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J. Biol. Chem., Vol. 283, Issue 19, 13140-13147, May 9, 2008

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Bacterial Nitric-oxide Synthases Operate without a Dedicated Redox Partner^*

Ivan Gusarov, Marina Starodubtseva, Zhi-Qiang Wang, Lindsey McQuade^¶, Stephen J. Lippard^¶, Dennis J. Stuehr^||, and Evgeny Nudler¹

From the Department of Biochemistry, New York University School of Medicine, New York, New York 10016, Department of Chemistry, Kent State University-Tuscarawas, New Philadelphia, Ohio 44663, ^¶Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and ^||Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195

Bacterial nitric-oxide (NO) synthases (bNOSs) are smaller than their mammalian counterparts. They lack an essential reductase domain that supplies electrons during NO biosynthesis. This and other structural peculiarities have raised doubts about whether bNOSs were capable of producing NO in vivo. Here we demonstrate that bNOS enzymes from Bacillus subtilis and Bacillus anthracis do indeed produce NO in living cells and accomplish this task by hijacking available cellular redox partners that are not normally committed to NO production. These "promiscuous" bacterial reductases also support NO synthesis by the oxygenase domain of mammalian NOS expressed in Escherichia coli. Our results suggest that bNOS is an early precursor of eukaryotic NOS and that it acquired its dedicated reductase domain later in evolution. This work also suggests that alternatively spliced forms of mammalian NOSs lacking their reductase domains could still be functional in vivo. On a practical side, bNOS-containing probiotic bacteria offer a unique advantage over conventional chemical NO donors in generating continuous, readily controllable physiological levels of NO, suggesting a possibility of utilizing such live NO donors for research and clinical needs.

Received for publication, December 13, 2007 , and in revised form, February 12, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Director's Pioneer Award (to E. N.) and by NIGMS, National Institutes of Health Grant GM65519 (to S. J. 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 Fig. S1 and Table S1.

¹ To whom correspondence should be addressed: 550 First Ave., MSB359, NY, NY 10016. Fax: 212-263-8166; E-mail: evgeny.nudler{at}med.nyu.edu.

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