2cig: Difference between revisions
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==Overview== | ==Overview== | ||
Isoniazid is a key drug used in the treatment of tuberculosis. Isoniazid, is a pro-drug, which, after activation by the katG-encoded catalase, peroxidase, reacts nonenzymatically with NAD(+) and NADP(+) to generate, several isonicotinoyl adducts of these pyridine nucleotides. One of these, the acyclic 4S isomer of isoniazid-NAD, targets the inhA-encoded enoyl-ACP, reductase, an enzyme essential for mycolic acid biosynthesis in, Mycobacterium tuberculosis. Here we show that the acyclic 4R isomer of, isoniazid-NADP inhibits the M. tuberculosis dihydrofolate reductase, (DHFR), an enzyme essential for nucleic acid synthesis. This biologically, relevant form of the isoniazid adduct is a subnanomolar bisubstrate, inhibitor of M. tuberculosis DHFR. Expression of M. tuberculosis DHFR in, ... | Isoniazid is a key drug used in the treatment of tuberculosis. Isoniazid, is a pro-drug, which, after activation by the katG-encoded catalase, peroxidase, reacts nonenzymatically with NAD(+) and NADP(+) to generate, several isonicotinoyl adducts of these pyridine nucleotides. One of these, the acyclic 4S isomer of isoniazid-NAD, targets the inhA-encoded enoyl-ACP, reductase, an enzyme essential for mycolic acid biosynthesis in, Mycobacterium tuberculosis. Here we show that the acyclic 4R isomer of, isoniazid-NADP inhibits the M. tuberculosis dihydrofolate reductase, (DHFR), an enzyme essential for nucleic acid synthesis. This biologically, relevant form of the isoniazid adduct is a subnanomolar bisubstrate, inhibitor of M. tuberculosis DHFR. Expression of M. tuberculosis DHFR in, Mycobacterium smegmatis mc(2)155 protects cells against growth inhibition, by isoniazid by sequestering the drug. Thus, M. tuberculosis DHFR is the, first new target for isoniazid identified in the last decade. | ||
==About this Structure== | ==About this Structure== | ||
2CIG is a | 2CIG is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis] with SO4, 1DG and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2CIG OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: tuberculosis]] | [[Category: tuberculosis]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 15:16:25 2007'' | ||
