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

Sandy, James; Holton, Simon J.; Fullam, Elizabeth; Sim, Edith; Noble, M.E.M.

doi:10.1110/ps.041163505

Cited by 60 publications

(82 citation statements)

References 29 publications

(48 reference statements)

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“…5) (Sandy et al, 2005a) and with MMNAT (Fullam, 2007) were compared to that formed with HLZ. INH binds to the pocket in a comparable way to that observed for HLZ (Fig.…”

Section: Comparison Of the Hydralazine Structure To Available Nat Strmentioning

confidence: 99%

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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“…5) (Sandy et al, 2005a) and with MMNAT (Fullam, 2007) were compared to that formed with HLZ. INH binds to the pocket in a comparable way to that observed for HLZ (Fig.…”

Section: Comparison Of the Hydralazine Structure To Available Nat Strmentioning

confidence: 99%

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

et al. 2010

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“…Although this artificial docking trial was performed only for the evaluation of pocket shape and size, INH may be able to dock to the NAT2-acetyl CoA complex. Several roles of the NAT2 substrate have been reported, such as the inactivation of NAT2 7) and "substrate inhibition" 24) ; however, the structures of NAT2 including the substrate should be investigated in more detail.…”

Section: Resultsmentioning

confidence: 99%

“…9) However, it has been proposed that substrates play several roles for NAT. For example, the substrate of NAT from M. smegmatis binds to NAT without acetylation of neither NAT nor acetyl CoA (i.e., absence of any acetyl source) 24) and this observation is not accounted for by the Ping-Pong Bi-Bi mechanism. Because NAT substrates have the potential to work with other mechanisms that have been previously proposed, the ternary complex structure obtained by the artificial docking trial Vol.…”

Section: Residues Associated With Genetic Polymorphismsmentioning

confidence: 99%

Computational Study of the Three-Dimensional Structure of N-Acetyltransferase 2-Acetyl Coenzyme A Complex

Oda

Kobayashi

Takahashi

2010

Biological & Pharmaceutical Bulletin

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N-Acetyltransferase (NAT) is a polymorphic phase II drug-metabolizing enzyme similar to uridine 5Ј-diphosphate (UDP)-glucuronosyltransferase and sulfotransferase. Classified as conjugation enzymes, these enzymes add polar groups to substrates. The addition of polar groups increases the solubility of these compounds in water, allowing drug molecules conjugated with polar groups to be easily excreted. NAT is the enzyme that catalyzes N-acetyl conjugation of allylamine derivatives, and it metabolizes several endogenous and exogenous compounds. There are two isozymes in human NAT-NAT1 and NAT2-but the substrate specificities of each isozyme are different.1) NAT2 metabolizes several drugs such as the anti-tubercular drug isoniazid (INH), and it is an important enzyme in drug design trials due to a unique polymorphism.2-4) This polymorphism causes individual differences in the rate of metabolism of allylamine. An individual with a faster rate is called a rapid acetylator (RA); an individual with a slower rate is called a slow acetylator (SA). Because the rate of SAs is higher in Caucasian than in Japanese populations, NAT2 plays an important role in the consideration of drug metabolisms of Caucasians. In the ligand binding site of NAT, there is an acetyl coenzyme A (CoA) molecule that acts as a cofactor and plays an important role in the acetylation of substrates. The cysteine residue (e.g., Cys68 in NAT2) is also important to drug metabolism. 5) A recently proposed reaction mechanism is as follows.6-9) First, the complex between NAT and acetyl CoA is formed. The acetyl group of acetyl CoA is then transferred to the sulfur atom of the cysteine residue. Second, the acetyl group is transferred from the acetylated cysteine to the substrate.Recently, the three-dimensional (3D) structure of human NAT2, as determined by X-ray crystallography, was reported.10) In the reported structure, instead of acetyl CoA, CoA was described as the cofactor in NAT2. In addition, the atomic distance between the sulfur atom of CoA and that of cysteine residue in the binding site of NAT2 was described as only 2.74 Å in the crystal structure, much shorter in comparison to the standard, non-bonded, sulfur-sulfur distance. (For reference, van der Waals radius of sulfur atom is 1.80 Å.) 11) Because the distance between these sulfurs was longer than the disulfide-bond length (around 2.05 Å in general), the crystal structure around these sulfurs was not reasonable if these sulfurs were covalently bonded. Therefore, the geometrically optimized structure of the NAT2-CoA complex, in which hydrogen atoms are added to thiol sulfur atoms, is expected to be different from the crystal structure. Furthermore, substitution of acetyl CoA for CoA may cause structural changes to NAT2.In this study, the CoA of the NAT2 crystal structure was substituted for acetyl CoA using molecular modeling. Molecular dynamics (MD) simulation of the modeled structure was used to refine the 3D structure of the NAT2-acetyl CoA complex. Furthermore, the ligand binding sites of NAT...

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“…The other derivatives having halogen substitution (Br and F) have not shown a considerable degree of activity this might be because of their size and shape, which play an important role in drug binding and their effectiveness [33][34][35][36][37].…”

Section: In Vitro Antitubercular Activitymentioning

confidence: 99%

Synthesis, Antimicrobial, Antitubercular and Cheminformatic Studies of 2-(1-Benzofuran-2-Yl)-N'-[(3z)-2-Oxo-1, 2-Dihydro-3h-Indol-3-Ylidene] Quinoline-4-Carbohydrazide and Its Derivatives

Santoshkumar

Satyanarayana

Anantacharya

et al. 2017

Int J Pharm Pharm Sci

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Objective: Synthesis of novel 2-(1-benzofuran-2-yl)-N'-[(3Z)-2-oxo-1, 2-dihydro-3H-indol-3-ylidene] quinoline-4-carbohydrazide and its derivatives for antimicrobial and antitubercular activity.Methods: Synthesis was carried out using the general method and the structures were confirmed by IR, 1 Results:The results revealed that at 25 mg/ml concentration, compounds 3a and 5a showed good antibacterial activity at 3.5±0.1, 3.8±0.3, 3.6±0.2 respectively against E. coli, K. pneumonia and S. typhimurium, when compared with drug streptomycin with similar concentration. The percentage of inhibition found at 50 µg/ml concentration, compounds 2b and 6a exhibited good antifungal activity at 53±1.15, 57±1.52 against A. flavus and C. neoformans, compared with standard drug fluconazole. The increase in activity was found to be dose dependent. The analogue 2a showed good antitubercular activity at 12.5±0.5 µg/ml, compounds 2b, 3a, 4a-b, 5a-b and 6a-b exhibited significant activity at 25±0.57 µg/ml and compound 3b showed moderate activity at 50±0.57 µg/ml. The mean value of P<0.05 were considered to be statistically significant. The absorption, distribution, metabolism, excretion and toxicity studies of the entitled molecules were analyzed and found to be in acceptable range.H-NMR, [13]C-NMR and mass spectral analysis. The antibacterial activity was carried by agar well diffusion method, antifungal activity was performed by poison food technique and antitubercular activity was carried out by Microplate Alamar Blue Assay (MABA) method with the help of H37Rv. In silico absorption, distribution, metabolism, excretion, toxicity (ADMET) study of the drug, likeliness was carried out in ACD/lab-2. Conclusion:The study reveals that compounds containing benzofuran coupled nitrogen heterocycles are essential for activity as they possess excellent drug-like characteristics, suggesting to be potentially best inhibitor of H37Rv strain. The in silico ADME analysis also revealed that all the compounds were in acceptable range to obey the pharmacokinetic parameters.

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

Cited by 60 publications

References 29 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

Computational Study of the Three-Dimensional Structure of N-Acetyltransferase 2-Acetyl Coenzyme A Complex

Synthesis, Antimicrobial, Antitubercular and Cheminformatic Studies of 2-(1-Benzofuran-2-Yl)-N'-[(3z)-2-Oxo-1, 2-Dihydro-3h-Indol-3-Ylidene] Quinoline-4-Carbohydrazide and Its Derivatives

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