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Nucleotide Synthesis in Cancer Cells
In neoplastic?cells, the de novo synthesis of nucleotides?is responsible for maintaining sufficient nucleotide libraries to support DNA replication and RNA production. The metabolic pathways that support nucleotide production are dependent on metabolic intermediates provided by glycolysis and the TCA cycle.1?Metabolic reprogramming that occurs during tumor formation helps to increase the utilization of these intermediates in anabolic pathways. Therefore, neoplastic cells control the flux of glycolysis at multiple control points to facilitate the accumulation of metabolites that enter the biosynthetic pathways.
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Metabolites from glycolysis are shunted into the pentose phosphate pathway (PPP) to produce ribose-5-phosphate (i.e., the five-carbon sugar molecule of nucleotides) for nucleotide synthesis. The pentose phosphate pathway is divided into two branches, an oxidative branch that produces ribose-5-phosphate and NADPH-reducing equivalents, and a non-oxidative branch that produces ribulose-5-phosphate. In neoplastic?cells, transketolases and transaldolases that catalyze the two-step reversible reaction of the non-oxidative phase of the pentose phosphate pathway have higher expression and activity1. The reactions of the nonoxidative branch of the PPP are reversible. Therefore, in order to maintain ribose-5-phosphate production, cells need to be supplied with high levels of the glycolytic intermediates glyceraldehyde-3-phosphate and fructose-6-phosphate. Most tumor cells express the inactive dimeric form of pyruvate kinase M2 (PKM2), which catalyzes the final step of glycolysis: pyruvate formation. And the decreased activity of PKM2?leads to the accumulation of upstream metabolic intermediates, which are then shunted to other biosynthetic pathways.2?Additionally, many oncogenic cells upregulate the activity and expression of PPP enzyme transketolase. High expression of trans-ketolase-like protein 1 (TKTL1), in particular, and other poor prognostic factors are correlated in most tumor cells.3
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In cancer cells, the synthesis of purines and pyrimidines?is also upregulated in tumor cells, including thymidylate synthase and inosine synthetase 2, and the enzymes catalyzing these biosynthetic pathways are upregulated by Myc gene induction.1,4?Because the amide group of glutamine is a nitro donor essential for purine and pyrimidine base biosynthesis, Myc genes also upregulate glutamine uptake and metabolism.5?In addition, glutamine metabolism is also the main mechanism of TCA back-completion, and in order for the TCA cycle to continue to function as a biosynthetic center, anaplerotic reactions are required to complement the TCA cycle to supplement the TCA intermediates transferred for nucleotide synthesis.
Reference：
1.Tong?X,?Zhao?F,?Thompson?CB.?2009.?The molecular determinants of de novo nucleotide biosynthesis in cancer cells.?Current Opinion in Genetics & Development.?19(1):32-37.?https://doi.org/10.1016/j.gde.2009.01.002
2.DeBerardinis?RJ,?Sayed?N,?Ditsworth?D,?Thompson?CB.?2008.?Brick by brick: metabolism and tumor cell growth.?Current Opinion in Genetics & Development.?18(1):54-61.?https://doi.org/10.1016/j.gde.2008.02.003
3.Langbein?S,?Zerilli?M,?zur Hausen?A,?Staiger?W,?Rensch-Boschert?K,?Lukan?N,?Popa?J,?Ternullo?MP,?Steidler?A,?Weiss?C,?et al.?2006.?Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted.?Br J Cancer.?94(4):578-585.?https://doi.org/10.10338/sj.bjc.6602962
4.Mannava?S,?Grachtchouk?V,?Wheeler?LJ,?Im?M,?Zhuang?D,?Slavina?EG,?Mathews?CK,?Shewach?DS,?Nikiforov?MA.?2008.?Direct role of nucleotide metabolism in C-MYC-dependent proliferation of melanoma cells.?Cell Cycle.?7(15):2392-2400.?https://doi.org/10.4161/cc.6390
5.Wise?DR,?Thompson?CB.?2010.?Glutamine addiction: a new therapeutic target in cancer.?Trends in Biochemical Sciences.?35(8):427-433.?https://doi.org/10.1016/j.tibs.2010.05.003
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