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Arylamine N-acetyltransferases in mycobacteria

DOI: 10.2174/138920008784892100 DOI Help
PMID: 18680471 PMID Help

Authors: E. Sim (University of Oxford) , J. Sandy (University of Oxford; Birkbeck University of London) , D. Evangelopoulos (University of Oxford) , E. Fullam (University of Oxford) , S. Bhakta (University of Oxford) , A. Krylova (University of Oxford) , M. Noble (University of Oxford) , N. Lack (University of Oxford) , I. Westwood (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Current Drug Metabolism , VOL 9 (6) , PAGES 510-9

State: Published (Approved)
Published: July 2008

Abstract: Polymorphic Human arylamine N-acetyltransferase (NAT2) inactivates the anti-tubercular drug isoniazid by acetyltransfer from acetylCoA. There are active NAT proteins encoded by homologous genes in mycobacteria including M. tuberculosis, M. bovis BCG, M. smegmatis and M. marinum. Crystallographic structures of NATs from M. smegmatis and M. marinum, as native enzymes and with isoniazid bound share a similar fold with the first NAT structure, Salmonella typhimurium NAT. There are three approximately equal domains and an active site essential catalytic triad of cysteine, histidine and aspartate in the first two domains. An acetyl group from acetylCoA is transferred to cysteine and then to the acetyl acceptor e.g. isoniazid. M. marinum NAT binds CoA in a more open mode compared with CoA binding to human NAT2. The structure of mycobacterial NAT may promote its role in synthesis of cell wall lipids, identified through gene deletion studies. NAT protein is essential for survival of M. bovis BCG in macrophage as are the proteins encoded by other genes in the same gene cluster (hsaA-D). HsaA-D degrade cholesterol, essential for mycobacterial survival inside macrophage. Nat expression remains to be fully understood but is co-ordinated with hsaA-D and other stress response genes in mycobacteria. Amide synthase genes in the streptomyces are also nat homologues. The amide synthases are predicted to catalyse intramolecular amide bond formation and creation of cyclic molecules, e.g. geldanamycin. Lack of conservation of the CoA binding cleft residues of M. marinum NAT suggests the amide synthase reaction mechanism does not involve a soluble CoA intermediate during amide formation and ring closure. - See more at:

Journal Keywords: Isoniazid; Tuberculosis; M. Smegmatis; M. Marinum; Arylamine

Diamond Keywords: Tuberculosis (TB); Bacteria

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: NONE-No attached Diamond beamline

Added On: 19/08/2009 23:07

Discipline Tags:

Biochemistry Chemistry Life Sciences & Biotech

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