2CIG

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

2CIG の概要

• エントリーDOI: 10.2210/pdb2cig/pdb
• 関連するPDBエントリー: 1DF7 1DG5 1DG7 1DG8
• 分子名称: DIHYDROFOLATE REDUCTASE, (4R)-ISONICOTINIC-ACETYL-NICOTINAMIDE-ADENINE DINUCLEOTIDE, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: nadp, isoniazid, reductase, inhibitor, bisubstrate, tuberculosis, oxidoreductase, one-carbon metabolism
• 由来する生物種: MYCOBACTERIUM TUBERCULOSIS
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19070.03

構造登録者

Argyrou, A.,Vetting, M.W.,Aladegbami, B.,Blanchard, J.S. (登録日: 2006-03-20, 公開日: 2006-04-25, 最終更新日: 2023-12-13)

主引用文献

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

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: 16648861
DOI: 10.1038/NSMB1089

実験手法

X-RAY DIFFRACTION (1.9 Å)