PAICS as a potential target for cancer therapy linking purine biosynthesis to cancer progression

Huo, Anqi; Xiong, Xiangyang

doi:10.1016/j.lfs.2023.122070

Cited by 2 publications

(1 citation statement)

References 165 publications

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“…In recent times, there has been a growing number of studies focusing on the roles of purine metabolites in cell biology and disease, including in cancer ( 41 , 42 ). Several studies have demonstrated that purine metabolites, such as adenosine and inosine, function as modulators to influence cancer development and therapy ( 43 , 44 ). In the present study, it was demonstrated that the TGF-β signaling pathway can trigger the expression of the enzyme LACC1, which in turn activates adenosine deaminase to convert adenosine into inosine.…”

Section: Discussionmentioning

confidence: 99%

Purine metabolite inosine induced by transforming growth factor‑β promotes epithelial‑mesenchymal transition in colorectal cancer

Hu,

Cheng,

Zhao

et al. 2024

Oncol Lett

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Transforming growth factor-β (TGF-β) signaling pathway serves a pivotal role in the pathogenesis of colorectal cancer (CRC). However, the specific molecular mechanisms by which the TGF-β signaling pathway regulates CRC are still not fully understood. In the present study, metabolomics and transcriptomics were used to screen for key metabolites and regulatory genes most related to the regulation of the TGF-β signaling pathway in CRC. Additionally, reverse transcription-quantitative PCR, western blotting and Transwell assays were performed to assess the process of epithelial-mesenchymal transition (EMT). Metabolomics analysis indicated that TGF-β1 has an impact on purine metabolism, leading to an increase in the purine metabolite inosine. The increase of inosine is essential for facilitating EMT and cell migration in CRC cells. Furthermore, the integrated analysis of metabolomics and transcriptomics data revealed that TGF-β1 induces the expression of laccase domain-containing 1 (LACC1), an enzyme involved in the regulation of inosine. Knockdown of LACC1 resulted in a reduction of TGF-β1-induced alterations in inosine levels, EMT and cell migration in CRC cells. The results of the present study suggest that the TGF-β signaling pathway is involved in the regulation of purine metabolism in CRC through the modulation of LACC1 expression. Furthermore, LACC1 appears to influence EMT and cell migration by elevating the levels of the purine metabolite inosine.

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Section: Discussionmentioning

confidence: 99%

Purine metabolite inosine induced by transforming growth factor‑β promotes epithelial‑mesenchymal transition in colorectal cancer

Hu,

Cheng,

Zhao

et al. 2024

Oncol Lett

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A Fragment-Based Screen for Inhibitors of Escherichia coli N5-CAIR Mutase

Sharma,

Firestine

2024

Preprint

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Although purine biosynthesis is a primary metabolic pathway, there are fundamental differences between how purines are synthesized in microbes versus humans. In humans, the purine intermediate, 4-carboxy-5-aminoimidazole ribonucleotide (CAIR) is directly synthesized from 5-aminoimidazole ribonucleotide (AIR) and carbon dioxide by the enzyme AIR carboxylase. In bacteria, yeast and fungi, CAIR is synthesized from AIR via an intermediate N5-carboxyaminoimidazole ribonucleotide (N5-CAIR) by the enzyme N5-CAIR mutase. The difference in pathways between humans and microbes indicate that N5-CAIR mutase is a potential antimicrobial drug target. To identify inhibitors of E. coli N5-CAIR mutase, a fragment-based screening campaign was conducted using a thermal shift assay and a library of 4,500 fragments. Twenty-eight fragments were initially identified that displayed dose-dependent binding to N5-CAIR mutase with Kd values ranging from 9-309 µM. Of the 28, 14 were obtained from commercial sources for retesting; however, only 5 showed dose-dependent binding to N5-CAIR mutase. The five fragments were assessed for their ability to inhibit enzyme activity. Four out of the 5 showed inhibition with Ki values of 4.8 to 159 µM. All fragments contained nitrogen heterocycles with 3 out of the 4 containing 5-membered heterocycles like those found in the substrate of the enzyme. The identified fragments show similarities to compounds identified from studies on B. anthracis N5-CAIR synthetase and human AIR carboxylase suggesting a common pharmacophore.

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PAICS as a potential target for cancer therapy linking purine biosynthesis to cancer progression

Cited by 2 publications

References 165 publications

Purine metabolite inosine induced by transforming growth factor‑β promotes epithelial‑mesenchymal transition in colorectal cancer

Purine metabolite inosine induced by transforming growth factor‑β promotes epithelial‑mesenchymal transition in colorectal cancer

A Fragment-Based Screen for Inhibitors of Escherichia coli N5-CAIR Mutase

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