2CIG: Dihydrofolate reductase from Mycobacterium tuberculosis inhibited by the acyclic 4R isomer of INH-NADP a derivative of the prodrug isoniazid

Citation:
Abstract
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.
PDB ID: 2CIGDownload
MMDB ID: 38622
PDB Deposition Date: 2006/3/20
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 1.9  Å
Source Organism:
Similar Structures:
Biological Unit for 2CIG: monomeric; determined by author and by software (PQS)
Molecular Components in 2CIG
Label Count Molecule
Protein (1 molecule)
1
Dihydrofolate Reductase
Molecule annotation
Chemicals (7 molecules)
1
1
2
4
3
2
* Click molecule labels to explore molecular sequence information.

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