Mapping Post-Translational Modifications of de Novo Purine Biosynthetic Enzymes: Implications for Pathway Regulation

Liu, Chunliang; Knudsen, Giselle M.; Pedley, Anthony M.; He, Jingxuan; Johnson, Jared L.; Yaron, Tomer M.; Cantley, Lewis C.; Benkovic, Stephen J.

doi:10.1021/acs.jproteome.8b00969

Cited by 16 publications

(15 citation statements)

References 62 publications

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“…Overall, this study expands our understanding of purinosome formation and reveals that the biochemical processes that drive this process are not solely dependent on substrate or cofactor availability. Previous studies have shown that purinosome formation is associated with post-translational modifications such as phosphorylation ( 49 ), possibly as a consequence of activated AKT/mTOR and/or G protein–coupled receptor-mediated signaling pathways ( 44 , 50 ). Exploring the similarities in the genetic reprogramming and signaling events between hypoxia and activation of de novo purine biosynthesis is expected to provide further insights into the molecular mechanism by which the enzyme of purine biosynthesis organize into purinosomes.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia drives the assembly of the multienzyme purinosome complex

Doigneaux

Pedley

Mistry

et al. 2020

Journal of Biological Chemistry

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The purinosome is a dynamic metabolic complex composed of enzymes responsible for de novo purine biosynthesis, whose formation has been associated with elevated purine demand. However, the physiological conditions that govern purinosome formation in cells remain unknown. Here, we report that purinosome formation is up-regulated in cells in response to a low-oxygen microenvironment (hypoxia). We demonstrate that increased purinosome assembly in hypoxic human cells requires the activation of hypoxia inducible factor 1 (HIF-1) and not HIF-2. Hypoxia-driven purinosome assembly was inhibited in cells lacking 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), a single enzyme in de novo purine biosynthesis, and in cells treated with a small molecule inhibitor of ATIC homodimerization. However, despite the increase in purinosome assembly in hypoxia, we observed no associated increase in de novo purine biosynthesis in cells. Our results indicate that this was likely due to a reduction in mitochondrial one-carbon metabolism, resulting in reduced mitochondrion-derived one-carbon units needed for de novo purine biosynthesis. The findings of our study further clarify and deepen our understanding of purinosome formation by revealing that this process does not solely depend on cellular purine demand.

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Section: Discussionmentioning

confidence: 99%

Hypoxia drives the assembly of the multienzyme purinosome complex

Doigneaux

Pedley

Mistry

et al. 2020

Journal of Biological Chemistry

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“…Under normal physiological conditions, purine metabolism maintains the balance of purine metabolites in the body via synthesis and degradation of purine nucleotides. However, the conditions with higher energy consumption of purine nucleotides, such as those in dividing and tumor cells, cause the de novo purine biosynthetic pathway to be activated and boost the accumulation of some purine metabolites (Chakravarthi et al, 2018; Liu et al, 2019). In the present study, changes in metabolic intermediates of purine metabolism were identified, including adenosine diphosphate, adenosine and hypoxanthine.…”

Section: Discussionmentioning

confidence: 99%

Cell metabolomics study on synergistic anti‐hepatocellular carcinoma effect of Aidi injection combined with doxorubicin

Wang

Zhu

Wang

et al. 2022

Biomedical Chromatography

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Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the second most common cause of cancer deaths. This study aimed to explore the inhibitory effect and mechanism of Aidi injection (ADI) combined with doxorubicin (DOX) in HCC treatment. The drug concentrations in the combined therapy was determined by investigating the effect of various concentrations of ADI and DOX on the viability of H22 cells. The combination index was also calculated. A metabolomic strategy based on a ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) platform was established to analyze the metabolites. As a result, the combination index values were less than 1, indicating that the combination of ADI and DOX exerted a synergistic effect on HCC treatment. The combination of 40‰ ADI and 1 μmol/l DOX had the strongest inhibitory effect and was used for subsequent metabolomic analysis. A total of 19 metabolic markers were obtained in metabolomic analysis, including amino acids (L-glutamic acid, L-arginine and L-tyrosine), organic acids (succinic acid and citric acid), adenosine and hypoxanthine. Compared with the treatment using DOX or ADI alone, the combined therapy further regulated the levels of metabolic markers in HCC, which may be the reason for the synergistic effect. Seven metabolic pathways were significantly enriched, including phenylalanine, tyrosine and tryptophan biosynthesis, D-glutamine and D-glutamate metabolism, alanine, aspartate and glutamate metabolism, phenylalanine metabolism, arginine biosynthesis, the tricarboxylic acid cycle and purine metabolism. These findings demonstrated that ADI combined with DOX can effectively inhibit the viability of H22 cells, which may exert a synergistic antitumor effect by balancing the metabolism of amino acids and energy-related substances.

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“…Furthermore, there is a growing body of evidence that signaling pathway enzymes such as protein kinase B (PKB) and ribosomal protein S6 kinase (S6K) influence IMP production directly through the phosphorylation of purine biosynthetic enzymes [12]. One such modification is the Thr397 phosphorylation of PPAT by PKB, detected in purine supplemented conditions only and affecting downstream inosine monophosphate (IMP) production [13]. Similarly, as the limiting metabolic input, regulation of PRPP levels affects the rate of purine synthesis.…”

Section: Purine Metabolismmentioning

confidence: 99%

“…Analysis of PRPP in different growth stages in HTC116 colon cancer cells demonstrated that rates of purine synthesis via both salvage and the de novo pathways increased by 5 and 3.3 fold, respectively, from the end of the G1 phase to the beginning of the S phase, with the de novo increase attributed to an increase in intracellular phosphate stimulating PRPP synthetase activity [14]. More broadly, high-throughput global proteomic studies have revealed 174 post-translational modifications within the six enzymes across the purine de novo biosynthetic pathway [13].…”

Section: Purine Metabolismmentioning

confidence: 99%

The Intersection of Purine and Mitochondrial Metabolism in Cancer

Vitto

Arachchige

Richardson

et al. 2021

Cells

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Nucleotides are essential to cell growth and survival, providing cells with building blocks for DNA and RNA, energy carriers, and cofactors. Mitochondria have a critical role in the production of intracellular ATP and participate in the generation of intermediates necessary for biosynthesis of macromolecules such as purines and pyrimidines. In this review, we highlight the role of purine and mitochondrial metabolism in cancer and how their intersection influences cancer progression, especially in ovarian cancer. Additionally, we address the importance of metabolic rewiring in cancer and how the evolving landscape of purine synthesis and mitochondria inhibitors can be potentially exploited for cancer treatment.

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Mapping Post-Translational Modifications of de Novo Purine Biosynthetic Enzymes: Implications for Pathway Regulation

Abstract: Purines represent a class of essential metabolites produced by the cell to maintain cellular homeostasis and facilitate cell proliferation. In times of high purine demand, the de novo purine biosynthetic pathway is activated; however, the mechanisms that facilitate this process are largely

Cited by 16 publications

References 62 publications

Hypoxia drives the assembly of the multienzyme purinosome complex

Hypoxia drives the assembly of the multienzyme purinosome complex

Cell metabolomics study on synergistic anti‐hepatocellular carcinoma effect of Aidi injection combined with doxorubicin

The Intersection of Purine and Mitochondrial Metabolism in Cancer

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