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Review
. 2024 Sep 3;16(9):1412.
doi: 10.3390/v16091412.

Unveiling the Connection: Viral Infections and Genes in dNTP Metabolism

Shih-Yen Lo  1   2 , Meng-Jiun Lai  1 , Chee-Hing Yang  1   3 , Hui-Chun Li  4
Affiliations
Review

Unveiling the Connection: Viral Infections and Genes in dNTP Metabolism

Shih-Yen Lo et al. Viruses. .

Abstract

Deoxynucleoside triphosphates (dNTPs) are crucial for the replication and maintenance of genomic information within cells. The balance of the dNTP pool involves several cellular enzymes, including dihydrofolate reductase (DHFR), ribonucleotide reductase (RNR), and SAM and HD domain-containing protein 1 (SAMHD1), among others. DHFR is vital for the de novo synthesis of purines and deoxythymidine monophosphate, which are necessary for DNA synthesis. SAMHD1, a ubiquitously expressed deoxynucleotide triphosphohydrolase, converts dNTPs into deoxynucleosides and inorganic triphosphates. This process counteracts the de novo dNTP synthesis primarily carried out by RNR and cellular deoxynucleoside kinases, which are most active during the S phase of the cell cycle. The intracellular levels of dNTPs can influence various viral infections. This review provides a concise summary of the interactions between different viruses and the genes involved in dNTP metabolism.

Keywords: SAMHD1; deoxynucleoside triphosphates; dihydrofolate reductase; ribonucleotide reductase; viruses.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Metabolism of dNTPs in normal cells [1,2,3,4]. Nucleotides could be derived from multiple intracellular sources, such as the products of glycolysis and folate cycle. Dihydrofolate is reduced to active tetrahydrofolate by dihydrofolate reductase (DHFR). Ribonucleotide reductase (RNR) reduces both pyrimidine and purine bases to deoxynucleosides. SAM and HD domain-containing protein 1 (SAMHD1) hydrolyzes dNTPs into deoxynucleosides (dNs) and inorganic triphosphates (PPPi).
Figure 2
Figure 2
Folate metabolic pathway [5,6,7,8]. DHFR catalyzes the transfer of a hydride from the cofactor nicotinamide adenine dinucleotide phosphate (NADPH), which serves as an electron donor, to dihydrofolate (DHF), resulting in the production of tetrahydrofolate (THF) through protonation. Specifically, DHFR facilitates the reduction of 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate using NADPH as a cofactor. Additionally, DHFR works in conjunction with thymidylate synthase, which catalyzes the reductive methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate, using N5-N10-methylenetetrahydrofolate (5,10-Methylene THF) as a cofactor.
Figure 3
Figure 3
Ribonucleotide reductase (RNR) converts the building blocks of RNA into those of DNA. In mammals, RNR enzymes reduce the 2′ carbon of nucleoside diphosphates (NDPs) to form the corresponding deoxynucleoside diphosphates (dNDPs). These dNDPs are then phosphorylated by nucleoside diphosphate kinase to produce deoxynucleoside triphosphates (dNTPs), which are essential for nuclear and mitochondrial DNA replication and repair [9].
Figure 4
Figure 4
SAMHD1, a deoxyribonucleoside triphosphate triphosphohydrolase, hydrolyzes dNTPs into deoxynucleosides (dNs) and inorganic triphosphates (PPPi) that are either recycled or degraded, thereby limiting the dNTP pool and impairing DNA replication [14].
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