Sandbox Reserved 1051: Difference between revisions
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Because the cell wall envelope of ''M. tuberculosis'' is essential for the bacteria’s viability and virulence, it is the primary target for antimycobacterial drugs. More specifically, it is known that the Ag85 complex with its three protein components (A, B, and C) plays a key role in cell wall biosynthesis and the [http://www.nature.com/nchembio/journal/v7/n4/images_article/nchembio.539-F1.jpg transfer of mycolic acid from one molecule of TMM to another]. The resultant molecule, TDM, has been suggested to be important in maintaining ''M. tuberculosis'' cell wall integrity. Studies have also suggested that removal of Ag85C from a strain of M. tuberculosis results in a significant decrease in the presence of cell-wall linked mycolic acids. Thus, scientists hypothesize that inhibition of Ag85C and its mycolyltransferase activity will disrupt TDM and its ability to maintain cell wall integrity.<ref name="Gobec"/> Knowing this, researchers have suggested that inhibition of mycolic acid transfer and, ultimately, Ag85C, must be involved in the continuously-developing class of antimycobacterial drugs aimed at combatting M. tuberculosis.<ref>PMID:9162010</ref> | Because the cell wall envelope of ''M. tuberculosis'' is essential for the bacteria’s viability and virulence, it is the primary target for antimycobacterial drugs. More specifically, it is known that the Ag85 complex with its three protein components (A, B, and C) plays a key role in cell wall biosynthesis and the [http://www.nature.com/nchembio/journal/v7/n4/images_article/nchembio.539-F1.jpg transfer of mycolic acid from one molecule of TMM to another]. The resultant molecule, TDM, has been suggested to be important in maintaining ''M. tuberculosis'' cell wall integrity. Studies have also suggested that removal of Ag85C from a strain of M. tuberculosis results in a significant decrease in the presence of cell-wall linked mycolic acids. Thus, scientists hypothesize that inhibition of Ag85C and its mycolyltransferase activity will disrupt TDM and its ability to maintain cell wall integrity.<ref name="Gobec"/> Knowing this, researchers have suggested that inhibition of mycolic acid transfer and, ultimately, Ag85C, must be involved in the continuously-developing class of antimycobacterial drugs aimed at combatting M. tuberculosis.<ref>PMID:9162010</ref> | ||
== '''Structure''' == | == '''Structure''' == | ||
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[http://proteopedia.org/wiki/index.php/4qdu Ag85C-ebselen] is characterized by a covalent bond between [http://en.wikipedia.org/wiki/Ebselen Ebselen] and Cys209, thus forcing the otherwise kinked helix alpha-9 to take on a relaxed conformation. This allows movement of the helix and causes disruption of the hydrogen bonds within the catalytic triad, ultimately inactivating Ag85C.<ref name="Favrot"/> | [http://proteopedia.org/wiki/index.php/4qdu Ag85C-ebselen] is characterized by a covalent bond between [http://en.wikipedia.org/wiki/Ebselen Ebselen] and Cys209, thus forcing the otherwise kinked helix alpha-9 to take on a relaxed conformation. This allows movement of the helix and causes disruption of the hydrogen bonds within the catalytic triad, ultimately inactivating Ag85C.<ref name="Favrot"/> | ||
Overall for the Ag85 complex, if the organism would mutate one of the Ag85 enzymes to generate resistance to a drug functioning similar to Ebselen, the mutant would probably display a low level of activity, thus inhibiting its function. Additionally, targeting Cys209 is a pertinent and potential location for drug therapy. Since any modification or mutation of Cys209 leads to either a dramatic decrease or complete loss of enzymatic activity, research suggests there is a low probability of developing resistance to a drug modifying the Cystine. The structures and results of the following mutations and modifications support a strategy for inhibiting the Ag85 complex with mechanism-based inhibitors that first react with Ser124 to promote the relaxation of alpha-9 helix and expose Cys209; secondly, react with Cys209 side chain thiol to covalently modify this conserved residue. Such a bifunctional inhibitor would offer specificity while minimizing the probability of selecting for drug resistant mutants.<ref name="Favrot"/> | |||
===Ag85C-Hg=== | ===Ag85C-Hg=== | ||