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J. Biol. Chem., Vol. 280, Issue 20, 19563-19568, May 20, 2005

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Chemical Synthesis of (S)-4,5-Dihydroxy-2,3-pentanedione, a Bacterial Signal Molecule Precursor, and Validation of Its Activity in Salmonella typhimurium^*

Sigrid C. J. De Keersmaecker, Csaba Varszegi, Nadja van Boxel, Lothar W. Habel, Kristine Metzger, Ruth Daniels, Kathleen Marchal, Dirk De Vos, and Jos Vanderleyden¶

From the Centre of Microbial and Plant Genetics and the Centre for Surface Chemistry and Catalysis, K. U. Leuven, Kasteelpark Arenberg 23, B-3001 Leuven, Belgium

We describe an original, short, and convenient chemical synthesis of enantiopure (S)-4,5-dihydroxy-2,3-pentanedione (DPD), starting from commercial methyl (S)-(-)-2,2-dimethyl-1,3-dioxolane-4-carboxylate. DPD is the precursor of autoinducer (AI)-2, the proposed signal for bacterial interspecies communication. AI-2 is synthesized by many bacterial species in three enzymatic steps. The last step, a LuxS-catalyzed reaction, leads to the formation of DPD, which spontaneously cyclizes into AI-2. AI-2-like activity of the synthesized molecule was ascertained by the Vibrio harveyi bioassay. To further validate the biological activity of synthetic DPD and to explore its potential in studying DPD (AI-2)-mediated signaling, a Salmonella typhimurium luxS mutant was constructed. Expression of the AI-2 regulated lsr operon can be rescued in this luxS mutant by addition of synthetic DPD or genetic complementation. Biofilm formation by S. typhimurium has been reported to be defective in a luxS mutant, and this was confirmed in this study to test DPD for chemical complementation. However, biofilm formation of the luxS mutant cannot be restored by addition of DPD. In contrast, introduction of luxS under control of its own promoter complemented biofilm formation. Further results demonstrated that biofilm formation of the luxS mutant cannot be restored with luxS under control of the strong nptII promoter. This indicates that altering the intrinsic promoter activity of luxS affects Salmonella biofilm formation. Conclusively, we synthesized biologically active DPD. Using this chemical compound in combination with genetic approaches opens new avenues in studying AI-2-mediated signaling.

Received for publication, November 9, 2004 , and in revised form, March 23, 2005.

^* This work was supported by IWT-projects GBOU-SQUAD-20160 and BLO-20428 (the Ministry of the Flemish Community) and by IAP-P5/03. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

^¶ To whom correspondence should be addressed. Tel.: 32-16321631; Fax: 32-16321963; E-mail: jozef.vanderleyden{at}biw.kuleuven.be.

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