Structural highlights
Function
[DYR_MYCTU] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid.,Argyrou A, Vetting MW, Aladegbami B, Blanchard JS Nat Struct Mol Biol. 2006 May;13(5):408-13. Epub 2006 Apr 30. PMID:16648861[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Argyrou A, Vetting MW, Aladegbami B, Blanchard JS. Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid. Nat Struct Mol Biol. 2006 May;13(5):408-13. Epub 2006 Apr 30. PMID:16648861 doi:10.1038/nsmb1089
