Nucleotide Synthesis via Salvage Pathway


The biosynthesis of purine and pyrimidine nucleotides takes place over de novo synthetic pathways from small molecules and by salvage pathways from preformed purine or pyrimidine bases or nucleosides. The pathways of de novo synthesis are the same in animals and microorganisms. Salvage pathways are considerably more energy‐efficient than de novo pathways, which require 5 (pyrimidine) or 6 (purine) moles of ATP for each mole of nucleotide produced. Salvage pathways are integral to the cause or treatment of a number of human diseases of purine or pyrimidine metabolism. Among disorders of purine metabolism, the Lesch–Nyhan disease is characterised by overproduction of uric acid, clinical gout, nephropathy, neurologic disease, and unusual self‐injurious behaviours.

Key Concepts:

  • Salvage of purines is catalysed by adenine phosphoribosyltransferase (APRT) and hypoxanthine guanine phosphoribosyltransferase (HGPRT).

  • Pyrimidine salvage is catalysed by thymidine kinase.

  • Pyrimidine salvage is effective in the treatment of orotic aciduria, a disorder of pyrimidine nucleotide synthesis.

  • Deficiency of APRT leads to renal calculi.

  • Deficiency of HGPRT is the cause of Lesch–Nyhan disease.

Keywords: pathways; enzymes; human disorders; purines; pyrimidines; adenine phosphoribosyltransferase (APRT); hypoxanthine guanine phosphoribosyltransferase (HGPRT)

Figure 1.

Pathways of mammalian purine nucleotide synthesis. The de novo pathway is shown schematically from the top as well as the central role of IMP in nucleotide interrelations. Salvage of purine bases is catalysed by hypoxanthine guanine phosphoribosyltransferase (HGPRT) and adenine phosphoribosyltransferase (APRT). Other abbreviations include: ASL, adenylosuccinate lyase; AMPDA, adenylate deaminase; ADA, adenosine deaminase; PNP, purine nucleoside phosphorylase; XO, xanthine oxidase; and PPi, inorganic pyrophosphate.

Figure 2.

Pathways of mammalian pyrimidine nucleotide synthesis. The de novo pathway is shown at the left. Among the salvage enzymatic pathways, uridine kinase catalyses the formation of CMP as well as UMP, while deoxycytidine kinase catalyses the synthesis of a dCMP and dUMP. Thymidine kinase is specific for the thymidine substrate.



Andersen PS, Smith JM and Mygind B (1992) Characterization of the upp gene encoding uracil phosphoribosyltransferase of Escherichia coli K‐12. European Journal of Biochemistry 204: 51–56.

Bailey CJ (2009) Orotic aciduria and uridine monophosphate synthease: a reappraisal. Journal of Inherited Metabolic Disease (electronic article). doi: 10.1007/s10545‐009‐1176‐y.

Boursaux‐Eude C, Margarita D, Gilles AM, Barzu O and Saint Girons I (1997) Borrelia burgdorferi uridine kinase: an enzyme of the pyrimidine salvage pathway for endogenous use of nucleotides. FEMS Microbiology Letters 151: 257–261.

Harlow KW, Nygaard P and Hove‐Jensen B (1995) Cloning and characterization of the gsk gene encoding guanosine kinase of Escherichia coli. Journal of Bacteriology 177: 2236–2240.

Hershey HV and Taylor MW (1986) Nucleotide sequence and deduced amino acid sequence of Escherichia coli adenine phosphoribosyltransferase and comparison with other analogous enzymes. Gene 43: 287–293.

Hochstadt J (1978) Hypoxanthine phosphoribosyltransferase and guanine phosphoribosyltransferase from enteric bacteria. Methods in Enzymology 51: 549–557.

Hoogenraad NJ and Lee DC (1974) Effect of uridine on de novo pyrimidine biosynthesis in rat hepatoma cells in culture. Journal of Biological Chemistry 249: 2763–2768.

Huguley CM, Bain JA, Rivers SL and Scoggins RB (1959) Refractory megaloblastic anaemia associated with excretion of orotic acid. Blood 14: 615–634.

Iltzsch MH (1993) Pyrimidine salvage pathways in Toxoplasma gondii. Journal of Eukaryotic Microbiology 40: 24–28.

Jinnah HA, Ceballos‐Picot I, Torres RJ et al. (2010) Attenuated variants of Lesch‐Nyhan disease. Brain 133: 671–689.

Jinnah HA, De Gregorio L, Harris JC, Nyhan WL and O'Neill JP (2000) The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutation Research 463: 309–326.

Lesch M and Nyhan WL (1964) A familial disorder of uric acid metabolism and central nervous system function. American Journal of Medicine 36: 561–570.

Marra G, Vercelloni PG, Edefonti A et al. (2012) Adenine phosphoribosyltransferase deficiency: an underdiagnosed cause of lithiasis and renal failure. JIMD Reports 5: 45–48.

Murray AW (1971) The biological significance of purine salvage. Annual Review of Biochemistry 40: 811–826.

Nelson DP and Carter CE (1969) Purification and characterization of thymidine 5′‐monophosphate kinase from Escherichia coli b. Journal of Biological Chemistry 244: 5254–5262.

Nygaard P (1983) Utilization of preformed purine bases and nucleosides. In: Munch‐Petersen A (ed.) Metabolism in Nucleotides, Nucleosides and Nucleobases in Microorganisms, pp. 27–93. London: Academic Press.

Oskoui M, Davidzon G, Pascual J et al. (2006) Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene. Archives of Neurology 63: 1122–1126.

Page T, Bakay B, Nissinen E and Nyhan WL (1981) Hypoxanthine guanine phosphoribosyltransferase variants: correlation of clinical phenotype with enzyme activity. Journal of Inherited and Metabolic Disease 4: 203–206.

Page T, Yu A, Fontanesi J and Nyhan WL (1997) Developmental disorder associated with increased cellular nucleotidase activity. Proceedings of the National Academy of Sciences of the United States of America 94: 11601–11606.

Saada A, Shaag A, Mandel H et al. (2001) Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nature Genetics 29: 324–344.

Seegmiller JE, Rosenbloom FM and Kelley WN (1967) Enzyme defect associated with a sex‐linked human neurological disorder and excessive purine synthesis. Science 155: 1682–1684.

Stuer‐Larudsen B and Nygaard P (1998) Purine salvage in two halophilic Archaea: characterization of salvage pathways and isolation of mutants resistant to purine analogs. Journal of Bacteriology 180: 457–463.

Van Acker KJ, Simmonds HA, Potter CF and Cameron JS (1977) Complete deficiency of adenine phosphoribosyltransferase: report of a family. New England Journal of Medicine 297: 127–132.

Van Groeningen CJ, Peters GJ, Nadal JG, Laurensse E and Pinedo HM (1991) Clinical and pharmacologic study of orally administered uridine. Journal of the National Cancer Institute 83: 437–441.

Further Reading

Murray AW, Elliott DC and Atkinson MR (1970) Nucleotide biosynthesis from preformed purines in mammalian cells: regulatory mechanisms and biological significance. Progress in Nucleic Acid Research and Molecular Biology 10: 87–119.

Neidhardt FC (1996) Escherichia coli and Salmonella. Cellular and Molecular Biology. Washington, DC: ASM Press.

Nyhan WL, Barshop BB and Al‐Aqeel AI (2012) Atlas of Inherited Metabolic Disease, 3rd edn. London: Hodder Arnold.

Rosenberg RN, DiMauro S, Paulson HL, Ptácek L and Nestler EJ (eds) (2007) The Molecular and Genetic Basis of Neurological and Psychiatric Disease, 4th edn. Philadelphia, PA: Lippincott, Williams & Wilkins.

Scriver CR, Beaudet AL, Sly WS and Valle D (eds) (2001) The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw‐Hill.

Simmonds HA and van Gennip AH (2003) Purine and pyrimidine disorders. In: Blau N, Duran M, Blaskovics M and Gibson KM (eds) Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases, pp. 445–465. Berlin: Springer.

Sinha SC and Smith JL (2001) The PRT protein family. Current Opinion in Structural Biology 11: 733–739.

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

* Required Field

How to Cite close
Nyhan, William L(Dec 2014) Nucleotide Synthesis via Salvage Pathway. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001399.pub3]