Aromatic N-hydroxyguanidines as new reduction cosubstrates for dopamine beta-hydroxylase |
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Authors: | Slama Patrick Boucher Jean-Luc Réglier Marius |
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Institution: | Chimie, Biologie et Radicaux libres, UMR-CNRS 6517, Faculté des Sciences et Techniques de Saint-Jérome, case 432, Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France. patrick.slama@iaf.cnrs-gif.fr |
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Abstract: | Conversion of neurotransmitter dopamine into norepinephrine is catalyzed by dopamine beta-hydroxylase (DbH). The reaction requires the presence of both molecular oxygen and a reducing cosubstrate, the assumed physiological cosubstrate being ascorbic acid. We have investigated the ability of a new family of molecules, N-aryl-N'-hydroxyguanidines, to serve as cosubstrates for DbH. N-(4-Methoxyphenyl)-N'-hydroxyguanidine proved to be an efficient reducing agent for DbH. The complete N-hydroxyguanidine moiety was required for activity, as any modification of this function resulted in non-cosubstrate compounds. Moreover, analysis of the products formed from N-(4-methoxyphenyl)-N'-hydroxyguanidine showed that the main oxidation product was a nitrosoimine. Modification of the aromatic para-substituent evidenced an influence of its electronic properties on the catalytic activity whereas steric factors seemed less important. In addition, changing the methoxy-substituent from the para- to the ortho-position led to an inactive compound. Our results demonstrate that N-aryl-N'-hydroxyguanidines are new efficient reducing cosubstrates for DbH and prove that specific interactions with the reducing cosubstrate do take place at the active site of the enzyme. |
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Keywords: | Dopamine β-hydroxylase N-Hydroxyguanidines Copper centers Reduction Nitrosoimine |
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