Abstract
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 α/β protein consisting of a central sheet of five parallel β-strands flanked by α- 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.
Keywords: tuberculosis, malaria, shikimate kinase, shikimate pathway, drug design, drug target, Mycobacterium tuberculosis, Plasmodium sp
Current Drug Targets
Title: Shikimate Kinase: A Potential Target for Development of Novel Antitubercular Agents
Volume: 8 Issue: 3
Author(s): Jose H. Pereira, Igor B. Vasconcelos, Jaim S. Oliveira, Rafael A. Caceres, Walter F. de Azevedo, Luis A. Basso and Diogenes S. Santos
Affiliation:
Keywords: tuberculosis, malaria, shikimate kinase, shikimate pathway, drug design, drug target, Mycobacterium tuberculosis, Plasmodium sp
Abstract: 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 α/β protein consisting of a central sheet of five parallel β-strands flanked by α- 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.
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Pereira H. Jose, Vasconcelos B. Igor, Oliveira S. Jaim, Caceres A. Rafael, de Azevedo F. Walter, Basso A. Luis and Santos S. Diogenes, Shikimate Kinase: A Potential Target for Development of Novel Antitubercular Agents, Current Drug Targets 2007; 8 (3) . https://dx.doi.org/10.2174/138945007780059013
DOI https://dx.doi.org/10.2174/138945007780059013 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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