Using a specific example discuss a possible target for the development of anti-mycobacterial therapeutics
ATP synthase is a main enzyme used to produce ATP in respiration of a cell. It makes use of a proton gradient in the mitochondrial cell membrane to generate ATP. By transporting protons back across the membrane, using ADP and a phosphate ion to create ATP. Normally most bacteria can gain enough ATP to grow optimally through substrate level phosphorylation, however it has been shown that M. tuberculosis, both the active and the latent version, do not produce enough ATP to grow sufficiently. This makes ATP synthase an excellent target for any anti-mycobacterial therapy. Therefore, blocking ATP production through ATP synthase, will deprive …show more content…
The F1 regions is made up primarily of α and β subunits together these subunits form around a central ‘rotor stalk’ which connects both the F1 and F0 complexes together. The catalytic activity i.e. the creation of ATP from ADP and Pi takes place in the F1 complex, whilst proton transport happens in the F0 complex. The F0 complex is made up of mostly C subunits, these are crucial to binding protons and therefore to ‘pump’ the protons through the membrane. Any of the subunits that bind to the ATP synthase can be potential targets to help kill the bacterial. ATP synthase also has other targets that could be used as well such as the metal ion it binds to activate it. ATP synthase requires a proton gradient between inside and outside the membrane, therefore another target, which would not compete with a binding site. However the difficulty of a target such as this is, the specificity of any drug administered. As The mycobacterial ATP synthase bares much similarity with human ATP synthase, any therapies would need to be able to distinguish between human ATP synthase and the mycobacterial version, this is the specificity of a drug.
An example on current therapy in anti-mycobacterial use, is the use of diarylquinolines, these compounds have been shown to have great activity against the bacteria, Mycobacterium tuberculosis. The compound with greatest activity and therefore the lead compound is TMC207. …show more content…
ATP synthase is completely reliant on the generation of a proton gradient by the electron carriers in the membrane, such as quinine or cytochromes. Further to this it has been shown that both active and latent mycobacteria are reliant on the ATP generated by ATP synthase, and therefore an ideal target is to affect the proton gradient, this would stop ATP synthase from even attempting to generating ATP if there are no protons to transfer to begin with, or if there is a smaller gradient it may be enough to affect ATP synthase activity and still have a bactericidal affect. There many ways this can be done, firstly to affect and inhibit the electron carriers within the membrane. The other method that could be used would be to pump the protons back inside the membrane, similar to ATP synthase, though, without the generation of ATP, whether this is done by affecting the membrane permeability to the protons or through a drug that transports them. Another way would be to use a drug that would alter the bind to the C ring of ATP synthase or impair the movement of the F1 subunit. The hindrance on the movement of the F1 subunit would result in ATP synthase being unable to turn and therefore twist the C ring to transport protons and stop ATP
ATP synthase is a main enzyme used to produce ATP in respiration of a cell. It makes use of a proton gradient in the mitochondrial cell membrane to generate ATP. By transporting protons back across the membrane, using ADP and a phosphate ion to create ATP. Normally most bacteria can gain enough ATP to grow optimally through substrate level phosphorylation, however it has been shown that M. tuberculosis, both the active and the latent version, do not produce enough ATP to grow sufficiently. This makes ATP synthase an excellent target for any anti-mycobacterial therapy. Therefore, blocking ATP production through ATP synthase, will deprive …show more content…
The F1 regions is made up primarily of α and β subunits together these subunits form around a central ‘rotor stalk’ which connects both the F1 and F0 complexes together. The catalytic activity i.e. the creation of ATP from ADP and Pi takes place in the F1 complex, whilst proton transport happens in the F0 complex. The F0 complex is made up of mostly C subunits, these are crucial to binding protons and therefore to ‘pump’ the protons through the membrane. Any of the subunits that bind to the ATP synthase can be potential targets to help kill the bacterial. ATP synthase also has other targets that could be used as well such as the metal ion it binds to activate it. ATP synthase requires a proton gradient between inside and outside the membrane, therefore another target, which would not compete with a binding site. However the difficulty of a target such as this is, the specificity of any drug administered. As The mycobacterial ATP synthase bares much similarity with human ATP synthase, any therapies would need to be able to distinguish between human ATP synthase and the mycobacterial version, this is the specificity of a drug.
An example on current therapy in anti-mycobacterial use, is the use of diarylquinolines, these compounds have been shown to have great activity against the bacteria, Mycobacterium tuberculosis. The compound with greatest activity and therefore the lead compound is TMC207. …show more content…
ATP synthase is completely reliant on the generation of a proton gradient by the electron carriers in the membrane, such as quinine or cytochromes. Further to this it has been shown that both active and latent mycobacteria are reliant on the ATP generated by ATP synthase, and therefore an ideal target is to affect the proton gradient, this would stop ATP synthase from even attempting to generating ATP if there are no protons to transfer to begin with, or if there is a smaller gradient it may be enough to affect ATP synthase activity and still have a bactericidal affect. There many ways this can be done, firstly to affect and inhibit the electron carriers within the membrane. The other method that could be used would be to pump the protons back inside the membrane, similar to ATP synthase, though, without the generation of ATP, whether this is done by affecting the membrane permeability to the protons or through a drug that transports them. Another way would be to use a drug that would alter the bind to the C ring of ATP synthase or impair the movement of the F1 subunit. The hindrance on the movement of the F1 subunit would result in ATP synthase being unable to turn and therefore twist the C ring to transport protons and stop ATP