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Isoniazid
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Isoniazid inhibits the synthesis of mycolic acids, a critical component of the lipid-rich mycobacterial cell wall, and has a bactericidal action on M. tuberculosis (Takayama et al., 1972; Quémard et al., 1991). Isoniazid is a prodrug that is converted by the mycobacterial enzyme catalase peroxidase (KatG) into the active form. Various radicals of isoniazid then covalently bind to nicotinamide adenine dinucleotide (NAD), and this inhibits the product of the inhA gene, an NADH-dependent enoyl-acyl carrier protein reductase that is part of the fatty acid synthase (FAS)-II responsible for mycolic acid synthesis (Vilchèze and Jacobs, 2007). Resistance to isoniazid can therefore arise by mutations in either katG or inhA (Zhang and Young, 1994; Rouse et al., 1995), and because inhA also appears to be the target of ethionamide, cross-resistance can occur between these two drugs (see Chapter 132, Ethionamide and Prothionamide). In one study that included 403 isoniazid-resistant M. tuberculosis isolates obtained from six different countries, 46% of strains had a mutation in codon 315 of katG (katG315), and in a further 12%, mutations associated with the inhA gene, particularly in the promoter region, were found (Hazbón et al., 2006). Mutations in katG typically correlate with high-level resistance and inhA mutations with low-level resistance (Stoeckle et al., 1993; Cockerill et al., 1995; Ferrazoli et al., 1995; Morris et al., 1995; Rouse et al., 1995). Multiple mutations in other genes [alkyl hydroperoxide reductase (ahpC), NADH dehydrogenase (ndh), and ketoacyl synthase (kasA)] have been found in isoniazid-resistant M. tuberculosis isolates; however, mutations in these genes also occur in isoniazid-sensitive M. tuberculosis isolates, and only ahpC promoter mutations correlated well with isoniazid resistance (Hazbón et al., 2006).
In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies of substituted 1,2,4-oxadiazole analogues against Mycobacterium tuberculosis
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Pran Kishore Deb, Nizar A. Al-Shar’i, Katharigatta N. Venugopala, Melendhran Pillay, Pobitra Borah
Structurally, the Pks13 enzyme is comprised of five domains, a N-terminal acyl carrier protein (N-ACP), a β-ketoacyl-synthase (KS), an acyltransferase (AT), and a C-terminal acyl carrier protein (C-ACP), a C-terminal thioesterase (TE) domain. The topological structure of Pks13 has the order ACP-KS-AT-ACP-TE (Figure 2(A)). The structure of Pks13-TE domain comprises of a core domain and a lid domain. The core domain is the larger domain and consists of seven β-sheets (β1–β7), and four α helices (α1–α3 and α11), while the smaller lid domain consists of six α helices (α4–α9)118 (Figure 2(B)). The active-site pocket of Pks13-TE is located at the interface of the lid and core domains, and it harbours the catalytic triad of Ser1533, Asp1560, and His1699 (Figure 2(D)). The substrate binding pocket, the very long mycolic acid precursor carbon chains (C80–90), is a deep hydrophobic pocket extending from the active site spanning the full length of the lid domain (Figure 2(C))118. The co-crystallized inhibitor in the 5V3Y crystal complex binds in the fatty acyl chain-binding groove at the entrance of the active site, thereby, blocking substrate access to the catalytic binding site (Figure 2(C)).
In silico screening for identification of fatty acid synthase inhibitors and evaluation of their antiproliferative activity using human cancer cell lines
Published in Journal of Receptors and Signal Transduction, 2018
Amrutha Nisthul A., Archana P. Retnakumari, Shabna A., Ruby John Anto, C. Sadasivan
For the identification of suitable fatty acid inhibitors, we have selected ketoacyl synthase (KS) domain of FASN as the protein target of interest. KS is the first catalytic domain of FASN in addition to five other catalytic domains malonyl/acetyltransferase (MAT), dehydratase (DH), enoyl reductase (ER), ketoacyl reductase (KR) and thioesterase (TE) and an acyl carrier protein (ACP) [20]. KS domain initiates the formation of fatty acids by catalyzing the condensation of the priming substrate acetyl CoA with elongation substrate malonyl CoA. KS also catalyzes the elongation reaction by sequential addition of six malonyl CoA moieties to the growing acyl chain to synthesize palmitic acid (16C), the major product of FASN [21].
Insights into structures of imidazo oxazines as potent polyketide synthase XIII inhibitors using molecular modeling techniques
Published in Journal of Receptors and Signal Transduction, 2020
Shanthakumar B., Kathiravan M. K.
The last step in mycolic acid synthesis is catalyzed by polyketide synthase 13 (PKS13). This catalytic reaction involves a claisen-type condensation in C26-α-alkyl branch and C40-60 meromycolate precursors. It is composed of five arena namely two acyl carrier protein domains, a β-ketoacyl synthase, an acyltransferase, and a C-terminal thioesterase (TE) domain. However, PKS13 is considered as a potential target since it interferes in a typical cycle of cell wall (lipid) formation.