Dataset Information

Mycobacterium tuberculosis ?-Carbonic Anhydrases: Novel Targets for Developing Antituberculosis Drugs.

ABSTRACT: The genome of Mycobacterium tuberculosis (Mtb) encodes three ?-carbonic anhydrases (CAs, EC 4.2.1.1) that are crucial for the life cycle of the bacterium. The Mtb ?-CAs have been cloned and characterized, and the catalytic activities of the enzymes have been studied. The crystal structures of two of the enzymes have been resolved. In vitro inhibition studies have been conducted using different classes of carbonic anhydrase inhibitors (CAIs). In vivo inhibition studies of pathogenic bacteria containing ?-CAs showed that ?-CA inhibitors effectively inhibited the growth of pathogenic bacteria. The in vitro and in vivo studies clearly demonstrated that ?-CAs of not only mycobacterial species, but also other pathogenic bacteria, can be targeted for developing novel antimycobacterial agents for treating tuberculosis and other microbial infections that are resistant to existing drugs. In this review, we present the molecular and structural data on three ?-CAs of Mtb that will give us better insights into the roles of these enzymes in pathogenic bacterial species. We also present data from both in vitro inhibition studies using different classes of chemical compounds and in vivo inhibition studies focusing on M. marinum, a model organism and close relative of Mtb.

SUBMITTER: Aspatwar A

PROVIDER: S-EPMC6834203 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Mycobacterium tuberculosis β-Carbonic Anhydrases: Novel Targets for Developing Antituberculosis Drugs.

Aspatwar Ashok A Kairys Visvaldas V Rala Sangeetha S Parikka Mataleena M Bozdag Murat M Carta Fabrizio F Supuran Claudiu T CT Parkkila Seppo S

International journal of molecular sciences 20191017 20

The genome of Mycobacterium tuberculosis (Mtb) encodes three β-carbonic anhydrases (CAs, EC 4.2.1.1) that are crucial for the life cycle of the bacterium. The Mtb β-CAs have been cloned and characterized, and the catalytic activities of the enzymes have been studied. The crystal structures of two of the enzymes have been resolved. In vitro inhibition studies have been conducted using different classes of carbonic anhydrase inhibitors (CAIs). In vivo inhibition ...[more]

PMID: 31627429

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Project description:BACKGROUND: The genomes of many insect and parasite species contain beta carbonic anhydrase (?-CA) protein coding sequences. The lack of ?-CA proteins in mammals makes them interesting target proteins for inhibition in treatment of some infectious diseases and pests. Many insects and parasites represent important pests for agriculture and cause enormous economic damage worldwide. Meanwhile, pollution of the environment by old pesticides, emergence of strains resistant to them, and their off-target effects are major challenges for agriculture and society. METHODS: In this study, we analyzed a multiple sequence alignment of 31 ?-CAs from insects, some parasites, and selected plant species relevant to agriculture and livestock husbandry. Using bioinformatics tools a phylogenetic tree was generated and the subcellular localizations and antigenic sites of each protein were predicted. Structural models for ?-CAs of Ancylostoma caninum, Ascaris suum, Trichinella spiralis, and Entamoeba histolytica, were built using Pisum sativum and Mycobacterium tuberculosis ?-CAs as templates. RESULTS: Six ?-CAs of insects and parasites and six ?-CAs of plants are predicted to be mitochondrial and chloroplastic, respectively, and thus may be involved in important metabolic functions. All 31 sequences showed the presence of the highly conserved ?-CA active site sequence motifs, CXDXR and HXXC (C: cysteine, D: aspartic acid, R: arginine, H: histidine, X: any residue). We discovered that these two motifs are more antigenic than others. Homology models suggested that these motifs are mostly buried and thus not well accessible for recognition by antibodies. CONCLUSIONS: The predicted mitochondrial localization of several ?-CAs and hidden antigenic epitopes within the protein molecule, suggest that they may not be considered major targets for vaccines. Instead, they are promising candidate enzymes for small-molecule inhibitors which can easily penetrate the cell membrane. Based on current knowledge, we conclude that ?-CAs are potential targets for development of small molecule pesticides or anti-parasitic agents with minimal side effects on vertebrates.

Dataset Information

Mycobacterium tuberculosis ?-Carbonic Anhydrases: Novel Targets for Developing Antituberculosis Drugs.

Publications

<i>Mycobacterium tuberculosis</i> <i>β</i>-Carbonic Anhydrases: Novel Targets for Developing Antituberculosis Drugs.

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