Shikimate Kinase: A Potential Target for Development of Novel Antitubercular Agents
| Autor: | Diógenes Santiago Santos, Jaim S. Oliveira, Jose Henrique Pereira, Luis Augusto Basso, Walter Filgueira de Azevedo, Rafael Andrade Caceres, Igor B. Vasconcelos |
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| Rok vydání: | 2007 |
| Předmět: |
Pharmacology
chemistry.chemical_classification biology Latent tuberculosis Kinase Clinical Biochemistry Antitubercular Agents Drug design Shikimic acid biology.organism_classification medicine.disease Shikimate kinase Mycobacterium tuberculosis Phosphotransferases (Alcohol Group Acceptor) chemistry.chemical_compound Drug Delivery Systems Enzyme Biochemistry chemistry Drug Discovery medicine Animals Humans Molecular Medicine Shikimate pathway |
| Zdroj: | Current Drug Targets. 8:459-468 |
| ISSN: | 1389-4501 |
| Popis: | Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. However, no new classes of drugs for TB have been developed in the past 30 years. Therefore there is an urgent need to develop faster acting and effective new antitubercular agents, preferably belonging to new structural classes, to better combat TB, including MDR-TB, to shorten the duration of current treatment to improve patient compliance, and to provide effective treatment of latent tuberculosis infection. The enzymes in the shikimate pathway are potential targets for development of a new generation of antitubercular drugs. The shikimate pathway has been shown by disruption of aroK gene to be essential for the Mycobacterium tuberculosis. The shikimate kinase (SK) catalyses the phosphorylation of the 3-hydroxyl group of shikimic acid (shikimate) using ATP as a co-substrate. SK belongs to family of nucleoside monophosphate (NMP) kinases. The enzyme is an alpha/beta protein consisting of a central sheet of five parallel beta-strands flanked by alpha-helices. The shikimate kinases are composed of three domains: Core domain, Lid domain and Shikimate-binding domain. The Lid and Shikimate-binding domains are responsible for large conformational changes during catalysis. More recently, the precise interactions between SK and substrate have been elucidated, showing the binding of shikimate with three charged residues conserved among the SK sequences. The elucidation of interactions between MtSK and their substrates is crucial for the development of a new generation of drugs against tuberculosis through rational drug design. |
| Databáze: | OpenAIRE |
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