Metabolites of De Novo Purine Synthesis: Metabolic Regulators and Cytotoxic Compounds
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F22%3A00567469" target="_blank" >RIV/68378050:_____/22:00567469 - isvavai.cz</a>
Alternative codes found
RIV/00064165:_____/22:10452648 RIV/00216208:11110/22:10452648
Result on the web
<a href="https://www.mdpi.com/2218-1989/12/12/1210" target="_blank" >https://www.mdpi.com/2218-1989/12/12/1210</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.3390/metabo12121210" target="_blank" >10.3390/metabo12121210</a>
Alternative languages
Result language
angličtina
Original language name
Metabolites of De Novo Purine Synthesis: Metabolic Regulators and Cytotoxic Compounds
Original language description
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.
Czech name
—
Czech description
—
Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Metabolites
ISSN
2218-1989
e-ISSN
2218-1989
Volume of the periodical
12
Issue of the periodical within the volume
12
Country of publishing house
CH - SWITZERLAND
Number of pages
16
Pages from-to
1210
UT code for WoS article
000904479700001
EID of the result in the Scopus database
—