Potential Mechanisms Connecting Purine Metabolism and Cancer Therapy

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.

Keywords: cancers; mammalian target of rapamycin; metabolism; purine; purinosome.

Figure 1

Purine metabolism pathways. Purine metabolism includes de novo purine biosynthetic pathway, purine salvage pathway, and degradation. The de novo purine biosynthetic pathway uses six enzymes to catalyze the transformation of phosphoribosylpyrophosphate (PRPP) into inosine 5′-monophosphate (IMP) via 10 highly conserved steps (orange). Purine salvage (green) recycles hypoxanthine, inosine, and adenine as substrates to generate purine nucleotides. Inosine and hypoxanthine can be further oxidized into xanthine and uric acid in the purine degradation pathway (blue).

Figure 2

Purinosome formation and its interaction with mitochondria. PPAT, GART, and FGAMS constitute the core scaffolding structure of purionsome, then, PAICS, ADSL, and ATIC appear to interact peripherally. Assembled purionsomes are mainly localized with mitochondria and interact mutually.

Figure 3

Mammalian target of rapamycin (mTOR)-mediated purine metabolism. In response to growth signal in cancer cells, mTOR activates ATF4, which upregulates enzymes of tetrahydrofolate cycle and provides one-carbon unit formate for de novo purine synthesis. mTOR also serve as a master regulator that senses and mediates amino acids pool, which may further regulate glutamine (Gln), glycine (Gly), and aspartate (Asp) flux into purinosomes.