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J. Biol. Chem., Vol. 278, Issue 23, 20687-20694, June 6, 2003

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The Treponema pallidum tro Operon Encodes a Multiple Metal Transporter, a Zinc-dependent Transcriptional Repressor, and a Semi-autonomously Expressed Phosphoglycerate Mutase^*,

Karsten R. O. Hazlett  , Frank Rusnak ¶ , David G. Kehres ||, Scott W. Bearden ** , Carson J. La Vake , Morgan E. La Vake , Michael E. Maguire ||, Robert D. Perry ** and Justin D. Radolf  

From the Center for Microbial Pathogenesis and Departments of Medicine and Genetics & Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06030-3710, the ^¶Department of Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, the ^||Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, and the ^**Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky 40536

The Treponema pallidum tro operon encodes an ABC transporter (TroABCD), a transcriptional repressor (TroR), and the essential glycolytic enzyme phosphoglycerate mutase (Gpm). The apparently discordant observations that the solute binding protein (TroA) binds Zn²⁺, whereas DNA binding by TroR in vitro is Mn²⁺-dependent, have generated uncertainty regarding the identities of the ligand(s) and co-repressor(s) of the permease. Moreover, this operonic structure suggests that Gpm expression, and hence glycolysis, the sole source of ATP for the bacterium, would be suspended during TroR-mediated repression. To resolve these discrepancies, we devised an experimental strategy permitting a more direct assessment of Tro operon function and regulation. We report that (i) apo-TroA has identical affinities for Zn²⁺ and Mn²⁺; (ii) the Tro transporter expressed in Escherichia coli imports Zn²⁺, Mn²⁺, and possibly iron; (iii) TroR represses transporter expression in E. coli at significantly lower concentrations of Zn²⁺ than of Mn²⁺; and (iv) TroR-mediated repression causes a disproportionately greater down-regulation of the transporter genes than of gpm. The much higher concentrations of Zn²⁺ than of Mn²⁺ in human body fluids suggests that Zn²⁺ is both the primary substrate and co-repressor of the permease in vivo. Our data also indicate that Gpm expression and, therefore, glycolysis would not be abrogated when T. pallidum encounters high Zn²⁺ levels.

Received for publication, January 23, 2003 , and in revised form, March 31, 2003.

This paper is dedicated to our friend and colleague, Frank Rusnak, who passed on September 7, 2002. Frank selflessly offered his time, guidance, encouragement, and wisdom to all he met. We will greatly miss you, Frank.

^* This work was supported in part by National Institutes of Health Grants AI-10573 (to K. R. O. H.), AI-26756 (to J. D. R.), AI25098 (to R. D. P.), and GM61748 (to M. E. M.) and by funds from the Mayo Foundation (to F. R.). 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 a supplemental table and supplemental figures.

Deceased.

Present address: Div. of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, CO 80521.

To whom correspondence should be addressed: Center for Microbial Pathogenesis, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030-3710. Tel.: 860-679-8391; Fax: 860-679-8130; E-mail: KHazlett{at}up.uchc.edu.

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