydroxylase AspH</title><author>Krishnan, Anandhu ; Waheed, Sodiq O ; Varghese, Ann ; Cherilakkudy, Fathima Hameed ; Schofield, Christopher J ; Karabencheva-Christova, Tatyana G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c388t-c69b1095105ff4c1e0250b2cf13bd040ab720882edae5135757b7aa17a7979b73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Binding</topic><topic>Biomimetics</topic><topic>Catalysis</topic><topic>Chemical synthesis</topic><topic>Chemistry</topic><topic>Coordination</topic><topic>Crystallography</topic><topic>Enzymes</topic><topic>Hydrogen atoms</topic><topic>Hydrogen bonding</topic><topic>Hydroxylation</topic><topic>Iron</topic><topic>Molecular dynamics</topic><topic>Organic chemistry</topic><topic>Oxidation</topic><topic>Quantum mechanics</topic><topic>Residues</topic><topic>Route selection</topic><topic>Stereoselectivity</topic><topic>Substrates</topic><topic>Water chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Krishnan, Anandhu</creatorcontrib><creatorcontrib>Waheed, Sodiq O</creatorcontrib><creatorcontrib>Varghese, Ann</creatorcontrib><creatorcontrib>Cherilakkudy, Fathima Hameed</creatorcontrib><creatorcontrib>Schofield, Christopher J</creatorcontrib><creatorcontrib>Karabencheva-Christova, Tatyana G</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Engineered Materials Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Materials Research Database</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Chemical science (Cambridge)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Krishnan, Anandhu</au><au>Waheed, Sodiq O</au><au>Varghese, Ann</au><au>Cherilakkudy, Fathima Hameed</au><au>Schofield, Christopher J</au><au>Karabencheva-Christova, Tatyana G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Unusual catalytic strategy by non-heme Fe()/2-oxoglutarate-dependent aspartyl hydroxylase AspH</atitle><jtitle>Chemical science (Cambridge)</jtitle><addtitle>Chem Sci</addtitle><date>2024-03-06</date><risdate>2024</risdate><volume>15</volume><issue>1</issue><spage>3466</spage><epage>3484</epage><pages>3466-3484</pages><issn>2041-6520</issn><eissn>2041-6539</eissn><abstract>Biocatalytic C-H oxidation reactions are of important synthetic utility, provide a sustainable route for selective synthesis of important organic molecules, and are an integral part of fundamental cell processes. The multidomain non-heme Fe(
ii
)/2-oxoglutarate (2OG) dependent oxygenase AspH catalyzes stereoselective (3
R
)-hydroxylation of aspartyl- and asparaginyl-residues. Unusually, compared to other 2OG hydroxylases, crystallography has shown that AspH lacks the carboxylate residue of the characteristic two-His-one-Asp/Glu Fe-binding triad. Instead, AspH has a water molecule that coordinates Fe(
ii
) in the coordination position usually occupied by the Asp/Glu carboxylate. Molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) studies reveal that the iron coordinating water is stabilized by hydrogen bonding with a second coordination sphere (SCS) carboxylate residue Asp721, an arrangement that helps maintain the six coordinated Fe(
ii
) distorted octahedral coordination geometry and enable catalysis. AspH catalysis follows a dioxygen activation-hydrogen atom transfer (HAT)-rebound hydroxylation mechanism, unusually exhibiting higher activation energy for rebound hydroxylation than for HAT, indicating that the rebound step may be rate-limiting. The HAT step, along with substrate positioning modulated by the non-covalent interactions with SCS residues (Arg688, Arg686, Lys666, Asp721, and Gln664), are essential in determining stereoselectivity, which likely proceeds with retention of configuration. The tetratricopeptide repeat (TPR) domain of AspH influences substrate binding and manifests dynamic motions during catalysis, an observation of interest with respect to other 2OG oxygenases with TPR domains. The results provide unique insights into how non-heme Fe(
ii
) oxygenases can effectively catalyze stereoselective hydroxylation using only two enzyme-derived Fe-ligating residues, potentially guiding enzyme engineering for stereoselective biocatalysis, thus advancing the development of non-heme Fe(
ii
) based biomimetic C-H oxidation catalysts, and supporting the proposal that the 2OG oxygenase superfamily may be larger than once perceived.
The second coordination sphere, Asp721, participates in a hydrogen bond with an iron-coordinated water molecule, thus compensating for the missing facial triad carboxylate in AspH and enabling stereoselective C-H oxidation.</abstract><cop>England</cop><pub>Royal Society of Chemistry</pub><pmid>38455014</pmid><doi>10.1039/d3sc05974j</doi><tpages>19</tpages><orcidid>https://orcid.org/0000-0003-3422-4531</orcidid><orcidid>https://orcid.org/0000-0001-8629-4377</orcidid><orcidid>https://orcid.org/0000-0002-0290-6565</orcidid><orcidid>https://orcid.org/0000-0002-0562-2832</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Binding Biomimetics Catalysis Chemical synthesis Chemistry Coordination Crystallography Enzymes Hydrogen atoms Hydrogen bonding Hydroxylation Iron Molecular dynamics Organic chemistry Oxidation Quantum mechanics Residues Route selection Stereoselectivity Substrates Water chemistry |
title | Unusual catalytic strategy by non-heme Fe()/2-oxoglutarate-dependent aspartyl hydroxylase AspH |
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