Nucleotide Degradation


Nucleotide degradation is an integrated process in all human cells that is intimately linked with the pathways of nucleotide synthesis and salvage. The clinical conditions associated with defects of enzymes catalysing nucleotide degradation provide a valuable insight into the importance of this network.

Keywords: inherited defects; immunodeficiency; bone marrow transplantation; neurological deficits; antimetabolite toxicity; neurotoxicity

Figure 1.

Metabolic end products of purine and pyrimidine degradation in humans. Routes of pyrimidine (green) and purine (red) nucleotide degradation showing the structural formula and numbering of the atoms in the respective ring structures of UMP (uridine 5′‐monophosphate) and IMP (inosine 5′‐monophosphate), central intermediates in nucleotide degradation. CMP and UMP are degraded to uridine and largely recycled, since most human cells, except liver, lack URP. A different battery of enzymes degrades TMP (thymidine 5′‐monophosphate) to thymine. The purine nucleotides IMP and GMP are degraded via the corresponding nucleosides to the constituent bases hypoxanthine and guanine, respectively, and recycled at this level. Further catabolism of nonrecycled degradation products in the liver leads to the formation of β‐alanine and β‐aminoisobutyric acid for pyrimidines, which enter the CAC, and the metabolic end product uric acid for purines (blue).

Figure 2.

Part of a DNA chain. (a) Structural formulae of the four constituent bases, adenine and guanine (red), cytosine and thymine (green), showing that the deoxyribose has a hydrogen atom at the 2′ position on the pentose ring, instead of the hydroxyl group of ribose. These bases are linked via the 3′‐OH group of the deoxyribose‐phosphate moiety to the 5′‐OH group of the next deoxyribose. (b) Schematic representation of the manner in which the above bases are linked on strands making infinite variation possible, depending on the order of these bases. (c) Schematic representation of the role of hydrogen bonding between bases on opposite strands in contributing to the stability of this double‐helical structure. The adenine–thymine base pair forms two hydrogen bonds, whereas the guanine–cytosine base pair forms three hydrogen bonds. Colour code for (b) and (c) as for (a).

Figure 3.

Structural formula of ATP. Structural formula of adenosine 5′‐triphosphate (ATP), indicating the numbering of the atoms in the ribose, as well as the purine ring.

Figure 4.

Fate of oral purine and pyrimidine nucleotides in humans. (a) Up to 50% of dietary purines are degraded to CO2 in the gut by bacteria. The remaining purines are degraded by a battery of enzymes present in the intestinal mucosa which includes XDH, thereby ensuring their conversion into uric acid prior to absorption. (b) Dietary pyrimidines are partially degraded to CO2 in the gut by bacteria. Because uridine phosphorylase (URP) is not present in the intestinal mucosa in humans, dietary pyrimidines escaping bacterial degradation are absorbed in the form of uridine and thymidine. The pyrimidine nucleosides are then taken up by tissues expressing the relevant kinases. In liver, uridine and thymidine are degraded to uracil and thymine by URP and thymidine phosphorylase (TP), respectively, and are catabolized further in three steps to β‐alanine and β‐aminoisobutyric acid, respectively, as shown in Figure . DPD, catalysing the first step is ubiquitously expressed in many tissues, but DHP and UP are only expressed in liver and kidney.

Figure 5.

Enzymes defective in inborn errors of nucleotide degradation. Metabolic pathways of purine (red) and pyrimidine (green) nucleotide degradation, via the nucleoside and base to the respective metabolic end products (blue), indicating the enzymes (pink) deficient in genetic disorders affecting these pathways. The ‘extra‐purine’ origin of adenine (end product of the polyamine pathway) and its degradation to 2,8‐dihydroxyadenine by XDH, when the salvage enzyme adenine phosphoribosyltransferase is defective, is indicated in the inset on the left. Abbreviations: ADA, adenosine deaminase; AMPDA, myoadenylate deaminase; BAPAT, β‐alanine–pyruvate aminotransferase; BAKAT, β‐alanine‐ketoglutarate aminotransferase; BAIBPAT, β‐amino isobutyrate‐pyruvate aminotransferase; CAC, citric acid cycle; DHP, dihydropyrimidinase; DPD, dihydropyrimidine dehydrogenase; PNP, purine nucleoside phosphorylase; TP, thymidine phosphorylase UMPH‐1, UMP‐hydrolase (or Py5′‐N, pyrimidine 5′‐nucleotidase); UP, ureidopropionase; URP, uridine phosphorylase; XDH, xanthine dehydrogenase.



Aldrich MB, Blackburn MR and Kellems RE (2000) The importance of adenosine deaminase for lymphocyte development and function. Biochemical and Biophysical Research Communications 272: 311–315.

Anderson JL, Habashi J, Carlquist JF et al. (2000) A common variant of the AMPD1 gene predicts improve cardiovascular survival in patients with coronary artery disease. Journal of the American College of Cardiology 36: 1248–1252.

Bianchi P, Fermo E, Allinito F et al. (2003) Molecular characterization of six unrelated Italian patients affected by pyrimidine 5′‐nucleotidase deficiency. British Journal of Haematology 122: 847–851.

Carpenter PA, Ziegler JB and Vowels MR (1996) Late diagnosis of purine nucleoside phosphorylase deficiency with allogeneic bone marrow transplantation. Bone Marrow Transplantation 17: 121–124.

De Korte D, Van Doorn CCH, Sijstermans JMJ, Van Gennip AH and Roos D (1989) Deficiency of pyrimidine 5′‐nucleotidase in human leukocytes. Journal of Inherited Metabolic Disorders 12: 267–272.

Deng Y, Wang Z, Ying K et al. (2002) NADPH‐dependent GMP reductase of human expression, purification, and kinetic properties. International Journal of Biochemistry & Cell Biology 34: 1035–1050.

Genetta T, Morisaki H, Morisaki T et al. (2001) A novel bipartite splicing enhancer promotes the inclusion of a mini‐exon in the AMP deaminase 1 gene. Journal of Biological Chemistry 276: 25589–25597.

Gross M (1997) Clinical heterogeneity and molecular mechanisms in inborn muscle AMP deaminase deficiency. Journal of Inherited Metabolic Disorders 20: 186–192.

Hamajima N, Kouwaki M, Vreken P et al. (1998) Dihydropyrimidinase deficiency: structural organisation, chromosomal localization and mutation analysis of the human dihydropyrimidinase gene. American Journal of Human Genetics 63: 717–726.

Johansson M (2003) Identification of a novel human uridine phosphorylase. Biochemical and Biophysical Research Communications 307: 41–46.

Mahnke‐Zizelman DK, van den Bergh F, Bausch‐Jurken MT et al. (1996) Cloning, sequence and characterization of the human AMPD2 gene: evidence for transcriptional regulation by two closely spaced promoters. Biochimica et Biophysica Acta 1308: 122–132.

McKusick VA (1998) Mendelian Inheritance in Man. Catalogs of Human Genes and Genetic Disorders, 12th edn. Baltimore: Johns Hopkins University Press.

Paglia DE, Valentine WN and Brockway RA (1984) Identification of thymidine nucleotidase and deoxyribonucleotidase activities among normal isoenzymes of 5′‐nucleotidase in human erythrocytes. Proceedings of the National Academy of Sciences of the USA 81: 588–592.

Scriver CR, Beaudet AL, Sly WS and Valle D (eds) (1995) In: Purines and pyrimidines. The Metabolic and Molecular Basis of Inherited Disease, 7th ed. vol. II, chaps 49–55, pp. 1655–1940. New York: McGraw‐Hill

Scriver CR, Beaudet AL and Sly WS et al.(eds) (2001) In: Purines and pyrimidines. The Metabolic and Molecular Basis of Inherited Disease, 8th edn. New York: McGraw‐Hill.

Stone TW and Simmonds HA (1991) Purines: Basic and Clinical Aspects. London: Kluwer.

Van Gennip AH, Abeling NGGM, Vreken P and Van Kuilenburg ABP (1997) Inborn errors of pyrimidine degradation: clinical biochemical and molecular aspects. Journal of Inherited Metabolic Diseases 20: 203–213.

Van Kuilenburg ABP, Vreken P, Abeling NGGM et al. (1999) Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Human Genetics 104: 1–9.

Van Kuilenburg ABP, Meinsma R, Zonnenberg BA et al. (2003) Dihydropyrimidinase deficiency and severe 5‐fluorouracil toxicity. Clinical Cancer Research 9: 4363–4367.

Van Kuilenburg ABP, Stroomer AEM, Van Lenthe H et al. (2004) New insights in dihydropyrimidine dehydrogenase deficiency. A pivotal role for β‐aminoisobutyric acid?. Biochemical Journal 379: 119–124.

Vreken P, Van Kuilenburg ABP, Hamajima N et al. (1999) cDNA cloning, genomic structure and chromosomal localization of the human BUP‐1 gene encoding β‐ureidopropionase. Biochimica et Biophysica Acta 1447: 251–257.

Yoshimura A, Kuwazuru Y, Furukawa T et al. (1990) Purification and tissue distribution of human thymidine phosphorylase; high expression in lymphocytes, reticulocytes and tumors. Biochimica et Biophysica Acta 1034: 107–113.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Bierau, Jörgen, van Kuilenburg, André BP, and van Gennip, Albert H(Sep 2005) Nucleotide Degradation. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0003908]