Potential Inhibitors for Isocitrate Lyase of<i>Mycobacterium tuberculosis</i>and Non-<i>M. tuberculosis</i>: A Summary

Lee, Yie-Vern; Wahab, Habibah A.; Choong, Yee Siew

doi:10.1155/2015/895453

Cited by 31 publications

(28 citation statements)

References 66 publications

(81 reference statements)

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“…However, to date, reports of potent and selective ICL inhibitors remain lacking (44,45). This deficiency likely reflects the challenges associated with ICL's small active site, which is composed primarily of polar and charged side chains.…”

Section: Discussionmentioning

confidence: 99%

Glyoxylate detoxification is an essential function of malate synthase required for carbon assimilation in Mycobacterium tuberculosis

Puckett

Trujillo

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The glyoxylate shunt is a metabolic pathway of bacteria, fungi, and plants used to assimilate even-chain fatty acids (FAs) and has been implicated in persistence of Mycobacterium tuberculosis (Mtb). Recent work, however, showed that the first enzyme of the glyoxylate shunt, isocitrate lyase (ICL), may mediate survival of Mtb during the acute and chronic phases of infection in mice through physiologic functions apart from fatty acid metabolism. Here, we report that malate synthase (MS), the second enzyme of the glyoxylate shunt, is essential for in vitro growth and survival of Mtb on even-chain fatty acids, in part, for a previously unrecognized activity: mitigating the toxicity of glyoxylate excess arising from metabolism of even-chain fatty acids. Metabolomic profiling revealed that MS-deficient Mtb cultured on fatty acids accumulated high levels of the ICL aldehyde endproduct, glyoxylate, and increased levels of acetyl phosphate, acetoacetyl coenzyme A (acetoacetyl-CoA), butyryl CoA, acetoacetate, and β-hydroxybutyrate. These changes were indicative of a glyoxylate-induced state of oxaloacetate deficiency, acetate overload, and ketoacidosis. Reduction of intrabacterial glyoxylate levels using a chemical inhibitor of ICL restored growth of MS-deficient Mtb, despite inhibiting entry of carbon into the glyoxylate shunt. In vivo depletion of MS resulted in sterilization of Mtb in both the acute and chronic phases of mouse infection. This work thus identifies glyoxylate detoxification as an essential physiologic function of Mtb malate synthase and advances its validation as a target for drug development.tuberculosis | metabolism | malate synthase | glyoxylate detoxification T he unusual evolution of Mycobacterium tuberculosis (Mtb) within humans as both host and reservoir has shaped its pathogenicity around adaptation of its carbon and energy metabolism to the diverse yet specific array of microenvironments encountered within human hosts (1). Current evidence indicates that Mtb can be found inside lipid-rich macrophages and in cavities, suggesting that these environments provide the pathogen with nutrients that facilitate persistence (2, 3). Consistent with this evidence, multiple Mtb genes involved in fatty acid (FA) and lipid uptake and catabolism have been shown to be essential to establish and maintain chronic infections in mice (4-8). Together, such studies have directed considerable attention to pathways of lipid catabolism as a key determinants of Mtb's pathogenicity and sources of potential drug targets (9).Our understanding of Mtb's metabolic pathways however remains rudimentary. This knowledge derives in large part from the functions of orthologous genes conserved in other organisms. Though powerful for its assignment of biochemical functions, comparative genomic approaches neglect potentially important differences in the ecologic niches and selective pressures that genes have evolved to serve. One emerging and prominent example of such dissociation is exemplified by our understanding of the function of M...

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Section: Discussionmentioning

confidence: 99%

Glyoxylate detoxification is an essential function of malate synthase required for carbon assimilation in Mycobacterium tuberculosis

Puckett

Trujillo

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, recent research suggests that inhibition of these metabolic cycles could be a potentially novel route to treat bacterial and fungal infections, 8 including tuberculosis. 9,10 The ICL/PEPM members adopt a distorted α/β barrel tertiary structure in which 7 of the 8 helices pack up against the 8 stranded parallel β-sheet. [1][2][3][11][12][13][14][15][16][17][18] In both sub classes, metal cofactors play important mechanistic roles in conjunction with a conserved Arg and Cys residues, as well as other polar residues.…”

Section: Introductionmentioning

confidence: 99%

Probing the Catalytic Mechanism Involved in the Isocitrate Lyase Superfamily: Hybrid Quantum Mechanical/Molecular Mechanical Calculations on 2,3-Dimethylmalate Lyase

2015

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The isocitrate lyase (ICL) superfamily catalyzes the cleavage of the C(2)-C(3) bond of various α-hydroxy acid substrates. Members of the family are found in bacteria, fungi, and plants and include ICL itself, oxaloacetate hydrolase (OAH), 2-methylisocitrate lyase (MICL), and (2R,3S)-dimethylmalate lyase (DMML) among others. ICL and related targets have been the focus of recent studies to treat bacterial and fungal infections, including tuberculosis. The catalytic process by which this family achieves C(2)-C(3) bond breaking is still not clear. Extensive structural studies have been performed on this family, leading to a number of plausible proposals for the catalytic mechanism. In this paper, we have applied quantum mechanical/molecular mechanical (QM/MM) methods to the most recently reported family member, DMML, to assess whether any of the mechanistic proposals offers a clear energetic advantage over the others. Our results suggest that Arg161 is the general base in the reaction and Cys124 is the general acid, giving rise to a rate-determining barrier of approximately 10 kcal/mol.

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“…Also, the research activity is being mimic of the Dear Dr. Li Pin Kao, complex molecular interactions of natural proteins by focusing on small-molecule structure-based drug design, In Silico drug design can be applied according to two approaches of drug design depending on the knowledge of the target, presence of the primary sequence, and 3D structure. These strategies are: Structure -Based Drug Design (SBDD) and Ligand -Based Drug Design (LBDD) [21,24,25]. Structural -Based Drug Design is generally the preferred method of drug design because it is the process that incorporates both experimental and computational techniques.…”

Section: Drug Design Approachmentioning

confidence: 99%

Drug Discovery - Yesterday and Tomorrow: The Common Approaches in Drug Design and Cancer

On¹

2018

CCLSJ

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The process of drug discovery has undergone radical changes and development over years. Traditionally, the drugs were discovered by employing chemistry and pharmacology-based cautious approach. When natural products were the most important source of drugs or drug precursors, but the conventional randomized drug research phenomenon was no longer effective at that time due to many negatives of these approaches like: high expenses of discovering new drugs, time-consuming and reduced success guarantee. Thus, with the development of the era, the concept of "Rational Drug Design" has enabled drug target identification and validation to be more specific. In addition, several novel technologies and approaches have been introducing economics, proteomics and other omics areas such as 3D QSAR, pharmacophore modeling and other, which playing a promising role in accelerating the pace of drug discovery process. Their view of the current research focuses on the importance of drug discovery in modern times and shows how old methods have been replaced and summarized. Some of examples of molecules are identified in addition to computational approaches used to discover it, specifically in the field of anticancer drug design

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Potential Inhibitors for Isocitrate Lyase ofMycobacterium tuberculosisand Non-M. tuberculosis: A Summary

Cited by 31 publications

References 66 publications

Glyoxylate detoxification is an essential function of malate synthase required for carbon assimilation in Mycobacterium tuberculosis

Glyoxylate detoxification is an essential function of malate synthase required for carbon assimilation in Mycobacterium tuberculosis

Probing the Catalytic Mechanism Involved in the Isocitrate Lyase Superfamily: Hybrid Quantum Mechanical/Molecular Mechanical Calculations on 2,3-Dimethylmalate Lyase

Drug Discovery - Yesterday and Tomorrow: The Common Approaches in Drug Design and Cancer

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