5'-methylthioadenosine and 5-methylthioribose : studies on their metabolism and function in mammalian cells Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/jq085p292

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  • Although the biological occurrence of 5'-methylthioadenosine (MTA) and 5-methylthioribose (MTR) were recognized more than a half century ago, very little light has been cast on the physiologic significance of either substance. My studies were designed to extend our knowledge of the metabolism of MTA and to determine if this pathway is important in the overall process of cell division. MTA has been shown to exert striking inhibitory effects on cell proliferation. My efforts to study the mode of action of MTA have focused on the modulation of cAMP metabolism by the nucleoside. Evidence is provided which establishes the enzyme cAMP phosphodiesterase as the primary target site for MTA. The importance of this inhibitory activity must await further studies on the size and fluctuation of the intracellular MTA pool during the cell cycle. One might think that since MTA inhibits enzyme reactions vital to cell growth, its rapid degradation is essential simply for maintenance of low intracellular levels. Recent studies suggest, however, that the degradation products of MTA are required for cell growth. A nutritional requirement of methylthio groups for mammalian cells was postulated on the basis that cells which cannot degrade MTA are unable to grow unless synthetic methylthio compounds are added to the culture medium. My attempts to elucidate the critical product of MTA determined that methylthioribose could satisfy the methylthio dependence of cells lacking MTA phosphorylase activity. In addition, I also found that the thiopentose stimulated the growth rate, saturation density, and viability of other cells in culture. The final section of my thesis describes the isolation of MTR from the serum of a variety of mammals. The results were substantiated through the use of various chemical, chromatographic, and spectroscopic methods. In conclusion, I have demonstrated the opposing effects of MTA and MTR towards cell division. These observations suggest that the degradation of MTA and subsequent formation of MTR may represent a pivotal site of control for cell proliferation.
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