2CIG
Dihydrofolate reductase from Mycobacterium tuberculosis inhibited by the acyclic 4R isomer of INH-NADP a derivative of the prodrug isoniazid.
Summary for 2CIG
| Entry DOI | 10.2210/pdb2cig/pdb |
| Related | 1DF7 1DG5 1DG7 1DG8 |
| Descriptor | DIHYDROFOLATE REDUCTASE, (4R)-ISONICOTINIC-ACETYL-NICOTINAMIDE-ADENINE DINUCLEOTIDE, GLYCEROL, ... (5 entities in total) |
| Functional Keywords | nadp, isoniazid, reductase, inhibitor, bisubstrate, tuberculosis, oxidoreductase, one-carbon metabolism |
| Biological source | MYCOBACTERIUM TUBERCULOSIS |
| Total number of polymer chains | 1 |
| Total formula weight | 19070.03 |
| Authors | Argyrou, A.,Vetting, M.W.,Aladegbami, B.,Blanchard, J.S. (deposition date: 2006-03-20, release date: 2006-04-25, Last modification date: 2023-12-13) |
| Primary citation | Argyrou, A.,Vetting, M.W.,Aladegbami, B.,Blanchard, J.S. Mycobacterium Tuberculosis Dihydrofolate Reductase is a Target for Isoniazid Nat.Struct.Mol.Biol., 13:408-413, 2006 Cited by PubMed 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. PubMed: 16648861DOI: 10.1038/NSMB1089 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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