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Title

Isonicotinic acid hydrazide conversion to isonicotinyl-NAD by catalase-peroxidases

AuthorsWiseman, Ben; Carpena, Xavi ; Feliz, Miguel; Donald, Lynda J.; Pons, Miquel; Fita, Ignacio ; Loewen, Peter C.
Issue Date2010
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 285: 26662-26673 (2010)
AbstractActivation of the pro-drug isoniazid (INH) as an anti-tubercular drug in Mycobacterium tuberculosis involves its conversion to isonicotinyl-NAD, a reaction that requires the catalase-peroxidase KatG. This report shows that the reaction proceeds in the absence of KatG at a slow rate in a mixture of INH, NAD+, Mn2+, and O2, and that the inclusion of KatG increases the rate by >7 times. Superoxide, generated by either Mn 2+- or KatG-catalyzed reduction of O2, is an essential intermediate in the reaction. Elimination of the peroxidatic process by mutation slows the rate of reaction by 60% revealing that the peroxidatic process enhances, but is not essential for isonicotinyl-NAD formation. The isonicotinyl-NAD.+ radical is identified as a reaction intermediate, and its reduction by superoxide is proposed. Binding sites for INH and its co-substrate, NAD+, are identified for the first time in crystal complexes of Burkholderia pseudomallei catalase-peroxidase with INH and NAD + grown by co-crystallization. The best defined INH binding sites were identified, one in each subunit, on the opposite side of the protein from the entrance to the heme cavity in a funnel-shaped channel. The NAD+ binding site is ∼20 Å from the entrance to the heme cavity and involves interactions primarily with the AMP portion of the molecule in agreement with the NMR saturation transfer difference results. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
URIhttp://hdl.handle.net/10261/53156
DOI10.1074/jbc.M110.139428
Identifiersdoi: 10.1074/jbc.M110.139428
issn: 0021-9258
e-issn: 1083-351X
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