NDLI: Mode of Binding of the Tuberculosis Prodrug Isoniazid to Heme Peroxidases

Content Provider	PubMed Central
Author	Singh, Amit K. Kumar, Ramasamy P. Pandey, Nisha Singh, Nagendra Sinha, Mau Bhushan, Asha Kaur, Punit Sharma, Sujata Singh, Tej P.
Abstract	Isoniazid (INH) is an anti-tuberculosis prodrug that is activated by mammalian lactoperoxidase and Mycobacterium tuberculosis catalase peroxidase (MtCP). We report here binding studies, an enzyme assay involving INH, and the crystal structure of the complex of bovine lactoperoxidase (LPO) with INH to illuminate binding properties and INH activation as well as the mode of diffusion and interactions together with a detailed structural and functional comparison with MtCP. The structure determination shows that isoniazid binds to LPO at the substrate binding site on the distal heme side. The substrate binding site is connected to the protein surface through a long hydrophobic channel. The acyl hydrazide moiety of isoniazid interacts with Phe422 O, Gln423 Oϵ1, and Phe254 O. In this arrangement, pyridinyl nitrogen forms a hydrogen bond with a water molecule, W-1, which in turn forms three hydrogen bonds with Fe3+, His109 Nϵ2, and Gln105 Nϵ2. The remaining two sides of isoniazid form hydrophobic interactions with the atoms of heme pyrrole ring A, Cβ and Cγ atoms of Glu258, and Cγ and Cδ atoms of Arg255. The binding studies indicate that INH binds to LPO with a value of 0.9 × 10−6 m for the dissociation constant. The nitro blue tetrazolium reduction assay shows that INH is activated by the reaction of LPO-H2O2 with INH. This suggests that LPO can be used for INH activation. It also indicates that the conversion of INH into isonicotinoyl radical by LPO may be the cause of INH toxicity.
Related Links	http://dx.doi.org/10.1074/jbc.m109.060327
Ending Page	1576
Page Count	8
Starting Page	1569
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	2
Volume Number	285
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2010-01-08
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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