Salvage Routes to Deoxyribonucleotide Synthesis

Purine salvage usually involves phosphoribosyltransferase reactions, which generate ribonucleoside monophosphates (rNMPs) from the purine bases and 5-phosphoribosyl-1-pyrophosphate (PRPP). These are phosphorylated to diphosphates (rNDPs) and then reduced to deoxyribonucleotides (dNDPs) with ribonucleotide reductase.

Another salvage route to making deoxyribonucleotides is via deoxyribonucleoside kinases, which can phosphorylate nucleosides to make nucleoside monophosphates. Human cells have four different deoxyribonucleoside kinases:

> 1. Thymidine kinase (located in the cytosol) - phosphorylates deoxythymidine;

> 2. Deoxycytidine kinase (located in cytosol) - phosphorylates deoxycytidine; also phosphorylates deoxyadenosine and deoxyguanosine at higher concentrations;

> 3. Deoxyguanosine kinase (located in mitochondria) - acts on deoxyguanosine; and

> 4. Thymidine kinase (located in mitochondria) - acts on deoxythymidine, deoxycytidine, and deoxyuridine

The activity of mitochondrial thymidine kinase is sufficiently broad that it will also act on the anti-HIV drug, 3'-azido-2'3'-dideoxythymidine (AZT). That is, the enzyme can phosphorylate AZT to a deoxyribonucleotide of azidothymidine, which is then incorporated into DNA. Evidence suggests that deoxyribonucleotides of AZT interfere with mitochondrial function, possibly by inhibiting mitochondrial DNA replication or transcription, which may explain some of the side effects of cardiotoxicity (damage to the heart muscle) observed with its use.

Cytosolic thymidine kinase salvages exogenous thymidine extremely efficiently. Experiments with radiolabeled precursors show that dTTP derived from salvage synthesis is usually incorporated into DNA in preference to thymidine nucleotides generated by de novo synthesis.

See also: Biosynthesis of Thymine Deoxyribonucleotides, Deoxyuridine Nucleotide Metabolism, Ribonucleotide Reductase and Deoxyribonucleotide Biosynthesis, Regulation of Ribonucleotide Reductase, Drug Design, Nucleotide Analogs in Medicine