Metabolites of De Novo Purine Synthesis: Metabolic Regulators and Cytotoxic Compounds

0567469 - ÚMG 2023 RIV CH eng J - Článek v odborném periodiku
Součková, O. - Škopová, V. - Barešová, V. - Sedlák, David - Bleyer, A. J. - Kmoch, S. - Zikánová, M.
Metabolites of De Novo Purine Synthesis: Metabolic Regulators and Cytotoxic Compounds.
Metabolites. Roč. 12, č. 12 (2022), č. článku 1210. E-ISSN 2218-1989
Grant CEP: GA MŠMT(CZ) LM2018130
Výzkumná infrastruktura: NCMG II - 90132
Institucionální podpora: RVO:68378050
Klíčová slova: purine synthesis * pfas * paics * adsl * atic * cytotoxicity * fgar * air * saicar * aicar
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 4.1, rok: 2022
Způsob publikování: Open access
https://www.mdpi.com/2218-1989/12/12/1210

Cytotoxicity of de novo purine synthesis (DNPS) metabolites is critical to the pathogenesis of three known and one putative autosomal recessive disorder affecting DNPS. These rare disorders are caused by biallelic mutations in the DNPS genes phosphoribosylformylglycineamidine synthase (PFAS), phosphoribosylaminoimidazolecarboxylase/phosphoribosylaminoimidazolesuccinocarboxamide synthase (PAICS), adenylosuccinate lyase (ADSL), and aminoimidazole carboxamide ribonucleotide transformylase/inosine monophosphate cyclohydrolase (ATIC) and are clinically characterized by developmental abnormalities, psychomotor retardation, and nonspecific neurological impairment. At a biochemical level, loss of function of specific mutated enzymes results in elevated levels of DNPS ribosides in body fluids. The main pathogenic effect is attributed to the accumulation of DNPS ribosides, which are postulated to be toxic to the organism. Therefore, we decided to characterize the uptake and flux of several DNPS metabolites in HeLa cells and the impact of DNPS metabolites to viability of cancer cell lines and primary skin fibroblasts. We treated cells with DNPS metabolites and followed their flux in purine synthesis and degradation. In this study, we show for the first time the transport of formylglycinamide ribotide (FGAR), aminoimidazole ribotide (AIR), succinylaminoimidazolecarboxamide ribotide (SAICAR), and aminoimidazolecarboxamide ribotide (AICAR) into cells and their flux in DNPS and the degradation pathway. We found diminished cell viability mostly in the presence of FGAR and AIR. Our results suggest that direct cellular toxicity of DNPS metabolites may not be the primary pathogenetic mechanism in these disorders.
Trvalý link: https://hdl.handle.net/11104/0338718