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J. Biol. Chem., Vol. 280, Issue 29, 27319-27328, July 22, 2005

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Siroheme- and [Fe₄-S₄]-dependent NirA from Mycobacterium tuberculosis Is a Sulfite Reductase with a Covalent Cys-Tyr Bond in the Active Site^*

Robert Schnell, Tatyana Sandalova, Ulf Hellman, Ylva Lindqvist, and Gunter Schneider¶

From the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm S-171 77, Sweden and Ludwig Institute for Cancer Research, Biomedical Centre, Uppsala S-751 24, Sweden

The nirA gene of Mycobacterium tuberculosis is up-regulated in the persistent state of the bacteria, suggesting that it is a potential target for the development of antituberculosis agents particularly active against the pathogen in its dormant phase. This gene encodes a ferredoxin-dependent sulfite reductase, and the structure of the enzyme has been determined using x-ray crystallography. The enzyme is a monomer comprising 555 amino acids and contains a [Fe₄-S₄] cluster and a siroheme cofactor. The molecule is built up of three domains with an / fold. The first domain consists of two ferredoxin-like subdomains, related by a pseudo-2-fold symmetry axis passing through the whole molecule. The other two domains, which provide much of the binding interactions with the cofactors, have a common fold that is unique to the sulfite/nitrite reductase family. The domains form a trilobal structure, with the cofactors and the active site located at the interface of all three domains in the center of the molecule. NirA contains an unusual covalent bond between the side chains of Tyr⁶⁹ and Cys¹⁶¹ in the active site, in close proximity to the siroheme cofactor. Removal of this covalent bond by site-directed mutagenesis impairs catalytic activity, suggesting that it is important for the enzymatic reaction. These residues are part of a sequence fingerprint, able to distinguish between ferredoxin-dependent sulfite and nitrite reductases. Comparison of NirA with the structure of the truncated NADPH-dependent sulfite reductase from Escherichia coli suggests a binding site for the external electron donor ferredoxin close to the [Fe₄-S₄] cluster.

Received for publication, March 8, 2005 , and in revised form, May 4, 2005.

The atomic coordinates and structure factors (code 1zj8 and 1zj9) 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 by European Community Contract QLK2-CT-2002-01682 and the Wallenberg Consortium North. 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.

^¶ To whom correspondence should be addressed: Dept. of Medical Biochemistry and Biophysics, Scheele's väg 2, Karolinska Institutet, Stockholm S-171 77, Sweden. Tel.: 46-8-52487675; Fax: 46-8-327626; E-mail: gunter.schneider{at}mbb.ki.se.

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