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Mimosine inhibits viral DNA synthesis through ribonucleotide reductase
Y Dai1, B Gold, J K Vishwanatha
1Eppley Institute, Omaha, Nebraska.
Abstract:
The plant amino acid mimosine (beta-N(3-hydroxy-4-pyridone)-alpha-amino propionic acid) is toxic for animals and reversibly inhibits the replication of animal cells in vitro. We have found that mimosine inhibits the DNA synthesis of a variety of DNA viruses, including adenovirus, parvovirus, and papovavirus and the replication of vaccinia and herpes simplex virus 1 in cells in culture. However, mimosine did not inhibit the replication of SV40 DNA in a cell-free system. Because mimosine inhibition of viral DNA synthesis was reversible by iron in the medium, we hypothesized that mimosine was inhibiting ribonucleotide reductase through its capacity to chelate the iron required in the R2 subunit of this enzyme. In support of this hypothesis, we found that mimosine-treated cells had a reduction in the pools of dGTP and dATP and that mimosine inhibited ribonucleotide reductase in vitro in an iron-dependent manner.
Insights
Mimosine, a plant amino acid, inhibits viral DNA synthesis by chelating iron, essential for ribonucleotide reductase. This effect is reversible with iron, impacting viral replication.
Area of Science:
- Biochemistry
- Virology
- Molecular Biology
Background:
- Mimosine is a plant amino acid known for its toxicity to animals and its ability to inhibit animal cell replication.
- Mimosine's effects on viral replication were not fully understood, prompting further investigation into its mechanism of action.
Purpose of the Study:
- To investigate the effect of mimosine on the DNA synthesis of various DNA viruses.
- To elucidate the mechanism by which mimosine inhibits viral DNA synthesis and replication.
Main Methods:
- Assessing mimosine's impact on the replication of adenovirus, parvovirus, papovavirus, vaccinia virus, and herpes simplex virus 1 in cell cultures.
- Evaluating mimosine's effect on SV40 DNA replication in a cell-free system.
- Measuring the levels of deoxynucleotide triphosphates (dGTP and dATP) in mimosine-treated cells.
- Testing mimosine's inhibitory activity on purified ribonucleotide reductase in vitro.
Main Results:
- Mimosine inhibited the DNA synthesis of multiple DNA viruses and the replication of vaccinia and herpes simplex virus 1 in cultured cells.
- Mimosine did not inhibit SV40 DNA replication in a cell-free system.
- The inhibitory effect of mimosine on viral DNA synthesis was reversed by the addition of iron.
- Mimosine treatment led to reduced intracellular pools of dGTP and dATP.
- Mimosine demonstrated iron-dependent inhibition of ribonucleotide reductase activity in vitro.
Conclusions:
- Mimosine inhibits viral DNA synthesis by targeting the enzyme ribonucleotide reductase.
- The mechanism involves mimosine's iron-chelating properties, which interfere with the iron cofactor in the R2 subunit of ribonucleotide reductase.
- This inhibition affects the availability of essential deoxynucleotides for viral DNA replication.