Deoxyribonucleotide Triphosphate Metabolism in Cancer and Metabolic Disease

Abstract

The maintenance of a healthy deoxyribonucleotide triphosphate (dNTP) pool is critical for the proper replication and repair of both nuclear and mitochondrial DNA. Temporal, spatial, and ratio imbalances of the four dNTPs have been shown to have a mutagenic and cytotoxic effect. It is, therefore, essential for cell homeostasis to maintain the balance between the processes of dNTP biosynthesis and degradation. Multiple oncogenic signaling pathways, such as c-Myc, p53, and mTORC1 feed into dNTP metabolism, and there is a clear role for dNTP imbalances in cancer initiation and progression. Additionally, multiple chemotherapeutics target these pathways to inhibit nucleotide synthesis. Less is understood about the role for dNTP levels in metabolic disorders and syndromes and whether alterations in dNTP levels change cancer incidence in these patients. For instance, while deficiencies in some metabolic pathways known to play a role in nucleotide synthesis are pro-tumorigenic (e.g., p53 mutations), others confer an advantage against the onset of cancer (G6PD). More recent evidence indicates that there are changes in nucleotide metabolism in diabetes, obesity, and insulin resistance; however, whether these changes play a mechanistic role is unclear. In this review, we will address the complex network of metabolic pathways, whereby cells can fuel dNTP biosynthesis and catabolism in cancer, and we will discuss the potential role for this pathway in metabolic disease.

Keywords: c-Myc; diabetes; mTORC1; obesity; p53; purines; pyrimidines.

Figure 1

Pathways of deoxyribonucleotide metabolism in mammalian cells. Simplified representation of purine (blue) and pyrimidine (orange) metabolism and their crosstalk with the major metabolic pathways, the pentose phosphate pathway [(PPP), red] and the tricarboxylic acid cycle (green). Key metabolic enzymes (green), their principal reactive substrates (gray), and the four deoxyribonucleotide triphosphate (dNTP) end-products (magenta) are shown. Glucose and glutamine feed into both purine and pyrimidine metabolism to donate carbons and nitrogens to all dNTPs. Abbreviations: RAT, phosphoribosylpyrophosphate amidotransferase; GARS, glycinamide ribonucleotide synthetase; GART, glycinamide ribonucleotide transformylase; FGAMS, phosphoribosylformyl-glycineamide synthetase; AIRS, phosphoribosylaminoimidazole synthetase; AIRC, phosphoribosylaminoimidazole carboxylase; SAICAR, phosphoribosylaminoimidazole-succinocarboxamide; ADSL, adenylosuccinate lyase; AICART, phosphoribosylaminoimidazolecarboxamide formyltransferase; IMPS, inosine monophosphate synthase; ADSS, adenylosuccinate synthetase; AK, adenylate kinase; NMPK, nucleotide monophosphate kinase; IMPS, inosine monophosphate dehydrogenase; GMPS, guanosine monophosphate synthetase; GK, guanylate kinase; XOR, xanthine oxidoreductase; HGPRT, hypoxanthine-guanine phosphoribosyltransferase; RNR, ribonucleotide reductase; CPS II, carbamoyl phosphate synthetase II; ATC, aspartate carbamoyltransferase; DHO, dihydroorotase; DHOD, dihydroorotase dehydrogenase; OPRT, orotate phosphoribosyltransferase; OMPD, orotidine monophosphate decarboxylase; CPTS, cytidine triphosphate synthetase; TS, thymidylate synthase; DUD, dihydrouracil dehydrogenase; DHP, dihydropyrimidinase; UP, ureidopropionase; Glut, glutamine; Gly, glycine; FTHF, N10-formyltetrahydrofolate; Asp, aspartate; PRPP, phosphoribosylpyrophosphate; Q, ubiquinone; MTHF, N5,N10-methylenetetrahydrofolate.