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J. Biol. Chem., Vol. 281, Issue 2, 1224-1232, January 13, 2006

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Crystal Structure of an Archaeal Pentameric Riboflavin Synthase in Complex with a Substrate Analog Inhibitor

STEREOCHEMICAL IMPLICATIONS^*

Arne Ramsperger12, Martin Augustin13, Ann-Kathrin Schott4, Stefan Gerhardt4, Tobias Krojer5, Wolfgang Eisenreich, Boris Illarionov, Mark Cushman¶, Adelbert Bacher, Robert Huber, and Markus Fischer6

From the Max-Planck-Institut für Biochemie, Abteilung für Strukturforschung, Am Klopferspitz 18, D-82152 Martinsried, Germany, the Lehrstuhl für Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany, and the ^¶Department of Medicinal Chemistry and Pharmacology, Purdue University, West Lafayette, Indiana 47907

Whereas eubacterial and eukaryotic riboflavin synthases form homotrimers, archaeal riboflavin synthases from Methanocaldococcus jannaschii and Methanothermobacter thermoautrophicus are homopentamers with sequence similarity to the 6,7-dimethyl-8-ribityllumazine synthase catalyzing the penultimate step in riboflavin biosynthesis. Recently it could be shown that the complex dismutation reaction catalyzed by the pentameric M. jannaschii riboflavin synthase generates riboflavin with the same regiochemistry as observed for trimeric riboflavin synthases. Here we present crystal structures of the pentameric riboflavin synthase from M. jannaschii and its complex with the substrate analog inhibitor, 6,7-dioxo-8-ribityllumazine. The complex structure shows five active sites located between adjacent monomers of the pentamer. Each active site can accommodate two substrate analog molecules in anti-parallel orientation. The topology of the two bound ligands at the active site is well in line with the known stereochemistry of a pentacyclic adduct of 6,7-dimethyl-8-ribityllumazine that has been shown to serve as a kinetically competent intermediate. The pentacyclic intermediates of trimeric and pentameric riboflavin synthases are diastereomers.

Received for publication, August 26, 2005 , and in revised form, October 26, 2005.

The atomic coordinates and structure factors (code 2B98 (native enzyme) and 2B99 (DORL complex) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Institutes of Health Grant UO1 CA89566 as well as by support from grants from the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, and the Hans-Fischer-Gesellschaft. 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.

¹ These authors have contributed equally to this work.

³ Present address: Proteros Biostructures GmbH, Am Klopferspitz 19, D-82152 Martinsried, Germany.

⁴ Present address: AstraZeneca, Protein Structure Laboratory, 26F14 Mereside, Alderley Park, Macclesfield SK104TG, England.

⁵ Present address: Inst. für Molekulare Pathologie (IMP), Dr. Bohrgasse 7, A-1030 Wien, Austria.

² To whom correspondence may be addressed. Tel.: 49-89-8578-2678; Fax: 49-89-8578-3516; E-mail: ramsperg{at}biochem.mpg.de.

⁶ To whom correspondence may be addressed. Tel.: 49-89-289-13336; Fax: 49-89-289-13363; E-mail: markus.fischer{at}ch.tum.de.

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