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J. Biol. Chem., Vol. 282, Issue 28, 20425-20434, July 13, 2007

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The 1.8 Å Crystal Structure of PA2412, an MbtH-like Protein from the Pyoverdine Cluster of Pseudomonas aeruginosa^*

Eric J. Drake, Jin Cao^¶, Jun Qu^¶||, Manish B. Shah, Robert M. Straubinger^¶||, and Andrew M. Gulick¹

From the Hautpman-Woodward Medical Research Institute, the Department of Structural Biology, University at Buffalo, State University of New York, the ^¶New York State Center of Excellence in Bioinformatics and Life Sciences, and the ^||Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14203-1196

Many bacteria use nonribosomal peptide synthetase (NRPS) proteins to produce peptide antibiotics and siderophores. The catalytic domains of the NRPS proteins are usually linked in large multidomain proteins. Often, additional proteins are coexpressed with NRPS proteins that modify the NRPS peptide products, ensure the availability of substrate building blocks, or play a role in the import or export of the NRPS product. Many NRPS clusters include a small protein of 80 amino acids with homology to the MbtH protein of mycobactin synthesis in Mycobacteria tuberculosis; no function has been assigned to these proteins. Pseudomonas aeruginosa utilizes an NRPS cluster to synthesize the siderophore pyoverdine. The pyoverdine peptide contains a dihydroxyquinoline-based chromophore, as well as two formyl-N-hydroxyornithine residues, which are involved in iron binding. The pyoverdine cluster contains four modular NRPS enzymes and 10–15 additional proteins that are essential for pyoverdine production. Coexpressed with the pyoverdine synthetic enzymes is a 72-amino acid MbtH-like family member designated PA2412. We have determined the three-dimensional structure of the PA2412 protein and describe here the structure and the location of conserved regions. Additionally, we have further analyzed a deletion mutant of the PA2412 protein for growth and pyoverdine production. Our results demonstrate that PA2412 is necessary for the production or secretion of pyoverdine at normal levels. The PA2412 deletion strain is able to use exogenously produced pyoverdine, showing that there is no defect in the uptake or utilization of the iron-pyoverdine complex.

Received for publication, December 26, 2006 , and in revised form, May 10, 2007.

The atomic coordinates and structure factors (code 2PST) 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 in part by pilot funds from the Dreamcatcher Foundation (Buffalo, NY) and by National Institutes of Health Grant GM-068440 (to A. M. G.) and an unrestricted gift of the Kapoor Charitable Foundation to the University at Buffalo School of Pharmacy and Pharmaceutical Sciences. This work is also based upon research conducted at the Cornell High Energy Synchrotron Source (CHESS), which was supported by National Science Foundation Award DMR 0225180 and by the National Institutes of Health through its National Center for Research Resources under Award 5P51 RR001646-23. This work was also supported in part by Shared Instrument Grants S10-RR014592, S10-RR021221, and S10-RR023650 from the National Center for Research Resources, National Institutes of Health. 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 To whom correspondence should be addressed: Hautpman-Woodward Medical Research Institute, 700 Ellicott St., Buffalo, NY 14203-1196. Tel.: 716-898-8619; Fax: 716-898-8660; E-mail: gulick{at}hwi.buffalo.edu.

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