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.

• Keywords
• ADSL, AICAR, AIR, ATIC, FGAR, PAICS, PFAS, SAICAR, cytotoxicity, purine synthesis,
• Publication type
• Journal Article MeSH

• MeSH
• Adenosine analogs & derivatives   cerebrospinal fluid   MeSH
• Aminoimidazole Carboxamide analogs & derivatives   cerebrospinal fluid   MeSH
• Fumarate Hydratase deficiency   genetics   MeSH
• Fumarates cerebrospinal fluid   urine   MeSH
• Infant MeSH
• Humans MeSH
• Central Nervous System Diseases enzymology   MeSH
• Purines cerebrospinal fluid   MeSH
• Ribonucleosides cerebrospinal fluid   MeSH
• Check Tag
• Infant MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenosine MeSH
• Aminoimidazole Carboxamide MeSH
• Fumarate Hydratase MeSH
• Fumarates MeSH
• fumaric acid MeSH Browser
• Purines MeSH
• Ribonucleosides MeSH
• succinyladenosine MeSH Browser
• succinylaminoimidazole carboxamide riboside MeSH Browser