When designing inhibitors for an enzyme, is its sub-cellular localization an important factor? Does it matter where the enzyme functions (e.g at cell surface vs. intracellular compartments)? Please provide some references.
It could be a factor. This does not generally appear to be an issue with subcellular fractions (e.g. mitochondrial outer and inner membranes) but may not be the same with cultured cells; one also needs to consider whether the enzyme is an integral membrane bound protein, and needs to be optimally liberated from membrane preparations. Examples are differential inhibition of cytosolic and membrane- derived kinase activity; enzyme binding to cell membranes isolated from culture cells; low activity state in a membrane fraction, which can be dramatically enhanced by prior detergent treatment.
Sim, A. T. R., Ratcliffe, E., Mumby, M. C., Villa-Moruzzi, E. and Rostas, J. A. P. (1994), Differential Activities of Protein Phosphatase Types 1 and 2A in Cytosolic and Participate Fractions from Rat Forebrain. Journal of Neurochemistry, 62: 1552–1559. doi: 10.1046/j.1471-4159.1994.62041552.x
Differential inhibition of cytosolic and membrane-derived protein kinase C activity by staurosporine and other kinase inhibitors
FEBS Letters, Volume 362, Issue 2, Pages 139-142
Joanna Budworth, Andreas Gescher
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