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J. Biol. Chem., Vol. 283, Issue 26, 18450-18460, June 27, 2008

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Pathway for Heme Uptake from Human Methemoglobin by the Iron-regulated Surface Determinants System of Staphylococcus aureus^*

Hui Zhu, Gang Xie, Mengyao Liu, John S. Olson, Marian Fabian, David M. Dooley^¶, and Benfang Lei¹

From the Departments of Veterinary Molecular Biology and ^¶Chemistry and Biochemistry, Montana State University, Bozeman, Montana 59718 and the Department of Biochemistry and Cell Biology and the W. M. Keck Center for Computational Biology, Rice University, Houston, Texas 77005

The iron-regulated surface proteins IsdA, IsdB, and IsdC and transporter IsdDEF of Staphylococcus aureus are involved in heme acquisition. To establish an experimental model of heme acquisition by this system, we have investigated hemin transfer between the various couples of human methemoglobin (metHb), IsdA, IsdB, IsdC, and IsdE by spectroscopic and kinetic analyses. The efficiencies of hemin transfer from hemin-containing donors (holo-protein) to different hemin-free acceptors (apo-protein) were examined, and the rates of the transfer reactions were compared with that of indirect loss of hemin from the relevant donor to H64Y/V68F apomyoglobin. The efficiencies, spectral changes, and kinetics of the transfer reactions demonstrate that: 1) metHb directly transfers hemin to apo-IsdB, but not to apo-IsdA, apo-IsdC, and apo-IsdE; 2) holo-IsdB directly transfers hemin to apo-IsdA and apo-IsdC, but not to apo-IsdE; 3) apo-IsdE directly acquires hemin from holo-IsdC, but not from holo-IsdB and holo-IsdA; and 4) IsdB and IsdC enhance hemin transfer from metHb to apo-IsdC and from holo-IsdB to apo-IsdE, respectively. Taken together with our recent finding that holo-IsdA directly transfers its hemin to apo-IsdC, these results provide direct experimental evidence for a model in which IsdB acquires hemin from metHb and transfers it directly or through IsdA to IsdC. Hemin is then relayed to IsdE, the lipoprotein component of the IsdDEF transporter.

Received for publication, February 22, 2008 , and in revised form, April 17, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants P20 RR-020185 (to B. L.), GM27659 (to D. M. D.), GM35649 (to J. S. O.), and HL47020 (to J. S. O.). This work was also supported by Grant C-0612 from the Robert A. Welch Foundation (to J. S. O.), United States Department of Agriculture NRI/CSREES Grant 2007-35204-18306, Formula Funds, and the Montana State University Agricultural Experimental Station (to B. L.). 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 Figs. S1-S7.

¹ To whom correspondence should be addressed: Dept. of Veterinary Molecular Biology, Montana State University, P.O. Box 173610, Bozeman, MT 59717. Tel.: 406-994-6389; Fax: 406-994-4303; E-mail: blei{at}montana.edu.

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