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The Mechanism of the Selective Antiproliferation Effect of Guanine-Based Biomolecules and Its Compensation

The Mechanism of the Selective Antiproliferation Effect of Guanine-Based Biomolecules and Its Compensation

Junyan Wang, Tao Bing, Nan Zhang, Luyao Shen, Junqing He, Xiangjun Liu, Linlin Wang, Dihua Shangguan

ACS Chem Biol. 2019 Jun 21;14(6):1164-1173.

PMID: 31083967

Abstract:

As endogenous biomolecules, guanine, guanine-based nucleosides, and nucleotides are essential for cellular DNA/RNA synthesis, energy metabolism, and signal transduction. However, these biomolecules have been found to have a cell-specific antiproliferation effect at higher concentrations, and the mechanism is unclear. In this study, we demonstrate that guanine deaminase (GDA) is a major factor in determining the cell-type selectivity to the antiproliferation effect of guanine-based biomolecules. GDA catalyzes the deamination of guanine to xanthine, which is an essential part of the guanine degradation pathway. GDA deficient cells could not efficiently remove the excess guanine-based biomolecules. These excess molecules disturb the metabolism of adenine-, cytosine-, and thymine-based nucleotides; subsequently inhibit the DNA synthesis and cell growth; and eventually result in the apoptosis/death of GDA deficient cells. The inhibition of DNA synthesis could be relieved by simultaneous addition of adenine- and cytosine-based nucleosides, and the inhibited DNA synthesis could be restarted by post addition of them, which subsequently reduces the antiproliferation effect of guanine-based biomolecules or even totally restores the cell proliferation. These results provide important information for the development of guanine-based drugs or guanine-rich oligonucleotide drugs, as well as for the safety evaluation of food with a high level of guanine-based compounds.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP73405-A	Guanine		73-40-5	Price

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