ParkinsonFranceV1, Hal, Corpus, bibRecord, 000014

4-hydroxyphenylpyruvate dioxygenase catalysis: identification of catalytic residues and production of a hydroxylated intermediate shared with a structurally unrelated enzyme.

Identifieur interne : 000014 ( Hal/Corpus ); précédent : 000013; suivant : 000015

4-hydroxyphenylpyruvate dioxygenase catalysis: identification of catalytic residues and production of a hydroxylated intermediate shared with a structurally unrelated enzyme.

Auteurs : Corinne Raspail ; Matthieu Graindorge ; Yohann Moreau ; Serge Crouzy ; Bertrand Lefebvre ; Adeline Y. Robin ; Renaud Dumas ; Michel Matringe

Source :

Journal of Biological Chemistry [ 0021-9258 ] ; 2011-05-25.

RBID : Hal:hal-00607269

English descriptors

mix :
- 4-hydroxyphenylpyruvate dioxygenase, HPPD, animal, catalytic activity, catalytic mechanism, enzyme, kinetics, metabolism, plant, shikimate pathway, substrate binding.

Abstract

4-Hydroxyphenylpyruvate dioxygenase (HPPD) catalyzes the conversion of 4-hydroxyphenylpyruvate (HPP) into homogentisate (HGA). 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 being trialled 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 (QM/MM) theoretical calculations, we investigate the role of catalytic residues potentially interacting with the substrate/intermediates. These results highlight, the central role of Q272 Q286 and Q358 in HPP binding and the first nucleophilic attack, the important movement of the aromatic ring of HPP during the reaction and the key role played by N261 and S246 in C1 hydroxylation and the final ortho rearrangement steps. Furthermore, the present 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.

Url:

https://hal.archives-ouvertes.fr/hal-00607269

DOI: 10.1074/jbc.M111.227595

Links to Exploration step

Hal:hal-00607269

Le document en format XML

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<front><div type="abstract" xml:lang="en">4-Hydroxyphenylpyruvate dioxygenase (HPPD) catalyzes the conversion of 4-hydroxyphenylpyruvate (HPP) into homogentisate (HGA). 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 being trialled 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 (QM/MM) theoretical calculations, we investigate the role of catalytic residues potentially interacting with the substrate/intermediates. These results highlight, the central role of Q272 Q286 and Q358 in HPP binding and the first nucleophilic attack, the important movement of the aromatic ring of HPP during the reaction and the key role played by N261 and S246 in C1 hydroxylation and the final ortho rearrangement steps. Furthermore, the present 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.</div>
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            <author role="aut">              <persName>                <forename type="first">Corinne</forename>
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            <author role="aut">              <persName>                <forename type="first">Matthieu</forename>
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            <author role="aut">              <persName>                <forename type="first">Yohann</forename>
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            <author role="aut">              <persName>                <forename type="first">Serge</forename>
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            <author role="aut">              <persName>                <forename type="first">Bertrand</forename>
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            <author role="aut">              <persName>                <forename type="first">Adeline Y</forename>
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            <author role="aut">              <persName>                <forename type="first">Michel</forename>
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            <editor role="depositor">              <persName>                <forename>Jacqueline</forename>
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                  <affiliation ref="#struct-161275"></affiliation>
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                <author role="aut">                  <persName>                    <forename type="first">Adeline Y</forename>
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                <author role="aut">                  <persName>                    <forename type="first">Renaud</forename>
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            <abstract xml:lang="en">4-Hydroxyphenylpyruvate dioxygenase (HPPD) catalyzes the conversion of 4-hydroxyphenylpyruvate (HPP) into homogentisate (HGA). 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 being trialled 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 (QM/MM) theoretical calculations, we investigate the role of catalytic residues potentially interacting with the substrate/intermediates. These results highlight, the central role of Q272 Q286 and Q358 in HPP binding and the first nucleophilic attack, the important movement of the aromatic ring of HPP during the reaction and the key role played by N261 and S246 in C1 hydroxylation and the final ortho rearrangement steps. Furthermore, the present 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.</abstract>
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	La maladie de Parkinson en France (serveur d'exploration)
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La maladie de Parkinson en France (serveur d'exploration)

4-hydroxyphenylpyruvate dioxygenase catalysis: identification of catalytic residues and production of a hydroxylated intermediate shared with a structurally unrelated enzyme.

4-hydroxyphenylpyruvate dioxygenase catalysis: identification of catalytic residues and production of a hydroxylated intermediate shared with a structurally unrelated enzyme.

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