Abstract
Unrestricted cell proliferation is a hallmark of cancer. Purines are basic components of nucleotides in cell proliferation, thus impaired purine metabolism is associated with the progression of cancer. The de novo biosynthesis of purine depends on six enzymes to catalyze the conversion of phosphoribosylpyrophosphate to inosine 5′-monophosphate. These enzymes cluster around mitochondria and microtubules to form purinosome, which is a multi-enzyme complex involved in de novo purine biosynthesis and purine nucleotides requirement. In this review, we highlighted the purine metabolism and purinosome biology with emphasis on the therapeutic potential of manipulating of purine metabolism or purinosome in cancers. We also reviewed current advances in our understanding of mammalian target of rapamycin for regulating purinosome formation or purine metabolism in cancers and discussed the future prospects for targeting purinosome to treat cancers.
Highlights
Normal cells undergo a series of highly regulated physiological responses to provide necessary substrates for the basic cellular processes, while cancer cells are involved in a complex metabolic rearrangement characterized by an increase in energy production and biosynthetic processes to sustain cell growth and proliferation [1,2,3,4,5,6,7,8]
We described the potential therapeutic strategies for cancers by targeting purine metabolism and purinosome, which may be used to reprogram cancer metabolism
AG2037 treatment markedly inhibits mTOR complex 1 (mTORC1) activation and robust tumor growth in mice bearing non-small-cell lung cancer xenografts [94]. These results confirm the mutual interaction among mammalian target of rapamycin (mTOR), mitochondria, and the de novo purine biosynthetic pathway, and further studies are needed to explore the therapeutic effects of inhibitors for purine biosynthesis and the underlying mechanism of mTOR-mediated purinosome-mitochondria localization and purine metabolism in cancers
Summary
Normal cells undergo a series of highly regulated physiological responses to provide necessary substrates for the basic cellular processes, while cancer cells are involved in a complex metabolic rearrangement characterized by an increase in energy production and biosynthetic processes to sustain cell growth and proliferation [1,2,3,4,5,6,7,8]. The de novo biosynthetic pathway is energy intensive, and numerous amino acid substrates and one-carbon units contribute to the 10-step enzymatic processes, such as glutamine, ATP, and Metabolic pathway is generally assembled with several sequential enzymes into a higher order protein structure to facilitate metabolic flux, and the formation of the protein complex of enzymes is known as metabolon [16].
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