AICAR transformylase/IMP cyclohydrolase (ATIC) is essential for de novo purine biosynthesis and infection by Cryptococcus neoformans

Wizrah, Maha S.I.; Chua, Sheena M.H.; Luo, Zhenyao; Manik, M.K.; Pan, Mengqi; Whyte, Jessica; Robertson, Avril A. B.; Kappler, Ulrike; Kobe, Boštjan; Fraser, James A.

doi:10.1016/j.jbc.2022.102453

Cited by 5 publications

(4 citation statements)

References 62 publications

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“…The defects of ade16 ade17 double mutant in S. cerevisiae are consistent with disruption of the AICAR transformylase/IMP cyclohydrolase (ATIC) encoded by the gene ADE16 in Cryptococcus neoformans which is a fungal pathogen causing meningoencephalitis in the immunocompromised ( Tibbetts and Appling, 2000 ; Wizrah et al, 2022 ). In C. neoformans , ADE16 deletion resulted in adenine and histidine auxotrophs and lead to the block of the establishment of infection to a murine model ( Wizrah et al, 2022 ). Similar to C. neoformans , F. graminearum also has only one orthologous gene ( ACD16 ) of yeast ADE16 and ADE17 .…”

Section: Importance Of Imp De Novo Synthesis In Pl...mentioning

confidence: 64%

Purine metabolism in plant pathogenic fungi

Sun,

Dai,

Cao

et al. 2024

Front. Microbiol.

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In eukaryotic cells, purine metabolism is the way to the production of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) and plays key roles in various biological processes. Purine metabolism mainly consists of de novo, salvage, and catabolic pathways, and some components of these pathways have been characterized in some plant pathogenic fungi, such as the rice blast fungus Magnaporthe oryzae and wheat head blight fungus Fusarium graminearum. The enzymatic steps of the de novo pathway are well-conserved in plant pathogenic fungi and play crucial roles in fungal growth and development. Blocking this pathway inhibits the formation of penetration structures and invasive growth, making it essential for plant infection by pathogenic fungi. The salvage pathway is likely indispensable but requires exogenous purines, implying that purine transporters are functional in these fungi. The catabolic pathway balances purine nucleotides and may have a conserved stage-specific role in pathogenic fungi. The significant difference of the catabolic pathway in planta and in vitro lead us to further explore and identify the key genes specifically regulating pathogenicity in purine metabolic pathway. In this review, we summarized recent advances in the studies of purine metabolism, focusing on the regulation of pathogenesis and growth in plant pathogenic fungi.

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Section: Importance Of Imp De Novo Synthesis In Pl...mentioning

confidence: 64%

Purine metabolism in plant pathogenic fungi

Sun,

Dai,

Cao

et al. 2024

Front. Microbiol.

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“…However, a key metabolic hallmark of increasing nucleotide de novo synthesis to fit cell growth is universal reprogramming in cancer cells [ 54 ]. IMP, a central intermediate metabolite in the purine metabolism pathway, is the precursor to generate adenosine monophosphate (AMP), inosine, and guanosine monophosphate (GMP) [ 55 ]. Up to date, a quantity of anti-cancer drugs, most purine nucleotide analogs, including 6-mercaptopurine, 6-thiocitrulline, and methotrexate which target the key enzymes in purine metabolism in clinical [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Inosine enhances tumor mitochondrial respiration by inducing Rag GTPases and nascent protein synthesis under nutrient starvation

Li,

Wu,

Jing

et al. 2023

Cell Death Dis

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Metabolic heterogeneity of tumor microenvironment (TME) is a hallmark of cancer and a big barrier to cancer treatment. Cancer cells display diverse capacities to utilize alternative carbon sources, including nucleotides, under poor nutrient circumstances. However, whether and how purine, especially inosine, regulates mitochondrial metabolism to buffer nutrient starvation has not been well-defined yet. Here, we identify the induction of 5′-nucleotidase, cytosolic II (NT5C2) gene expression promotes inosine accumulation and maintains cancer cell survival in the nutrient-poor region. Inosine elevation further induces Rag GTPases abundance and mTORC1 signaling pathway by enhancing transcription factor SP1 level in the starved tumor. Besides, inosine supplementary stimulates the synthesis of nascent TCA cycle enzymes, including citrate synthesis (CS) and aconitase 1 (ACO1), to further enhance oxidative phosphorylation of breast cancer cells under glucose starvation, leading to the accumulation of iso-citric acid. Inhibition of the CS activity or knockdown of ACO1 blocks the rescue effect of inosine on cancer survival under starvation. Collectively, our finding highlights the vital signal role of inosine linking mitochondrial respiration and buffering starvation, beyond serving as direct energy carriers or building blocks for genetic code in TME, shedding light on future cancer treatment by targeting inosine metabolism.

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“…At the same time, in another study, the aforementioned TYMS gene variants were not associated with oral mucositis caused by high doses of MTX [36]. ATIC 5-amino-imidazole-4-carboxamide ribonucleotide transformylase is an enzyme that catalyzes the addition of a formyl group to AICAR to form formyl AICAR (FAICAR) in the last stages of de novo purine synthesis [37]. The inhibition of ATIC by MTX leads to intracellular accumulation of AICAR and its metabolites and an increase in the adenosine levels.…”

Section: Thymidylate Synthasementioning

confidence: 97%

“…Park et al [39] demonstrated the association of the 347C>G (rs2372536, c.347C>G or p.Thr116Ser, "benign" in ClinVar) variant of the ATIC gene with a good histological response to chemotherapy in patients with osteosarcoma. As for the effect of this gene on the risk of toxic effects, a recent study by Gong et al [37] found no significant effect of ATIC gene variants (rs2372536, rs4673993, rs12995526, and rs7563206) on the risk of mucositis in children L. Fischuk, O. Skavinska, O. Ievseienkova, Z. Rossokha, L. Sheiko with acute lymphoblastic leukemia, lymphoma, or osteosarcoma.…”

Section: Thymidylate Synthasementioning

confidence: 99%

Genetic Predictors of Toxic Effects of Methotrexate in Cancer Patients

Fishchuk,

Skavinska,

Ievseienkova

et al. 2024

Exp. oncol.

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Today, methotrexate (MTX) is used in combination with other medicines to treat a wide range of malignancies. Despite its proven high efficacy, MTX often causes serious side effects, which may result in the need to reduce the dose of MTX or discontinue the drug altogether. This, in turn, can provoke the development of MTX resistance and cancer progression. Predicting the risk of MTX-induced toxicity is currently difficult due to the variability of pharmacokinetics and pharmacodynamics in different patients, so the scientific literature is intensively searching for potential biomarkers. Based on the data available in the current literature, we analyzed the relationship between variants in the genes encoding the key components of MTX intracellular metabolism and the MTX-induced side effects and drug response. According to the results of our work, the most studied variants are those of the SLC19A1 gene, which encodes the reduced folate carrier protein 1, and the MTHFR gene, which encodes the enzyme methylenetetrahydrofolate reductase. Studies of the effect of methylation of the promoter regions of genes on the therapeutic effect of MTX are also very promising. In conclusion, the study of molecular genetic markers of MTX toxicity is extremely relevant and necessary because it can help to avoid the effect of multidrug resistance and improve the quality of life and survival of patients.

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AICAR transformylase/IMP cyclohydrolase (ATIC) is essential for de novo purine biosynthesis and infection by Cryptococcus neoformans

Cited by 5 publications

References 62 publications

Purine metabolism in plant pathogenic fungi

Purine metabolism in plant pathogenic fungi

Inosine enhances tumor mitochondrial respiration by inducing Rag GTPases and nascent protein synthesis under nutrient starvation

Genetic Predictors of Toxic Effects of Methotrexate in Cancer Patients

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