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Papers In Press, published online ahead of print May 24, 2005
J. Biol. Chem, 10.1074/jbc.M502560200
Submitted on March 8, 2005
Revised on May 4, 2005
Accepted on May 24, 2005
Dep Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm 171 77
Corresponding Author: gunter.schneider{at}mbb.ki.se
The nirA gene of Mycobacterium tuberculosis is upregulated 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 a/ß fold. The first domain consists of two ferredoxin-like subdomains, related by a pseudo-twofold 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.
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