2. Academic Validation
  3. Entecavir competitively inhibits deoxyguanosine and deoxyadenosine phosphorylation in isolated mitochondria and the perfused rat heart

Entecavir competitively inhibits deoxyguanosine and deoxyadenosine phosphorylation in isolated mitochondria and the perfused rat heart

  • J Biol Chem. 2022 May;298(5):101876. doi: 10.1016/j.jbc.2022.101876.
Avery S Ward 1,  Chia-Heng Hsiung 2,  Daniel G Kesterson 3,  Vasudeva G Kamath 4,  Edward E McKee 5
Affiliations

Affiliations

  • 1 Department of Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, Michigan, USA.
  • 2 Department of Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, Michigan, USA; School of Science, Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang Province, China.
  • 3 Department of Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, Michigan, USA; Department of Health Management and Policy, University of Michigan School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
  • 4 Department of Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, Michigan, USA; Department of Basic Medical Sciences, Touro College of Osteopathic Medicine, Middletown, New York, USA.
  • 5 Department of Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, Michigan, USA. Electronic address: mckee1ee@cmich.edu.
PMID: 35358513 DOI: 10.1016/j.jbc.2022.101876
Abstract

Deoxyguanosine kinase (DGK) is reported responsible for the phosphorylation of deoxyadenosine (dA) and deoxyguanosine (dG) in the mitochondrial purine salvage pathway. Antiviral nucleoside analogs known as nucleoside Reverse Transcriptase inhibitors (NRTIs) must be phosphorylated by host Enzymes for the analog to become active. We address the possibility that NRTI purine analogs may be competitive inhibitors of DGK. From a group of such analogs, we demonstrate that entecavir (ETV) competitively inhibited the phosphorylation of dG and dA in rat mitochondria. Mitochondria from the brain, heart, kidney, and liver showed a marked preference for phosphorylation of dG over dA (10-30-fold) and ETV over dA (2.5-4-fold). We found that ETV inhibited the phosphorylation of dG with an IC50 of 15.3 ± 2.2 μM and that ETV and dG were both potent inhibitors of dA phosphorylation with IC50s of 0.034 ± 0.007 and 0.028 ± 0.006 μM, respectively. In addition, the phosphorylation of dG and ETV followed Michaelis-Menten kinetics and each competitively inhibited the phosphorylation of the other. We observed that the kinetics of dA phosphorylation were strikingly different from those of dG phosphorylation, with an exponentially lower affinity for DGK and no effect of dA on dG or ETV phosphorylation. Finally, in an isolated heart perfusion model, we demonstrated that dG, dA, and ETV were phosphorylated and dG phosphorylation was inhibited by ETV. Taken together, these data demonstrate that DGK is inhibited by ETV and that the primary role of DGK is in the phosphorylation of dG rather than dA.

Keywords

mitochondria; mitochondrial disease; nucleoside/nucleotide biosynthesis; nucleoside/nucleotide metabolism.

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