4-Hydroxyphenylpyruvate Dioxygenase Catalysis
Identifieur interne : 000720 ( Pmc/Checkpoint ); précédent : 000719; suivant : 0007214-Hydroxyphenylpyruvate Dioxygenase Catalysis
Auteurs : Corinne Raspail [France] ; Matthieu Graindorge [France] ; Yohann Moreau ; Serge Crouzy ; Bertrand Lefèbvre ; Adeline Y. Robin [France] ; Renaud Dumas [France] ; Michel Matringe [France]Source :
- The Journal of Biological Chemistry [ 0021-9258 ] ; 2011.
Abstract
4-Hydroxyphenylpyruvate dioxygenase (HPPD) catalyzes the conversion of 4-hydroxyphenylpyruvate (HPP) into homogentisate. HPPD is the molecular target of very effective synthetic herbicides. HPPD inhibitors may also be useful in treating life-threatening tyrosinemia type I and are currently in trials for treatment of Parkinson disease. The reaction mechanism of this key enzyme in both plants and animals has not yet been fully elucidated. In this study, using site-directed mutagenesis supported by quantum mechanical/molecular mechanical theoretical calculations, we investigated the role of catalytic residues potentially interacting with the substrate/intermediates. These results highlight the following: (i) the central role of Gln-272, Gln-286, and Gln-358 in HPP binding and the first nucleophilic attack; (ii) the important movement of the aromatic ring of HPP during the reaction, and (iii) the key role played by Asn-261 and Ser-246 in C1 hydroxylation and the final ortho-rearrangement steps (numbering according to the
Url:
DOI: 10.1074/jbc.M111.227595
PubMed: 21613226
PubMed Central: 3138293
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">4-Hydroxyphenylpyruvate Dioxygenase Catalysis</title><author><name sortKey="Raspail, Corinne" sort="Raspail, Corinne" uniqKey="Raspail C" first="Corinne" last="Raspail">Corinne Raspail</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation><affiliation wicri:level="3"><nlm:aff wicri:cut=", and" id="aff5">Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</nlm:aff><country wicri:rule="zip">France</country><wicri:regionArea>Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</wicri:regionArea><placeName><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Rhône-Alpes</region><settlement type="city">Grenoble</settlement></placeName></affiliation></author><author><name sortKey="Graindorge, Matthieu" sort="Graindorge, Matthieu" uniqKey="Graindorge M" first="Matthieu" last="Graindorge">Matthieu Graindorge</name><affiliation wicri:level="3"><nlm:aff wicri:cut=", and" id="aff5">Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</nlm:aff><country wicri:rule="zip">France</country><wicri:regionArea>Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</wicri:regionArea><placeName><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Rhône-Alpes</region><settlement type="city">Grenoble</settlement></placeName></affiliation><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Moreau, Yohann" sort="Moreau, Yohann" uniqKey="Moreau Y" first="Yohann" last="Moreau">Yohann Moreau</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff3">CNRS UMR 5249 Laboratoire de Chimie et Biologie des Métaux, Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant,</nlm:aff><wicri:noCountry code="subfield">Institut de Recherches en Technologies et Sciences pour le Vivant</wicri:noCountry></affiliation></author><author><name sortKey="Crouzy, Serge" sort="Crouzy, Serge" uniqKey="Crouzy S" first="Serge" last="Crouzy">Serge Crouzy</name><affiliation><nlm:aff id="aff3">CNRS UMR 5249 Laboratoire de Chimie et Biologie des Métaux, Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant,</nlm:aff><wicri:noCountry code="subfield">Institut de Recherches en Technologies et Sciences pour le Vivant</wicri:noCountry></affiliation></author><author><name sortKey="Lefebvre, Bertrand" sort="Lefebvre, Bertrand" uniqKey="Lefebvre B" first="Bertrand" last="Lefèbvre">Bertrand Lefèbvre</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Robin, Adeline Y" sort="Robin, Adeline Y" uniqKey="Robin A" first="Adeline Y." last="Robin">Adeline Y. Robin</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation><affiliation wicri:level="3"><nlm:aff wicri:cut=", and" id="aff5">Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</nlm:aff><country wicri:rule="zip">France</country><wicri:regionArea>Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</wicri:regionArea><placeName><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Rhône-Alpes</region><settlement type="city">Grenoble</settlement></placeName></affiliation></author><author><name sortKey="Dumas, Renaud" sort="Dumas, Renaud" uniqKey="Dumas R" first="Renaud" last="Dumas">Renaud Dumas</name><affiliation wicri:level="3"><nlm:aff wicri:cut=", and" id="aff5">Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</nlm:aff><country wicri:rule="zip">France</country><wicri:regionArea>Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</wicri:regionArea><placeName><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Rhône-Alpes</region><settlement type="city">Grenoble</settlement></placeName></affiliation><affiliation><nlm:aff id="aff4">CNRS, UMR 5168, Laboratoire de Physiologie Cellulaire et Végétale,</nlm:aff><wicri:noCountry code="subfield">Laboratoire de Physiologie Cellulaire et Végétale</wicri:noCountry></affiliation></author><author><name sortKey="Matringe, Michel" sort="Matringe, Michel" uniqKey="Matringe M" first="Michel" last="Matringe">Michel Matringe</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation><affiliation wicri:level="3"><nlm:aff wicri:cut=", and" id="aff5">Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</nlm:aff><country wicri:rule="zip">France</country><wicri:regionArea>Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</wicri:regionArea><placeName><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Rhône-Alpes</region><settlement type="city">Grenoble</settlement></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21613226</idno><idno type="pmc">3138293</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138293</idno><idno type="RBID">PMC:3138293</idno><idno type="doi">10.1074/jbc.M111.227595</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">000466</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000466</idno><idno type="wicri:Area/Pmc/Curation">000463</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000463</idno><idno type="wicri:Area/Pmc/Checkpoint">000720</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000720</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">4-Hydroxyphenylpyruvate Dioxygenase Catalysis</title><author><name sortKey="Raspail, Corinne" sort="Raspail, Corinne" uniqKey="Raspail C" first="Corinne" last="Raspail">Corinne Raspail</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation><affiliation wicri:level="3"><nlm:aff wicri:cut=", and" id="aff5">Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</nlm:aff><country wicri:rule="zip">France</country><wicri:regionArea>Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</wicri:regionArea><placeName><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Rhône-Alpes</region><settlement type="city">Grenoble</settlement></placeName></affiliation></author><author><name sortKey="Graindorge, Matthieu" sort="Graindorge, Matthieu" uniqKey="Graindorge M" first="Matthieu" last="Graindorge">Matthieu Graindorge</name><affiliation wicri:level="3"><nlm:aff wicri:cut=", and" id="aff5">Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</nlm:aff><country wicri:rule="zip">France</country><wicri:regionArea>Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</wicri:regionArea><placeName><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Rhône-Alpes</region><settlement type="city">Grenoble</settlement></placeName></affiliation><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Moreau, Yohann" sort="Moreau, Yohann" uniqKey="Moreau Y" first="Yohann" last="Moreau">Yohann Moreau</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff3">CNRS UMR 5249 Laboratoire de Chimie et Biologie des Métaux, Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant,</nlm:aff><wicri:noCountry code="subfield">Institut de Recherches en Technologies et Sciences pour le Vivant</wicri:noCountry></affiliation></author><author><name sortKey="Crouzy, Serge" sort="Crouzy, Serge" uniqKey="Crouzy S" first="Serge" last="Crouzy">Serge Crouzy</name><affiliation><nlm:aff id="aff3">CNRS UMR 5249 Laboratoire de Chimie et Biologie des Métaux, Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant,</nlm:aff><wicri:noCountry code="subfield">Institut de Recherches en Technologies et Sciences pour le Vivant</wicri:noCountry></affiliation></author><author><name sortKey="Lefebvre, Bertrand" sort="Lefebvre, Bertrand" uniqKey="Lefebvre B" first="Bertrand" last="Lefèbvre">Bertrand Lefèbvre</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Robin, Adeline Y" sort="Robin, Adeline Y" uniqKey="Robin A" first="Adeline Y." last="Robin">Adeline Y. Robin</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation><affiliation wicri:level="3"><nlm:aff wicri:cut=", and" id="aff5">Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</nlm:aff><country wicri:rule="zip">France</country><wicri:regionArea>Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</wicri:regionArea><placeName><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Rhône-Alpes</region><settlement type="city">Grenoble</settlement></placeName></affiliation></author><author><name sortKey="Dumas, Renaud" sort="Dumas, Renaud" uniqKey="Dumas R" first="Renaud" last="Dumas">Renaud Dumas</name><affiliation wicri:level="3"><nlm:aff wicri:cut=", and" id="aff5">Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</nlm:aff><country wicri:rule="zip">France</country><wicri:regionArea>Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</wicri:regionArea><placeName><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Rhône-Alpes</region><settlement type="city">Grenoble</settlement></placeName></affiliation><affiliation><nlm:aff id="aff4">CNRS, UMR 5168, Laboratoire de Physiologie Cellulaire et Végétale,</nlm:aff><wicri:noCountry code="subfield">Laboratoire de Physiologie Cellulaire et Végétale</wicri:noCountry></affiliation></author><author><name sortKey="Matringe, Michel" sort="Matringe, Michel" uniqKey="Matringe M" first="Michel" last="Matringe">Michel Matringe</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation><affiliation wicri:level="3"><nlm:aff wicri:cut=", and" id="aff5">Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</nlm:aff><country wicri:rule="zip">France</country><wicri:regionArea>Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble</wicri:regionArea><placeName><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Rhône-Alpes</region><settlement type="city">Grenoble</settlement></placeName></affiliation></author></analytic><series><title level="j">The Journal of Biological Chemistry</title><idno type="ISSN">0021-9258</idno><idno type="eISSN">1083-351X</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>4-Hydroxyphenylpyruvate dioxygenase (HPPD) catalyzes the conversion of 4-hydroxyphenylpyruvate (HPP) into homogentisate. HPPD is the molecular target of very effective synthetic herbicides. HPPD inhibitors may also be useful in treating life-threatening tyrosinemia type I and are currently in trials for treatment of Parkinson disease. The reaction mechanism of this key enzyme in both plants and animals has not yet been fully elucidated. In this study, using site-directed mutagenesis supported by quantum mechanical/molecular mechanical theoretical calculations, we investigated the role of catalytic residues potentially interacting with the substrate/intermediates. These results highlight the following: (i) the central role of Gln-272, Gln-286, and Gln-358 in HPP binding and the first nucleophilic attack; (ii) the important movement of the aromatic ring of HPP during the reaction, and (iii) the key role played by Asn-261 and Ser-246 in C1 hydroxylation and the final ortho-rearrangement steps (numbering according to the <italic>Arabidopsis</italic> HPPD crystal structure 1SQD). Furthermore, this study reveals that the last step of the catalytic reaction, the 1,2 shift of the acetate side chain, which was believed to be unique to the HPPD activity, is also catalyzed by a structurally unrelated enzyme.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Biol Chem</journal-id><journal-id journal-id-type="hwp">jbc</journal-id><journal-id journal-id-type="pmc">jbc</journal-id><journal-id journal-id-type="publisher-id">JBC</journal-id><journal-title-group><journal-title>The Journal of Biological Chemistry</journal-title></journal-title-group><issn pub-type="ppub">0021-9258</issn><issn pub-type="epub">1083-351X</issn><publisher><publisher-name>American Society for Biochemistry and Molecular Biology</publisher-name><publisher-loc>9650 Rockville Pike, Bethesda, MD 20814, U.S.A.</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">21613226</article-id><article-id pub-id-type="pmc">3138293</article-id><article-id pub-id-type="publisher-id">M111.227595</article-id><article-id pub-id-type="doi">10.1074/jbc.M111.227595</article-id><article-categories><subj-group subj-group-type="heading"><subject>Enzymology</subject></subj-group></article-categories><title-group><article-title>4-Hydroxyphenylpyruvate Dioxygenase Catalysis</article-title><subtitle>IDENTIFICATION OF CATALYTIC RESIDUES AND PRODUCTION OF A HYDROXYLATED INTERMEDIATE SHARED WITH A STRUCTURALLY UNRELATED ENZYME<xref ref-type="fn" rid="FN1"><sup><inline-graphic xlink:href="sbox.jpg"></inline-graphic></sup></xref></subtitle><alt-title alt-title-type="short">4-Hydroxyphenylpyruvate Dioxygenase</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Raspail</surname><given-names>Corinne</given-names></name><xref ref-type="aff" rid="aff2"><sup>‡</sup></xref><xref ref-type="aff" rid="aff5"><sup>§</sup></xref><xref ref-type="author-notes" rid="FN2"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Graindorge</surname><given-names>Matthieu</given-names></name><xref ref-type="aff" rid="aff5"><sup>§</sup></xref><xref ref-type="aff" rid="aff1"><sup>¶</sup></xref><xref ref-type="author-notes" rid="FN2"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Moreau</surname><given-names>Yohann</given-names></name><xref ref-type="aff" rid="aff1"><sup>¶</sup></xref><xref ref-type="aff" rid="aff3"><sup>‖</sup></xref></contrib><contrib contrib-type="author"><name><surname>Crouzy</surname><given-names>Serge</given-names></name><xref ref-type="aff" rid="aff3"><sup>‖</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lefèbvre</surname><given-names>Bertrand</given-names></name><xref ref-type="aff" rid="aff6">**</xref></contrib><contrib contrib-type="author"><name><surname>Robin</surname><given-names>Adeline Y.</given-names></name><xref ref-type="aff" rid="aff2"><sup>‡</sup></xref><xref ref-type="aff" rid="aff5"><sup>§</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dumas</surname><given-names>Renaud</given-names></name><xref ref-type="aff" rid="aff5"><sup>§</sup></xref><xref ref-type="aff" rid="aff4"><sup>‡‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Matringe</surname><given-names>Michel</given-names></name><xref ref-type="aff" rid="aff2"><sup>‡</sup></xref><xref ref-type="aff" rid="aff5"><sup>§</sup></xref><xref ref-type="corresp" rid="cor1"><sup>2</sup></xref></contrib><aff id="aff1">From the<label>¶</label>Université Joseph Fourier, Grenoble 1,</aff><aff id="aff2">the<label>‡</label>Institut National de la Recherche Agronomique, UMR 1200, Laboratoire de Physiologie Cellulaire et Végétale,</aff><aff id="aff3"><label>‖</label>CNRS UMR 5249 Laboratoire de Chimie et Biologie des Métaux, Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant,</aff><aff id="aff4"><label>‡‡</label>CNRS, UMR 5168, Laboratoire de Physiologie Cellulaire et Végétale,</aff><aff id="aff5"><label>§</label>Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Physiologie Cellulaire et Végétale, 17 Rue des Martyrs, F-38054 Grenoble, and</aff><aff id="aff6">the<label>**</label>Unité de Biospectrometrie, Centre de Recherches du Service de Santé des Armées, F-38702 La Tronche, France</aff></contrib-group><author-notes><corresp id="cor1"><label>2</label> To whom correspondence should be addressed: <addr-line>Laboratoire de Physiologie Cellulaire et Végétale, Institut de Recherches en Technologies et Sciences pour le Vivant, Institut National de la Recherche Agronomique, UMR 1200, 17 Rue des Martyrs, Grenoble 38054, France.</addr-line> Tel.: <phone>33-4-38-782-358</phone>; Fax: <fax>33-4-38-785-091</fax>; E-mail: <email>mmatringe@cea.fr</email>.</corresp><fn fn-type="equal" id="FN2"><label>1</label><p>Both authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><day>22</day><month>7</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>25</day><month>5</month><year>2011</year></pub-date><volume>286</volume><issue>29</issue><fpage>26061</fpage><lpage>26070</lpage><history><date date-type="received"><day>7</day><month>2</month><year>2011</year></date><date date-type="rev-recd"><day>5</day><month>5</month><year>2011</year></date></history><permissions><copyright-statement>© 2011 by The American Society for Biochemistry and Molecular Biology, Inc.</copyright-statement><copyright-year>2011</copyright-year></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zbc02911026061.pdf"></self-uri><abstract><p>4-Hydroxyphenylpyruvate dioxygenase (HPPD) catalyzes the conversion of 4-hydroxyphenylpyruvate (HPP) into homogentisate. HPPD is the molecular target of very effective synthetic herbicides. HPPD inhibitors may also be useful in treating life-threatening tyrosinemia type I and are currently in trials for treatment of Parkinson disease. The reaction mechanism of this key enzyme in both plants and animals has not yet been fully elucidated. In this study, using site-directed mutagenesis supported by quantum mechanical/molecular mechanical theoretical calculations, we investigated the role of catalytic residues potentially interacting with the substrate/intermediates. These results highlight the following: (i) the central role of Gln-272, Gln-286, and Gln-358 in HPP binding and the first nucleophilic attack; (ii) the important movement of the aromatic ring of HPP during the reaction, and (iii) the key role played by Asn-261 and Ser-246 in C1 hydroxylation and the final ortho-rearrangement steps (numbering according to the <italic>Arabidopsis</italic> HPPD crystal structure 1SQD). Furthermore, this study reveals that the last step of the catalytic reaction, the 1,2 shift of the acetate side chain, which was believed to be unique to the HPPD activity, is also catalyzed by a structurally unrelated enzyme.</p></abstract><kwd-group><kwd>Enzyme Catalysis</kwd><kwd>Enzyme Mutation</kwd><kwd>Enzyme Structure</kwd><kwd>Metabolism</kwd><kwd>Metalloenzymes</kwd><kwd>Dioxygenase</kwd><kwd>QM/MM</kwd></kwd-group></article-meta></front></pmc><affiliations><list><country><li>France</li></country><region><li>Auvergne-Rhône-Alpes</li><li>Rhône-Alpes</li></region><settlement><li>Grenoble</li></settlement></list><tree><noCountry><name sortKey="Crouzy, Serge" sort="Crouzy, Serge" uniqKey="Crouzy S" first="Serge" last="Crouzy">Serge Crouzy</name><name sortKey="Lefebvre, Bertrand" sort="Lefebvre, Bertrand" uniqKey="Lefebvre B" first="Bertrand" last="Lefèbvre">Bertrand Lefèbvre</name><name sortKey="Moreau, Yohann" sort="Moreau, Yohann" uniqKey="Moreau Y" first="Yohann" last="Moreau">Yohann Moreau</name></noCountry><country name="France"><region name="Auvergne-Rhône-Alpes"><name sortKey="Raspail, Corinne" sort="Raspail, Corinne" uniqKey="Raspail C" first="Corinne" last="Raspail">Corinne Raspail</name></region><name sortKey="Dumas, Renaud" sort="Dumas, Renaud" uniqKey="Dumas R" first="Renaud" last="Dumas">Renaud Dumas</name><name sortKey="Graindorge, Matthieu" sort="Graindorge, Matthieu" uniqKey="Graindorge M" first="Matthieu" last="Graindorge">Matthieu Graindorge</name><name sortKey="Matringe, Michel" sort="Matringe, Michel" uniqKey="Matringe M" first="Michel" last="Matringe">Michel Matringe</name><name sortKey="Robin, Adeline Y" sort="Robin, Adeline Y" uniqKey="Robin A" first="Adeline Y." last="Robin">Adeline Y. 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