The development of a holistic and effective strategy for the control of cell proliferation, and perhaps malignancy expression, depends on the knowledge of the targets of inhibitors of cell growth and their different mechanisms of action. Polyamines play a vital role in prokaryotic and eukaryotic cell growth and differentiation. A compound(s) produced by Pseudomonas cepacia and Bacillus thuringiensis, which inhibit the growth of the fungus Macrophomina phaseolina, may also inhibit methionine and polyamine biosynthesis.
The specific aims of the proposed study are: to purify and characterize the inhibitor(s) produced by Pseudomonas and Bacillus, and to determine the presence of this inhibitor(s) in other bacteria; to determine the enzymatic mechanism by which Macrophomina is inhibited by this compound(s); to examine to what extent this compound(s) inhibits the growth of other cell types; and to determine the relationship between cell growth inhibition by this compound(s) and polyamine biosynthesis. The inhibitor will be purified by ion exchange and high pressure liquid chromatography, and characterized by elemental analysis, an ultraviolet, infrared, nuclear magnetic resonance, and mass spectroscopies. In vitro susceptibility tests, polyamine content determination, and biochemical target determination experiments will be performed. Purification and kinetic characterization, and inhibition studies of the enzymes involved, beta-cystathionase and polyamine biosynthesis enzymes, will follow. Our long term goal is to determine the role, at the molecular level, of this inhibitor(s) in the control of cell growth and differentiation. With this knowledge effective chemotherapeutic strategies can be designed, using selective agents which can penetrate the cell and specifically inhibit essential reactions.
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