The Mechanism of the Selective Antiproliferation Effect of Guanine-Based Biomolecules and Its Compensation.
ACS Chem Biol
; 14(6): 1164-1173, 2019 06 21.
Article
en En
| MEDLINE
| ID: mdl-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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proliferación Celular
/
Guanina
/
Nucleósidos
/
Nucleótidos
Límite:
Humans
Idioma:
En
Revista:
ACS Chem Biol
Año:
2019
Tipo del documento:
Article
País de afiliación:
China