DOI: 10.1110/ps.041163505. Binding of the anti‐tubercular drug isoniazid to the arylamine <i>N</i>‐acetyltransferase protein from <i>Mycobacterium smegmatis</i>

Binding of the anti‐tubercular drug isoniazid to the arylamine N‐acetyltransferase protein from Mycobacterium smegmatis

10.1110/ps.041163505

Crossref journal-article

Wiley

Protein Science (311)

Abstract

AbstractIsoniazid is a frontline drug used in the treatment of tuberculosis (TB). Isoniazid is a prodrug, requiring activation in the mycobacterial cell by the catalase/peroxidase activity of the katG gene product. TB kills two million people every year and the situation is getting worse due to the increase in prevalence of HIV/AIDS and emergence of multidrug‐resistant strains of TB. Arylamine N‐acetyltransferase (NAT) is a drug‐metabolizing enzyme (E.C. 2.1.3.5). NAT can acetylate isoniazid, transferring an acetyl group from acetyl coenzyme A onto the terminal nitrogen of the drug, which in its N‐acetylated form is therapeutically inactive. The bacterium responsible for TB, Mycobacterium tuberculosis, contains and expresses the gene encoding the NAT protein. Isoniazid binds to the NAT protein from Salmonella typhimurium and we report here the mode of binding of isoniazid in the NAT enzyme from Mycobacterium smegmatis, closely related to the M. tuberculosis and S. typhimurium NAT enzymes. The mode of binding of isoniazid to M. smegmatis NAT has been determined using data collected from two distinct crystal forms. We can say with confidence that the observed mode of binding of isoniazid is not an artifact of the crystallization conditions used. The NAT enzyme is active in mycobacterial cells and we propose that isoniazid binds to the NAT enzyme in these cells. NAT activity in M. tuberculosis is likely therefore to modulate the degree of activation of isoniazid by other enzymes within the mycobacterial cell. The structure of NAT with isoniazid bound will facilitate rational drug design for anti‐tubercular therapy.

Bibliography

Sandy, J., Holton, S., Fullam, E., Sim, E., & Noble, M. (2005). Binding of the antiâtubercular drug isoniazid to the arylamine Nâacetyltransferase protein from Mycobacterium smegmatis. Protein Science, 14(3), 775â782. Portico.

Authors 5

James Sandy (first)
Simon Holton (additional)
Elizabeth Fullam (additional)
Edith Sim (additional)
Martin Noble (additional)

References 27 Referenced 50

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{'key': 'e_1_2_6_17_1', 'volume-title': 'Investigation of the catalytic triad of arylamine N‐acetyltransferases: Essential residues required for acetyl transfer to arylamines', 'author': 'Mushtaq A.', 'year': '2004'} / Investigation of the catalytic triad of arylamine N‐acetyltransferases: Essential residues required for acetyl transfer to arylamines by Mushtaq A. (2004)
10.1128/JB.181.4.1343-1347.1999 / J. Bacteriol. / Cloning and characterization of arylamine N‐acetyltransferase genes from Mycobacterium smegmatis and Mycobacterium tuberculosis: Increased expression results in isoniazid resistance by Payton M. (1999)
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10.1038/358591a0

Dates

Type	When
Created	20 years, 6 months ago (Feb. 18, 2005, 2:52 p.m.)
Deposited	1 year, 10 months ago (Oct. 12, 2023, 6:42 p.m.)
Indexed	4 weeks, 2 days ago (Aug. 6, 2025, 9:28 a.m.)
Issued	20 years, 6 months ago (March 1, 2005)
Published	20 years, 6 months ago (March 1, 2005)
Published Online	16 years, 8 months ago (Jan. 1, 2009)
Published Print	20 years, 6 months ago (March 1, 2005)

Funders 0

None

BibTeX

@article{Sandy_2005, title={Binding of the anti‐tubercular drug isoniazid to the arylamine N‐acetyltransferase protein from Mycobacterium smegmatis}, volume={14}, ISSN={1469-896X}, url={http://dx.doi.org/10.1110/ps.041163505}, DOI={10.1110/ps.041163505}, number={3}, journal={Protein Science}, publisher={Wiley}, author={Sandy, James and Holton, Simon and Fullam, Elizabeth and Sim, Edith and Noble, Martin}, year={2005}, month=mar, pages={775–782} }

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