Model Studies of TTQ-Containing Amine Dehydrogenases

Shinobu Itoh, Naoki Takada, Shigenobu Haranou, Takeya Ando, Mitsuo Komatsu, Yoshiki Ohshiro, Shunichi Fukuzumi

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The reactions of a TTQ model compound [1,3-methyl-4-(3′-methylindol-2′-yl)indole-6,7-dione] with several amines have been investigated in organic media to obtain mechanistic information on the action of quinoprotein methylamine and aromatic amine dehydrogenases. It has been found that compound 1 acts as an efficient catalyst for the autorecycling oxidation of benzylamine by molecular oxygen in CH3OH. In order to evaluate the oxidation mechanism of amines by 1, the product analyses and kinetic studies have been carried out under anaerobic conditions. In the first stage of the reaction of 1 with amines, 1 is converted into an iminoquinone-type adduct (so-called substrate imine), which was isolated and characterized by using cyclopropylamine as a substrate. The observed NOE of the isolated product indicates clearly that the addition position of the amine is C-6 of the quinone. The molecular orbital calculations suggest that the thermodynamic stability of the carbinolamine intermediate is a major factor to determine such regioselectivity; the C-6 carbinolamine is more stable than the C-7 counterpart by 2.9 kcal/mol. The reactivity of several primary amines and the electronic effect of the p-substituents of benzylamine derivatives in the iminoquinone formation suggest that the addition step of the amine to the quinone is rate-determining. When amines having an acidic α-proton such as benzylamine derivatives are employed as substrates, formation of the iminoquinone adduct was followed by rearrangement to the product imine. The kinetic analysis has revealed that this rearrangement consists of noncatalyzed and general base-catalyzed processes. Large kinetic isotope effects of 7.8 and 9.2 were observed for both the noncatalyzed and general base-catalyzed processes, respectively, since these steps involve a proton abstraction from the α-position of the substrate. In the reaction with benzhydrylamine, the product imine was isolated quantitatively and well characterized by several spectroscopic data. In the case of benzylamine, the product imine is further converted into the aminophenol derivative by the imine exchange reaction with excess benzylamine. These results indicate clearly that the amine oxidation by compound 1 proceeds via a transamination mechanism as suggested for the enzymatic oxidation of amines by TTQ cofactor.

Original languageEnglish
Pages (from-to)8967-8974
Number of pages8
JournalJournal of Organic Chemistry
Issue number25
StatePublished - 1996


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