Probing the architecture of the Mycobacterium marinum arylamine N-acetyltransferase active site.
10.1007/s13238-010-0037-7
- Author:
Areej M ABUHAMMAD
1
;
Edward D LOWE
2
;
Elizabeth FULLAM
1
;
Martin NOBLE
2
;
Elspeth F GARMAN
2
;
Edith SIM
3
Author Information
1. Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
2. Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
3. Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK. edith.sim@pharm.ox.ac.uk.
- Publication Type:Journal Article
- MeSH:
Acetyltransferases;
metabolism;
Arylamine N-Acetyltransferase;
chemistry;
genetics;
metabolism;
Catalysis;
Catalytic Domain;
Crystallization;
Mycobacterium;
enzymology;
metabolism;
Mycobacterium marinum;
enzymology;
Mycobacterium tuberculosis;
enzymology;
genetics;
metabolism;
Protein Binding
- From:
Protein & Cell
2010;1(4):384-392
- CountryChina
- Language:English
-
Abstract:
Treatment of latent tuberculosis infection remains an important goal of global TB eradication. To this end, targets that are essential for intracellular survival of Mycobacterium tuberculosis are particularly attractive. Arylamine N-acetyltransferase (NAT) represents such a target as it is, along with the enzymes encoded by the associated gene cluster, essential for mycobacterial survival inside macrophages and involved in cholesterol degradation. Cholesterol is likely to be the fuel for M. tuberculosis inside macrophages. Deleting the nat gene and inhibiting the NAT enzyme prevents survival of the microorganism in macrophages and induces cell wall alterations, rendering the mycobacterium sensitive to antibiotics to which it is normally resistant. To date, NAT from M. marinum (MMNAT) is considered the best available model for NAT from M. tuberculosis (TBNAT). The enzyme catalyses the acetylation and propionylation of arylamines and hydrazines. Hydralazine is a good acetyl and propionyl acceptor for both MMNAT and TBNAT. The MMNAT structure has been solved to 2.1 Å resolution following crystallisation in the presence of hydralazine and is compared to available NAT structures. From the mode of ligand binding, features of the binding pocket can be identified, which point to a novel mechanism for the acetylation reaction that results in a 3-methyltriazolo[3,4-a]phthalazine ring compound as product.
