A Model Compound of Novel Cofactor Tryptophan Tryptophylquinone of Bacterial Methylamine Dehydrogenases. Synthesis and Physicochemical Properties

Shinobu Itoh, Masaki Ogino, Shigenobu Haranou, Tadashi Terasaka, Takeva Ando, Mitsuo Komatsu, Yoshiki Ohshiro, Shunichi Fukuzumi, Kenji Kano, Kazuyoshi Takagi, Tokuji Ikeda

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Abstract

The synthesis and physicochemical characterization of the model compound (1) of novel cofactor TTQ (tryptophan tryptophylquinone), the active center of bacterial methylamine dehydrogenases (MADH), are described. The synthesis of compound 1 [3-methyl-4-(3’-methylindol-2’-yl)indole-6,7-dione] has been accomplished by starting with 2-carbomethoxy-3-methyl-7-methoxyindole (2) as follows. Friedel—Crafts acylation on 2 with propionyl chloride gave the 4-acylated compound, which was converted into 3-methyl-4-propionyl-7-methoxyindole (5) by ester hydrolysis followed by thermal decarboxylation. Construction of the second indole ring by Fischer indolization with phenylhydrazine hydrochloride, followed by deprotection of the methoxy group, gave 7-hydroxy derivative 7, which was finally converted into model compound 1 by oxidation with Fremy’s salt. Another simple pathway mimicking one of the postulated biosynthetic routes was also investigated; hydroxyskatoles were oxidized into a 6,7-indolequinone derivative and then coupled with skatole itself using AlCl3 as a catalyst to give 1. Strong resemblances in several spectroscopic properties and in molecular geometry exist between 1 and TTQ cofactor in MADH. Compound 1 exhibits a pair of reversible waves ascribed to a two-electron redox reaction of the quinoid moiety. At pH 7.0, the formal potential vs NHE is 0.107 V, which is close to that of the native enzyme (0.126 V). The spectroscopic titration and the formal potential measurements were employed to determine the pKa values of 1 (10.6-10.9) and its reduced form 1H2 (10.1). Detailed digital simulation analysis of the voltammograms has revealed a two-step one-electron transfer mechanism via its semiquinone radical (1·-), allowing for the evaluation of the two one-electron redox potentials. The EPR spectroscopic measurements suggest a partial π-conjugation between the two indole rings and a nonrigid conformation. Reaction of 1 with free ammonia leads to iminoquinone 13, which is reduced electrochemically at a more positive electrode potential than 1. The thermodynamics and kinetics of the iminoquinone formation are also reported in detail. Generation of a radical species derived from 13 and its stability in comparison with 1·- were also examined electrochemically and by EPR measurements.

Original languageEnglish
Pages (from-to)1485-1493
Number of pages9
JournalJournal of the American Chemical Society
Volume117
Issue number5
DOIs
StatePublished - 1995

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