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

Overview

Journal Metabolites

Publisher MDPI

Date 2022 Dec 23

PMID 36557247

Authors

Olga Souckova

Vaclava Skopova

Veronika Baresova

David Sedlak

Anthony J Bleyer

Stanislav Kmoch

Marie Zikanova

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Expanding clinical spectrum of PAICS deficiency: Comprehensive analysis of two sibling cases.

Weng W, Skopova V, Baresova V, Liu Y, Hsueh H, Chien Y Eur J Hum Genet. 2024; .

PMID: 39604553 DOI: 10.1038/s41431-024-01752-2.

Inborn Errors of Purine Salvage and Catabolism.

Camici M, Garcia-Gil M, Allegrini S, Pesi R, Bernardini G, Micheli V Metabolites. 2023; 13(7).

PMID: 37512494 PMC: 10383617. DOI: 10.3390/metabo13070787.

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