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J. Biol. Chem., Vol. 278, Issue 42, 41160-41166, October 17, 2003

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Ebony, a Novel Nonribosomal Peptide Synthetase for -Alanine Conjugation with Biogenic Amines in Drosophila^*

Arnd Richardt , Tobias Kemme , Stefanie Wagner, Dirk Schwarzer , Mohamed A. Marahiel  and Bernhard T. Hovemann ¶

From the Fakultät für Chemie, AG Molekulare Zellbiochemie, Ruhr-Universität Bochum, Universitätsstrasse 150, 44780 Bochum, Germany and Fachbereich Chemie/Biochemie, Philipps-Universität, Hans-Meerwein-Strasse, 35032 Marburg, Germany

Using Ebony protein either expressed in Escherichia coli or in Schneider S2 cells, we provide evidence for its substrate specificity and reaction mechanism. Ebony activates -alanine to aminoacyladenylate by an adenylation domain and covalently attaches it as a thioester to a thiolation domain in a nonribosomal peptide synthetase (NRPS) related mechanism. In a second reaction, biogenic amines act as external nucleophiles on -alanyl-S-pantetheine-Ebony, thereby releasing in a fast reaction the dipeptide (peptidoamine) in a process that is novel in higher eucaryotes. Therefore, we define Ebony as a -alanyl-biogenic amine synthetase. Insight into the reaction mechanism stems from mutational analysis of an invariant serine that disclosed Ebony as a multienzyme with functional analogy to the starting modules of NRPSs. In light of a putative biogenic amine-deactivating capacity, Ebony function in the nervous system must be reconsidered. We propose that in the Drosophila eye Ebony is involved in the transmission process by inactivation of histamine through -alanyl conjugation.

Received for publication, April 24, 2003 , and in revised form, June 11, 2003.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants Ho 714/9-3 (to B. T. H.) and Ma 811/14-2 (to M. A. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^¶ To whom correspondence should be addressed. Tel.: 49-234-3224235; Fax: 49-234-3214105; E-mail: bernhard.hovemann{at}rub.de.

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