Arylamine <i>N</i>-Acetyltransferase Is Required for Synthesis of Mycolic Acids and Complex Lipids in <i>Mycobacterium bovis</i> BCG and Represents a Novel Drug Target

Bhakta, Sanjib; Besra, Gurdyal S.; Upton, Anna M.; Parish, Tanya; Sholto-Douglas-Vernon, Carolyn; Gibson, Kevin J.; Knutton, Stuart; Gordon, Siamon; daSilva, Rosangela P.; Anderton, Matthew C.; Sim, Edith

doi:10.1084/jem.20031956

Cited by 96 publications

(120 citation statements)

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“…Deleting the nat gene prevents survival of bacilli in macrophages and induces an altered cell wall, rendering the microorganism sensitive to antibiotics to which it is normally resistant (Bhakta et al, 2004). NAT inhibitors were demonstrated to have similar effects to that of deleting the gene (Westwood, 2005;Westwood et al, 2006), suggesting the validity of NAT as a potential anti-tubercular target.…”

Section: Introductionmentioning

confidence: 73%

Probing the architecture of the Mycobacterium marinum arylamine N-acetyltransferase active site

et al. 2010

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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.

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Section: Introductionmentioning

confidence: 73%

Probing the architecture of the Mycobacterium marinum arylamine N-acetyltransferase active site

et al. 2010

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“…Overexpression of nat from M. tuberculosis confers increased resistance to INH in Mycobacterium smegmatis (11), which is a nonpathogenic mycobacterium that is used as a model for M. tuberculosis, whereas a nat knockout strain of M. smegmatis has increased sensitivity to the drug (12). Because nat is required for synthesis of normal mycolic acid and complex lipids in M. bovis BCG (2), NAT, particularly in mycobacteria, has the potential to be a drug target (2). Recent studies have shown that bacterial NATs acetylate not only INH but also numerous arylamines, including important drugs.…”

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confidence: 99%

ArylamineN-Acetyltransferase Responsible for Acetylation of 2-Aminophenols inStreptomyces griseus

2007

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An arylamine N-acetyltransferase (NAT) responsible for the N acetylation of exogenous 3-amino-4-hydroxybenzoic acid in Streptomyces griseus was identified and characterized. This enzyme was distinct from other eukaryotic and bacterial NATs in that it acetylated various 2-aminophenol derivatives more effectively than it acetylated 5-aminosalicylic acid, and thus it may be involved in the metabolism of xenobiotic compounds.

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“…Consequently, the methylation of the SIRT1 gene may be a significant gene modification involved in the occurrence of T2D. The other two genes, NAT6 and PLA2G12B, which were also hyper-methylated in T2D muscle, are involved in the metabolism of lipids (24). PLA2G12B belongs to the PLA2 family, and catalyzes the hydrolysis of glycolipids to release free fatty acids and lysophospholipids (25).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of abnormal DNA methylation in muscle samples from monozygotic twins discordant for type 2 diabetes

Liu

Sun

Wang

et al. 2012

Molecular Medicine Reports

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Abstract. The present study aimed to examine the changes in DNA methylation of gene promoters associated with type 2 diabetes (T2D). The DNA methylation profile dataset GSE38291 was downloaded from the Gene Expression Omnibus database. A paired t-test was used to analyze differences in the DNA methylation of gene promoters between T2D and normal muscle samples. Gene Ontology (GO) enrichment analysis was performed using online tool, The Database for Annotation, Visualization and Integrated Discovery. Whole-Genome rVISTA was used to analyze the enriched transcription factor (TF) binding sites upstream of the transcription start site in the differentially methylated genes. A total of 38 genes, including Sirtuin 1, N-acetyltransferase 6, phospholipase A2 group XIIB and nuclear factor of activated T cells calcineurin-dependent 1, were identified to be differentially methylated between these two groups. One GO term, DNA geometric change (GO:0032392), was significantly enriched (P<0.05) by the hyper-methylated genes. In addition, the binding sites of one gene, zinc finger E-box binding homeobox 1, and three TFs, methyl CpG binding protein 2, TFEB and TFAP4, were significantly enriched in the hyper-and hypo-methylated genes, respectively. The resulting T2D-associated genes and potential TFs provided a novel insight into the molecular mechanisms underlying the pathology of T2D. These genes may become promising target genes for the development of treatments for T2D.

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Arylamine N-Acetyltransferase Is Required for Synthesis of Mycolic Acids and Complex Lipids in Mycobacterium bovis BCG and Represents a Novel Drug Target

Cited by 96 publications

References 48 publications

Probing the architecture of the Mycobacterium marinum arylamine N-acetyltransferase active site

Probing the architecture of the Mycobacterium marinum arylamine N-acetyltransferase active site

ArylamineN-Acetyltransferase Responsible for Acetylation of 2-Aminophenols inStreptomyces griseus

Bioinformatics analysis of abnormal DNA methylation in muscle samples from monozygotic twins discordant for type 2 diabetes

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