Arylamine N-acetyltransferase of Mycobacterium tuberculosis is a polymorphic enzyme and a site of isoniazid metabolism.

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Upton AM, Mushtaq A, Victor TC, Sampson SL, Sandy J, Smith DM, van Helden PV, Sim E

Arylamine N-acetyltransferase of Mycobacterium tuberculosis is a polymorphic enzyme and a site of isoniazid metabolism.

Mol Microbiol. 2001 Oct;42(2):309-17.

PubMed ID

11703656 [ View in PubMed

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Abstract

Arylamine N-acetyltransferases (NATs; E.C 2.3.1.5) N-acetylate arylhydralazine and arylamine substrates using acetyl coenzyme A. Human NAT2 acetylates and inactivates the antituberculosis drug, isoniazid (INH), and is polymorphic. We previously demonstrated that there is a homologue of human NAT2 in Mycobacterium tuberculosis, whose product N-acetylates INH in vitro. We now demonstrate that the nat gene is expressed in M. tuberculosis and M. bovis Bacille Calmette-Guerin (BCG), using reverse transcription-polymerase chain reaction and Western blotting. The NAT protein is active in M. bovis BCG in vivo, as detected by the presence of N-acetyl INH in M. bovis BCG lysates grown in INH. Sequence analysis of the M. tuberculosis nat coding region reveals a single nucleotide polymorphism in 18% of a random cohort of M. tuberculosis clinical isolates, conferring a G to R change. The recombinant mutant protein appears less stable than the wild type, and has an apparent affinity for INH of 10-fold less than the wild type. Modelling the change in M. tuberculosis NAT shows that the G to R change is close to the active site, and supports the experimental findings. Minimum inhibitory concentration data suggest that this polymorphism in nat is linked to low-level changes in the INH susceptibility of M. tuberculosis clinical isolates.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Isoniazid	Arylamine N-acetyltransferase	Protein	Mycobacterium tuberculosis	Unknown	Inhibitor	Details
Isoniazid	Arylamine N-acetyltransferase 2	Protein	Humans	Unknown	Substrate	Details