Rational Inhibitor Design, Synthesis and NMR Spectroscopic Study by Transferred Nuclear Overhauser Spectroscopy of Novel Inhibitors of Cinnamyl Alcohol Dehydrogenase, a Critical Enzyme in Lignification
Abstract Cinnamyl alcohol dehydrogenase is one of the enzymes controlling the first two committed steps of lignification. Using a 3-dimensional similarity model of this enzyme, a series of novel phos-phonates (1-5) was designed as potential inhibitors. Phosphonates 1-5 were synthesized in good yield...
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| Veröffentlicht in: | Journal of enzyme inhibition 1999, Vol.14 (3), p.217-237 |
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| creator | Kennedy, Karen Baltas, Michel Douglas, Kenneth T. Duran, Hubert Embrey, Kevin J. Giraudon, Jean-Guillaume McKie, James H. Grima-Pettenati, Jacqueline Gorrichon, Liliane |
| description | Abstract
Cinnamyl alcohol dehydrogenase is one of the enzymes controlling the first two committed steps of lignification. Using a 3-dimensional similarity model of this enzyme, a series of novel phos-phonates (1-5) was designed as potential inhibitors. Phosphonates 1-5 were synthesized in good yield by reaction of the corresponding cinnamaldehydes with tetraethylmethylene diphos-phonate. Monophosphonic acids 6 and 7 were obtained by basic hydrolysis of the corresponding phosphonates while phosphonamidate 8 was synthesized by reacting benzylamine with the iminium salt intermediate of the monophosphonic acid. Using recombinant cinnamyl alcohol dehydrogenase (CAD, EC 1.1.1.195) the inhibitory activity of these compounds was evaluated and compared with that of the carbonyl analogues. Inhibition kinetic studies showed compounds 2 and 3 to be mixed type linear inhibitors while compound 4 was uncompetitive. H NMR studies of inhibitor 2, for which K1 and K1 were 20 and 86 pM, respectively, in the presence of CAD based on selective line-broadening showed an increased interaction of the 3-Ome group of the aromatic ring of the inhibitor with the active site of the CAD. A transferred nuclear overhauser effect spectroscopy (TRNOESY) experiment for inhibitor 2 with CAD was used to determine the conformation of this compound bound to CAD. These results were found to be consistent with the 3-dimensional structural model of the enzyme |
| doi_str_mv | 10.3109/14756369909030318 |
| format | Article |
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Cinnamyl alcohol dehydrogenase is one of the enzymes controlling the first two committed steps of lignification. Using a 3-dimensional similarity model of this enzyme, a series of novel phos-phonates (1-5) was designed as potential inhibitors. Phosphonates 1-5 were synthesized in good yield by reaction of the corresponding cinnamaldehydes with tetraethylmethylene diphos-phonate. Monophosphonic acids 6 and 7 were obtained by basic hydrolysis of the corresponding phosphonates while phosphonamidate 8 was synthesized by reacting benzylamine with the iminium salt intermediate of the monophosphonic acid. Using recombinant cinnamyl alcohol dehydrogenase (CAD, EC 1.1.1.195) the inhibitory activity of these compounds was evaluated and compared with that of the carbonyl analogues. Inhibition kinetic studies showed compounds 2 and 3 to be mixed type linear inhibitors while compound 4 was uncompetitive. H NMR studies of inhibitor 2, for which K1 and K1 were 20 and 86 pM, respectively, in the presence of CAD based on selective line-broadening showed an increased interaction of the 3-Ome group of the aromatic ring of the inhibitor with the active site of the CAD. A transferred nuclear overhauser effect spectroscopy (TRNOESY) experiment for inhibitor 2 with CAD was used to determine the conformation of this compound bound to CAD. These results were found to be consistent with the 3-dimensional structural model of the enzyme</description><identifier>ISSN: 1475-6366</identifier><identifier>ISSN: 8755-5093</identifier><identifier>EISSN: 1475-6374</identifier><identifier>DOI: 10.3109/14756369909030318</identifier><identifier>PMID: 10445045</identifier><language>eng</language><publisher>Switzerland: Informa UK Ltd</publisher><subject>Alcohol dehydrogenase ; Alcohol Oxidoreductases - antagonists & inhibitors ; Alcohol Oxidoreductases - genetics ; Drug Design ; Enzyme inhibition ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Eucalyptus - enzymology ; Eucalyptus - genetics ; Inhibitor conformation ; Lignification ; Lignin - biosynthesis ; Molecular Conformation ; Nuclear Magnetic Resonance, Biomolecular ; Organophosphonates - chemistry ; Organophosphonates - pharmacology ; Phosphonates ; Plants, Medicinal ; Propanols - metabolism ; Recombinant Proteins - drug effects ; TRNOESY ; Vinyl Compounds - chemistry ; Vinyl Compounds - pharmacology</subject><ispartof>Journal of enzyme inhibition, 1999, Vol.14 (3), p.217-237</ispartof><rights>1999 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted 1999</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c402t-9e22f9e2fde8ee6182959f0c995bec1cf0216206b0315f858f5ce2e63bdeb6cb3</citedby><cites>FETCH-LOGICAL-c402t-9e22f9e2fde8ee6182959f0c995bec1cf0216206b0315f858f5ce2e63bdeb6cb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.tandfonline.com/doi/pdf/10.3109/14756369909030318$$EPDF$$P50$$Ginformaworld$$H</linktopdf><linktohtml>$$Uhttps://www.tandfonline.com/doi/full/10.3109/14756369909030318$$EHTML$$P50$$Ginformaworld$$H</linktohtml><link.rule.ids>314,776,780,4010,27479,27900,27901,27902,59116,59117,61194,61375</link.rule.ids><linktorsrc>$$Uhttps://www.tandfonline.com/doi/abs/10.3109/14756369909030318$$EView_record_in_Taylor_&_Francis$$FView_record_in_$$GTaylor_&_Francis</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10445045$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kennedy, Karen</creatorcontrib><creatorcontrib>Baltas, Michel</creatorcontrib><creatorcontrib>Douglas, Kenneth T.</creatorcontrib><creatorcontrib>Duran, Hubert</creatorcontrib><creatorcontrib>Embrey, Kevin J.</creatorcontrib><creatorcontrib>Giraudon, Jean-Guillaume</creatorcontrib><creatorcontrib>McKie, James H.</creatorcontrib><creatorcontrib>Grima-Pettenati, Jacqueline</creatorcontrib><creatorcontrib>Gorrichon, Liliane</creatorcontrib><title>Rational Inhibitor Design, Synthesis and NMR Spectroscopic Study by Transferred Nuclear Overhauser Spectroscopy of Novel Inhibitors of Cinnamyl Alcohol Dehydrogenase, a Critical Enzyme in Lignification</title><title>Journal of enzyme inhibition</title><addtitle>J Enzyme Inhib</addtitle><description>Abstract
Cinnamyl alcohol dehydrogenase is one of the enzymes controlling the first two committed steps of lignification. Using a 3-dimensional similarity model of this enzyme, a series of novel phos-phonates (1-5) was designed as potential inhibitors. Phosphonates 1-5 were synthesized in good yield by reaction of the corresponding cinnamaldehydes with tetraethylmethylene diphos-phonate. Monophosphonic acids 6 and 7 were obtained by basic hydrolysis of the corresponding phosphonates while phosphonamidate 8 was synthesized by reacting benzylamine with the iminium salt intermediate of the monophosphonic acid. Using recombinant cinnamyl alcohol dehydrogenase (CAD, EC 1.1.1.195) the inhibitory activity of these compounds was evaluated and compared with that of the carbonyl analogues. Inhibition kinetic studies showed compounds 2 and 3 to be mixed type linear inhibitors while compound 4 was uncompetitive. H NMR studies of inhibitor 2, for which K1 and K1 were 20 and 86 pM, respectively, in the presence of CAD based on selective line-broadening showed an increased interaction of the 3-Ome group of the aromatic ring of the inhibitor with the active site of the CAD. A transferred nuclear overhauser effect spectroscopy (TRNOESY) experiment for inhibitor 2 with CAD was used to determine the conformation of this compound bound to CAD. These results were found to be consistent with the 3-dimensional structural model of the enzyme</description><subject>Alcohol dehydrogenase</subject><subject>Alcohol Oxidoreductases - antagonists & inhibitors</subject><subject>Alcohol Oxidoreductases - genetics</subject><subject>Drug Design</subject><subject>Enzyme inhibition</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Eucalyptus - enzymology</subject><subject>Eucalyptus - genetics</subject><subject>Inhibitor conformation</subject><subject>Lignification</subject><subject>Lignin - biosynthesis</subject><subject>Molecular Conformation</subject><subject>Nuclear Magnetic Resonance, Biomolecular</subject><subject>Organophosphonates - chemistry</subject><subject>Organophosphonates - pharmacology</subject><subject>Phosphonates</subject><subject>Plants, Medicinal</subject><subject>Propanols - metabolism</subject><subject>Recombinant Proteins - drug effects</subject><subject>TRNOESY</subject><subject>Vinyl Compounds - chemistry</subject><subject>Vinyl Compounds - pharmacology</subject><issn>1475-6366</issn><issn>8755-5093</issn><issn>1475-6374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9Uk1v1DAQjRAVLYUfwAX5xKnb2vlwE8GlWkqptLRSt5wjxxk3rhx7GTtF7j_sv8LRVmgRgos9Gr33_Gaes-wdo8cFo80JK08rXvCmoQ0taMHqF9nB3Fvw4rR8-bvmfD977f09pTnLWfkq22e0LCtaVgfZ040I2llhyKUddKeDQ_IZvL6zR2QdbRhS7YmwPbn6dkPWG5ABnZduoyVZh6mPpIvkFoX1ChAhwSZpQCC5fgAcxOQBd1mROEWu3APsvOfn3lJbK8ZoyJmRbnAmmRhij-4OrPBwRARZog5aJqPn9jGOQLQlq2RTq9ScR3iT7SlhPLx9vg-z71_Ob5dfF6vri8vl2WohS5qHRQN5rtKheqgBOKvzpmoUlU1TdSCZVGlJPKe8S_usVF3VqpKQAy-6Hjouu-Iw-7DV3aD7MYEP7ai9BGOEBTf5NsXBq5yXCci2QJlm9wiq3aAeBcaW0XbOr_0rv8R5_yw-dSP0O4xtYAnwaQvQVjkcxU-Hpm-DiMahSjFI7Wftf-t__IM-gDBhkAKhvXcTpn_g_-PuF2BPwCc</recordid><startdate>1999</startdate><enddate>1999</enddate><creator>Kennedy, Karen</creator><creator>Baltas, Michel</creator><creator>Douglas, Kenneth T.</creator><creator>Duran, Hubert</creator><creator>Embrey, Kevin J.</creator><creator>Giraudon, Jean-Guillaume</creator><creator>McKie, James H.</creator><creator>Grima-Pettenati, Jacqueline</creator><creator>Gorrichon, Liliane</creator><general>Informa UK Ltd</general><general>Taylor & Francis</general><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></search><sort><creationdate>1999</creationdate><title>Rational Inhibitor Design, Synthesis and NMR Spectroscopic Study by Transferred Nuclear Overhauser Spectroscopy of Novel Inhibitors of Cinnamyl Alcohol Dehydrogenase, a Critical Enzyme in Lignification</title><author>Kennedy, Karen ; Baltas, Michel ; Douglas, Kenneth T. ; Duran, Hubert ; Embrey, Kevin J. ; Giraudon, Jean-Guillaume ; McKie, James H. ; Grima-Pettenati, Jacqueline ; Gorrichon, Liliane</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c402t-9e22f9e2fde8ee6182959f0c995bec1cf0216206b0315f858f5ce2e63bdeb6cb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Alcohol dehydrogenase</topic><topic>Alcohol Oxidoreductases - antagonists & inhibitors</topic><topic>Alcohol Oxidoreductases - genetics</topic><topic>Drug Design</topic><topic>Enzyme inhibition</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Eucalyptus - enzymology</topic><topic>Eucalyptus - genetics</topic><topic>Inhibitor conformation</topic><topic>Lignification</topic><topic>Lignin - biosynthesis</topic><topic>Molecular Conformation</topic><topic>Nuclear Magnetic Resonance, Biomolecular</topic><topic>Organophosphonates - chemistry</topic><topic>Organophosphonates - pharmacology</topic><topic>Phosphonates</topic><topic>Plants, Medicinal</topic><topic>Propanols - metabolism</topic><topic>Recombinant Proteins - drug effects</topic><topic>TRNOESY</topic><topic>Vinyl Compounds - chemistry</topic><topic>Vinyl Compounds - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kennedy, Karen</creatorcontrib><creatorcontrib>Baltas, Michel</creatorcontrib><creatorcontrib>Douglas, Kenneth T.</creatorcontrib><creatorcontrib>Duran, Hubert</creatorcontrib><creatorcontrib>Embrey, Kevin J.</creatorcontrib><creatorcontrib>Giraudon, Jean-Guillaume</creatorcontrib><creatorcontrib>McKie, James H.</creatorcontrib><creatorcontrib>Grima-Pettenati, Jacqueline</creatorcontrib><creatorcontrib>Gorrichon, Liliane</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of enzyme inhibition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Kennedy, Karen</au><au>Baltas, Michel</au><au>Douglas, Kenneth T.</au><au>Duran, Hubert</au><au>Embrey, Kevin J.</au><au>Giraudon, Jean-Guillaume</au><au>McKie, James H.</au><au>Grima-Pettenati, Jacqueline</au><au>Gorrichon, Liliane</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rational Inhibitor Design, Synthesis and NMR Spectroscopic Study by Transferred Nuclear Overhauser Spectroscopy of Novel Inhibitors of Cinnamyl Alcohol Dehydrogenase, a Critical Enzyme in Lignification</atitle><jtitle>Journal of enzyme inhibition</jtitle><addtitle>J Enzyme Inhib</addtitle><date>1999</date><risdate>1999</risdate><volume>14</volume><issue>3</issue><spage>217</spage><epage>237</epage><pages>217-237</pages><issn>1475-6366</issn><issn>8755-5093</issn><eissn>1475-6374</eissn><abstract>Abstract
Cinnamyl alcohol dehydrogenase is one of the enzymes controlling the first two committed steps of lignification. Using a 3-dimensional similarity model of this enzyme, a series of novel phos-phonates (1-5) was designed as potential inhibitors. Phosphonates 1-5 were synthesized in good yield by reaction of the corresponding cinnamaldehydes with tetraethylmethylene diphos-phonate. Monophosphonic acids 6 and 7 were obtained by basic hydrolysis of the corresponding phosphonates while phosphonamidate 8 was synthesized by reacting benzylamine with the iminium salt intermediate of the monophosphonic acid. Using recombinant cinnamyl alcohol dehydrogenase (CAD, EC 1.1.1.195) the inhibitory activity of these compounds was evaluated and compared with that of the carbonyl analogues. Inhibition kinetic studies showed compounds 2 and 3 to be mixed type linear inhibitors while compound 4 was uncompetitive. H NMR studies of inhibitor 2, for which K1 and K1 were 20 and 86 pM, respectively, in the presence of CAD based on selective line-broadening showed an increased interaction of the 3-Ome group of the aromatic ring of the inhibitor with the active site of the CAD. A transferred nuclear overhauser effect spectroscopy (TRNOESY) experiment for inhibitor 2 with CAD was used to determine the conformation of this compound bound to CAD. These results were found to be consistent with the 3-dimensional structural model of the enzyme</abstract><cop>Switzerland</cop><pub>Informa UK Ltd</pub><pmid>10445045</pmid><doi>10.3109/14756369909030318</doi><tpages>21</tpages></addata></record> |
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| ispartof | Journal of enzyme inhibition, 1999, Vol.14 (3), p.217-237 |
| issn | 1475-6366 8755-5093 1475-6374 |
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| source | Taylor & Francis Open Access |
| subjects | Alcohol dehydrogenase Alcohol Oxidoreductases - antagonists & inhibitors Alcohol Oxidoreductases - genetics Drug Design Enzyme inhibition Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Eucalyptus - enzymology Eucalyptus - genetics Inhibitor conformation Lignification Lignin - biosynthesis Molecular Conformation Nuclear Magnetic Resonance, Biomolecular Organophosphonates - chemistry Organophosphonates - pharmacology Phosphonates Plants, Medicinal Propanols - metabolism Recombinant Proteins - drug effects TRNOESY Vinyl Compounds - chemistry Vinyl Compounds - pharmacology |
| title | Rational Inhibitor Design, Synthesis and NMR Spectroscopic Study by Transferred Nuclear Overhauser Spectroscopy of Novel Inhibitors of Cinnamyl Alcohol Dehydrogenase, a Critical Enzyme in Lignification |
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