Discovery of Novel Acetohydroxyacid Synthase Inhibitors as Active Agents against<i>Mycobacterium tuberculosis</i>by Virtual Screening and Bioassay

Wang, Di; Zhu, Xingyi; Cui, C. Q.; Ming, Dong; Jiang, Hualiang; Li, Zhengming; Liu, Zhen; Zhu, Weiliang; Wang, Jianguo

doi:10.1021/ci3004545

Cited by 42 publications

(33 citation statements)

References 37 publications

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“…Numerous studies have shown that M. tuberculosis strains deficient in enzymes involved in various amino acid biosynthetic pathways are compromised in their ability to infect mice in comparison with the ability of parental strain (40 -42). In addition, several of these enzymes involved in amino acid biosynthesis are being currently explored for development of more potent antitubercular scaffolds (43)(44)(45)(46)(47)(48). L-Serine biosynthesis is an attractive and unexplored anti-microbial drug target because L-serine is not only involved in protein synthesis but also acts as precursor for various cellular metabolites (15, 49 -54).…”

Section: Discussionmentioning

confidence: 99%

High Throughput Screen Identifies Small Molecule Inhibitors Specific for Mycobacterium tuberculosis Phosphoserine Phosphatase

Arora

Tiwari

Mandal

et al. 2014

Journal of Biological Chemistry

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Background: Phosphoserine phosphatase (PSP) is an essential enzyme involved in L-serine biosynthesis. Results: High throughput screen was performed to identify specific PSP inhibitors with activity against intracellular bacteria. Conclusion: Validation of PSP as a drug target would lead to identification of scaffolds with a novel mechanism. Significance: This is the first report demonstrating selective inhibition of M. tuberculosis PSP enzyme.

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Section: Discussionmentioning

confidence: 99%

High Throughput Screen Identifies Small Molecule Inhibitors Specific for Mycobacterium tuberculosis Phosphoserine Phosphatase

Arora

Tiwari

Mandal

et al. 2014

Journal of Biological Chemistry

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“…The methyl thiazolyl tetrazolium (MTT) assay, which tests for cell proliferation and survival, was used in the present study, as previously described (14). Cells were incubated into 96-well culture plate, 5x10 3 cells in each well, to incubate for 72 h. In total, 50 µl MTT solution was added to each well and incubated at 37˚C for 4 h. Following incubation, MTT was aspirated and 150 µl dimethyl sulfoxide was added to each well to dissolve the formazan precipitate.…”

Section: Methodsmentioning

confidence: 99%

Downregulated microRNA-26a modulates prostate cancer cell proliferation and apoptosis by targeting COX-2

2016

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Abstract. ) is expressed at lower levels in prostate cancer cells compared with normal prostate cells. However, the regulatory mechanism of miR-26a in tumorigenesis and metastasis is not clear. In the present study, the expression profile of cellular miR-26a was analyzed by reverse transcription-quantitative polymerase chain reaction. The potential target of miR-26a was identified by luciferase assay and western blotting. Examination of miR-26a function was performed by transfection with miR-26a mimics and inhibitor. It was found that miR-26a expression was decreased in prostate cancer tissues and cell lines, with androgen-independent prostate cancer (AIPC) showing lower miR-26a expression compared with androgen-dependent prostate cancer (ADPC). Overexpression of miR-26a by transfecting miR-26a mimics could significantly enhance apoptosis, and this upregulation of apoptosis was triggered by cytochrome c oxidase subunit II inhibition. Furthermore, it was found that lower miR-26a density resulted in an evidently poor prognosis. Understanding the important roles of miR-26a in regulating cell apoptosis in human prostate cancer cells may aid the exploration of AIPC transformation mechanisms and contribute to the development of miRNA-based therapy in the future.

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“…Tuberculosis caused by M. tuberculosis is the second leading cause of death, AHAS is recognized as a safe target for developing antimicrobial compounds. Oxygen atoms of benzoyl esters inhibitor form bonds with amino acids K203 and R326 of M. tuberculosis AHAS (Wang et al., ). These two residues leading to a strong binding affinity between inhibitor and AHAS are both conserved (Figure b).…”

Section: Resultsmentioning

confidence: 99%

Molecular evolution of acetohydroxyacid synthase in bacteria

Liu

Wang

2017

MicrobiologyOpen

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Acetohydroxyacid synthase (AHAS) is the key enzyme in the biosynthetic pathways of branched chain amino acids in bacteria. Since it does not exist in animal and plant cells, AHAS is an attractive target for developing antimicrobials and herbicides. In some bacteria, there is a single copy of AHAS, while in others there are multiple copies. Therefore, it is necessary to investigate the origin and evolutionary pathway of various AHASs in bacteria. In this study, all the available protein sequences of AHAS in bacteria were investigated, and an evolutionary model of AHAS in bacteria is proposed, according to gene structure, organization and phylogeny. Multiple copies of AHAS in some bacteria might be evolved from the single copy of AHAS, the ancestor. Gene duplication, domain deletion and horizontal gene transfer might occur during the evolution of this enzyme. The results show the biological significance of AHAS, help to understand the functions of various AHASs in bacteria, and would be useful for developing industrial production strains of branched chain amino acids or novel antimicrobials.

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Discovery of Novel Acetohydroxyacid Synthase Inhibitors as Active Agents againstMycobacterium tuberculosisby Virtual Screening and Bioassay

Cited by 42 publications

References 37 publications

High Throughput Screen Identifies Small Molecule Inhibitors Specific for Mycobacterium tuberculosis Phosphoserine Phosphatase

High Throughput Screen Identifies Small Molecule Inhibitors Specific for Mycobacterium tuberculosis Phosphoserine Phosphatase

Downregulated microRNA-26a modulates prostate cancer cell proliferation and apoptosis by targeting COX-2

Molecular evolution of acetohydroxyacid synthase in bacteria

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