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Purine nucleotide metabolism in E. coli and S. cerevisiae . Gene names: E. coli , green font; S. cerevisiae , blue font. Abbreviations: SAMP, adenylosuccinate; EndoV, endonuclease V; EndoVIII, endonuclease VIII; NDP kinase, nucleoside diphosphate kinase.
Source publication
Deamination of nucleobases in DNA and RNA results in the formation of xanthine (X), hypoxanthine (I), oxanine, and uracil, all of which are miscoding and mutagenic in DNA and can interfere with RNA editing and function. Among many forms of nucleic acid damage, deamination arises from several unrelated mechanisms, including hydrolysis, nitrosative c...
Contexts in source publication
Context 1
... metabolic network that, when disrupted, have signifi- cant consequences for genetic toxicology and RNA function. Given the conservation of purine metabolism, the discovery of similar nodes in both E. coli and yeast should have relevance to the strong association in humans between purine metabolic de- fects and pathology and disease. As shown in Fig. 2, the genes with the greatest effect on hypoxanthine incorporation into DNA and RNA are located early (purA, guaB) in the metabolic path- ways or later at the "pool cleansing" step prior to incorporation of nucleotides into nucleic acids (rdgB). The latter is consistent with the observation that loss of the mammalian rdgB homolog, ITPA, ...
Context 2
... in a knockout mouse model (32)(33)(34). That loss of purA or guaB would cause twofold to 10-fold increases of hypoxanthine in DNA and RNA is reasonable given the accumulation of IMP that could be pre- sumed to occur with loss of the enzymes, with excess IMP becom- ing a substrate for kinases and ribonucleotide reductases in the metabolic network (Fig. 2). These critical metabolic steps are also subject to genetic polymorphisms in humans, with significant implications for misincorporation of hypoxanthine in DNA and RNA. For example, a T-to-G substitution in the promoter region of the human IMPDH2 gene, a homolog of E. coli purA encoding SAMP synthetase (Fig. 1), reduced gene expression ...
Citations
... Inhibition of XO leads, therefore, to a decrease in serum uric acid levels, with a concomitant increase in levels of hypoxanthine, xanthine, and guanine. These substances, however, exhibit significant toxicity [4,5]. As a result, drugs lowering serum uric acid may lead to increased risk of cancer [6]. ...
Xanthine oxidase inhibitors, including allopurinol and febuxostat, are the first-line treatment of hyperuricemia. This meta-analysis investigated the association between urate-lowering therapy and all-cause mortality in different chronic diseases to match its users and non-users in a real-world setting. Overall, 11 studies were included, which reported adjusted hazard ratios for all-cause mortality over at least 12 months. Meta-analysis of all included studies showed no effect of the therapy on all-cause mortality. However, subgroup analyses showed its beneficial effect in patients with chronic kidney disease (14% risk reduction) and hyperuricemia (14% risk reduction), but not in patients with heart failure (28% risk increase). Urate-lowering therapy reduces all-cause mortality among patients with hyperuricemia and chronic kidney disease, but it seems to increase mortality in patients with heart failure and should be avoided in this subgroup.
... Interestingly, most BAs greatly increased in liver traces with L-PSN exposure, a finding also observed in a previous study that measured the higher contents of BAs in the livers of mice when exposed to PS MPs . It has been reported that MPs cause hepatic cholestasis, and as a result, BAs profiles can ultimately lead to the accumulation of other metabolites responsible for liver damage or hepatitis (Pang et al., 2012). ...
... Changes in purine metabolism, known to cause tumor risks and activate innate and adaptive immune responses (Cheng et al., 2022a), were also greatly promoted by PSN. Moreover, malfunctions in purine metabolism motivated by the deamination of nucleotides lead to miscoding in RNA and DNA (Pang et al., 2012). Miscoding products were formed as deoxyinosine, inosine, deoxyuridine, xanthosine, and uracil. ...
Nanoplastics (NPs) are increasingly pervasive in the environment, raising concerns about their potential health implications, particularly within aquatic ecosystems. This study investigated the impact of polystyrene nano-particles (PSN) on zebrafish liver metabolism using liquid chromatography hybrid quadrupole time of flight mass spectrometry (LC-QTOF-MS) based non-targeted metabolomics. Zebrafish were exposed to 50 nm PSN for 28 days at low (L-PSN) and high (H-PSN) concentrations (0.1 and 10 mg/L, respectively) via water. The results revealed significant alterations in key metabolic pathways in low and high exposure groups. The liver metab-olites showed different metabolic responses with L-PSN and H-PSN. A total of 2078 metabolite features were identified from the raw data obtained in both positive and negative ion modes, with 190 metabolites deemed statistically significant in both L-PSN and H-PSN groups. Disruptions in lipid metabolism, inflammation, oxidative stress, DNA damage, and amino acid synthesis were identified. Notably, L-PSN exposure induced changes in DNA building blocks, membrane-associated biomarkers, and immune-related metabolites, while H-PSN exposure was associated with oxidative stress, altered antioxidant metabolites, and liver injury. For the first time, L-PSN was found depolymerized in the liver by cytochrome P450 enzymes. Utilizing an analytical approach to the adverse outcome pathway (AOP), impaired lipid metabolism and oxidative stress have been identified as potentially conserved key events (KEs) associated with PSN exposure. These KEs further induced liver inflammation , steatosis, and fibrosis at the tissue and organ level. Ultimately, this could significantly impact biological health. The study highlights the PSN-induced effects on zebrafish liver metabolism, emphasizing the need for a better understanding of the risks associated with NPs contamination in aquatic ecosystems.
... In addition, disruption of purine metabolism may also affect nucleic acid synthesis. Purine nucleotides are components of RNA and DNA (Xu et al. 2019), and are essential for cell growth and division (Pang et al. 2012). Disruption of purine metabolism may lead to abnormalities in nucleic acid synthesis, thereby affecting the gene expression and protein synthesis required for the synthesis of reproductive hormones. ...
With the rapid development of industrialization and urbanization, the issue of copper (Cu) and cadmium (Cd) pollution in aquatic ecosystems has become increasingly severe, posing threats to the ovarian tissue and reproductive capacity of aquatic organisms. However, the combined effects of Cu and Cd on the ovarian development of fish and other aquatic species remain unclear. In this study, female Nile tilapia (Oreochromis niloticus) were individually or co-exposed to Cu and/or Cd in water. Ovarian and serum samples were collected at 15, 30, 60, 90, and 120 days, and the bioaccumulation, ovarian development, and hormone secretion were analyzed. Results showed that both single and combined exposure significantly reduced the gonadosomatic index and serum hormone levels, upregulated estrogen receptor (er) and progesterone receptor (pr) gene transcription levels, and markedly affected ovarian metabolite levels. Combined exposure led to more adverse effects than single exposure. The data demonstrate that the Cu and Cd exposure can impair ovarian function and structure, with more pronounced adverse effects under Cu and Cd co-exposure. The Cu and Cd affect the metabolic pathways of nucleotides and amino acids, leading to ovarian damage. This study highlights the importance of considering combined toxicant exposure in aquatic toxicology research and provides insights into the potential mechanisms underlying heavy metal-induced reproductive toxicity in fish.
... Hypoxanthine serves as a metabolic intermediate in the biosynthesis of purine nucleotides in living organisms where it is mainly produced by adenine deamination [1][2][3][4][5][6][7]. It is here where the mutagenic nature of the hypoxanthine appears; showing the same hydrogen-bonding (HB) pattern as guanine, it yields the guanine-cytosine pair during DNA replication and, if left unrepaired, this could result in cancer development [8,9]. Besides that, prototropic tautomerism of hypoxanthine has been extensively studied [10][11][12][13] since it has been demonstrated that the interaction between different tautomers by pairs lead to hydrogen transfers that could be considered as possible mutation mechanisms present in DNA. ...
We present a joint theoretical-experimental study on the inner-shell photoionization of hypoxanthine clusters in the gas phase. Simulations were performed using a computational strategy that combines molecular dynamics to explore the conformers of the clusters, density functional theory for geometry optimization and inner shell photoionization calculations. Two main intermolecular interactions are observed: hydrogen-bonds (HB) and π-π stacking. When increasing the cluster size, a combination of both kinds of interaction occurs. We show that such intermolecular interactions play a role in the chemical shift observed in X-ray photoemission spectroscopy experiments. In particular, we highlight the interplay between charge depletion and charge accumulation in regions where HBs stabilize the clusters.
... Purine, an essential base, plays a crucial role as a building block of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) in living organisms (1). It consists primarily of guanine, adenine, hypoxanthine, and xanthine, which are commonly found in various food sources. ...
... Other data show that nearly 60% of patients with hyperuricemia and gout in China are aged 18-35. 1 Thus, gout is no longer a disease affecting the middleaged and old. The young population is suggested to incorporate the prevention and treatment of gout into their knowledge, especially those who prefer eating high-purine foods such as seafood, drinking excessively, working and resting irregularly, being overweight, and smoking (11). ...
The incidence of hyperuricemia is on the rise in China, primarily due to dietary habits. However, limited data exists regarding dietary purine intake in the country. This study aimed to estimate the daily dietary purine intake among Chinese residents from 2014 to 2021 and evaluate the temporal trend using joinpoint regression analysis. The analysis revealed an annual percentage change (APC) of 0.8% (95% CI: 0.1–1.5%) in dietary purine intake prior to the joinpoint (2014–2019). Following the joinpoint (2019–2021), the APC significantly increased to 6.5% (95% CI: 3.3–9.8%), indicating a noteworthy upward trend (p = 0.045). Furthermore, the average daily purine intake varied significantly among different regions of China, with the southern region showing the highest dietary intake of purines. Considering the diverse contributions of various food sources to dietary purine intake, it was observed that meat consumption had the greatest impact, accounting for 36.2% of purine intake, followed by cereals consumption (25.3%) and vegetables and edible fungi (24.2%). These findings hold significance for dietary intervention and management strategies aimed at reducing purine intake among the population.
... The deoxyribonucleotide dITP may be generated from dATP by non-enzymatic hydrolysis or by reduction in ITP [5]. However, the accumulation of inosine may cause human diseases and the accumulation of its triphosphate form (dITP) could lead to the misincorporation of inosine into DNA strands opposite C [1,[6][7][8][9], causing AT → GC mutations. ...
Inosine, a purine nucleoside containing the hypoxanthine (HX) nucleobase, can form in DNA via hydrolytic deamination of adenine. Due to its structural similarity to guanine and the geometry of Watson–Crick base pairs, inosine can mispair with cytosine upon catalysis by DNA polymerases, leading to AT → GC mutations. Additionally, inosine plays an essential role in purine nucleotide biosynthesis, and inosine triphosphate is present in living cells. In a recent publication, Averill and Jung examined the possibility of polη catalyzed incorporation of deoxyinosine triphosphate (dITP) across dC and dT in a DNA template. They found that dITP can be incorporated across C or T, with the ratio of 13.7. X ray crystallography studies revealed that the mutagenic incorporation of dITP by human polη was affected by several factors including base pair geometry in the active site of the polymerase, tautomerization of nucleobases, and the interaction of the incoming dITP nucleotide with active site residues of polη. This study demonstrates that TLS incorporation of inosine monophosphate (IMP) into growing DNA chains contributes to its mutagenic potential in cells.
... In addition to their role in balancing the purine pool, inosine, hypoxanthine, and xanthine can be incorporated into DNA when accumulated within the cell. This misincorporation of these bases into DNA is mutagenic, and has been shown to lead to point mutations [31,32]. Given that genomic instability has been linked to multidrug resistance in various cancers, this alteration in purine metabolism may be a mechanism that is driving resistance to alkylating agents [33][34][35]. ...
... In addition to their role in balancing the purine pool, inosine, hypoxanthine, and xanthine can be incorporated into DNA when accumulated within the cell. This misincorporation of these bases into DNA is mutagenic, and has been shown to lead to point mutations [31,32]. Given that genomic instability has been linked to multi-drug resistance in various cancers, this alteration in purine metabolism may be a mechanism that is driving resistance to alkylating agents [33][34][35]. ...
This study aimed to elucidate the molecular determinants influencing the response of cancer cells to alkylating agents, a major class of chemotherapeutic drugs used in cancer treatment. The study utilized data from the National Cancer Institute (NCI)-60 cell line screening program and employed a comprehensive multi-omics approach integrating transcriptomic, proteomic, metabolomic, and SNP data. Through integrated pathway analysis, the study identified key metabolic pathways, such as cysteine and methionine metabolism, starch and sucrose metabolism, pyrimidine metabolism, and purine metabolism, that differentiate drug-sensitive and drug-resistant cancer cells. The analysis also revealed potential druggable targets within these pathways. Furthermore, copy number variant (CNV) analysis, derived from SNP data, between sensitive and resistant cells identified notable differences in genes associated with metabolic changes (WWOX, CNTN5, DDAH1, PGR), protein trafficking (ARL17B, VAT1L), and miRNAs (MIR1302-2, MIR3163, MIR1244-3, MIR1302-9). The findings of this study provide a holistic view of the molecular landscape and dysregulated pathways underlying the response of cancer cells to alkylating agents. The insights gained from this research can contribute to the development of more effective therapeutic strategies and personalized treatment approaches, ultimately improving patient outcomes in cancer treatment.
... The enzyme hydrolyzes both ribose and deoxyribose nucleoside triphosphates containing noncanonical purines, such as inosine triphosphate (ITP), to their monophosphate form [4]. This activity is thought to protect cells from accumulating high concentrations of ITP, which has potential to be incorporated into nucleic acids or interfere with normal nucleotide metabolism [3,[5][6][7]. At this time, 45 very young patients have been identified with very rare and generally fatal mutations which result in severe ITPA deficiency [5,[8][9][10][11][12][13][14][15][16]. ...
The inosine triphosphate pyrophosphatase (ITPA) enzyme plays a critical cellular role by removing noncanonical nucleoside triphosphates from nucleotide pools. One of the first pathological ITPA mutants identified is R178C (rs746930990), which causes a fatal infantile encephalopathy, termed developmental and epileptic encephalopathy 35 (DEE 35). The accumulation of noncanonical nucleotides such as inosine triphosphate (ITP), is suspected to affect RNA and/or interfere with normal nucleotide function, leading to development of DEE 35. Molecular dynamics simulations have shown that the very rare R178C mutation does not significantly perturb the overall structure of the protein, but results in a high level of structural flexibility and disrupts active-site hydrogen bond networks, while preliminary biochemical data indicate that ITP hydrolyzing activity is significantly reduced for the R178C mutant. Here we report Michaelis-Menten enzyme kinetics data for the R178C ITPA mutant and three other position 178 ITPA mutants. These data confirm that position 178 is essential for ITPA activity and even conservative mutation at this site (R178K) results in significantly reduced enzyme activity. Our data support that disruption of the active-site hydrogen bond network is a major cause of diminished ITP hydrolyzing activity for the R178C mutation. These results suggest an avenue for developing therapies to address DEE 35.
... Some findings suggest that this route may be a major source of (d)ITP. On an ITPase-null background, deletion of enzymes involved in purine biosynthesis can dramatically increase the presence of inosine and deoxyinosine in RNA and DNA (Pang et al., 2012). A straightforward explanation for this observation is that disruption of purine biosynthesis leads to elevated IMP levels, increased IMP phosphorylation, (d)ITP generation, and subsequent incorporation into nucleic acids. ...
... Consistently, guanylate kinase is found to efficiently phosphorylate IMP while it shows no activity on XMP (Agarwal et al., 1971;Agarwal et al., 1978). Less efficient generation of (d)XTP may explain the comparatively very low levels of nucleic acid xanthine observed in bacteria and yeast (Pang et al., 2012), and the low levels of free XTP compared to free ITP directly detected in human cell lines (Jiang et al., 2018). Other possible sources of (d)ITP and (d)XTP include oxidative and nitrosative deamination of (d)ATP and (d)GTP (Dedon & Tannenbaum, 2004). ...
... Endonuclease V participates in the removal of various DNA lesions, resulting from damage as well as misincorporation events, and usually functions to reduce the occurrence of transition mutations (Burgis et al., 2003;Weiss, 2001). In rdgB mutant cells, there is an approximately 5-fold increase in dITP incorporation into DNA and an approximately 10-fold increase in ITP incorporation into RNA (Pang et al., 2012). Very interestingly, concurrent inactivation of the prokaryotic ADSS and/or IMPDH genes, purA and guaB, which utilize IMP as a substrate, massively increases these levels. ...
Inosine triphosphate pyrophosphatase (ITPase), encoded by the ITPA gene in humans, is an important enzyme that preserves the integrity of cellular nucleotide pools by hydrolyzing the noncanonical purine nucleotides (deoxy)inosine and (deoxy)xanthosine triphosphate into monophosphates and pyrophosphate. Variants in the ITPA gene can cause partial or complete ITPase deficiency. Partial ITPase deficiency is benign but clinically relevant as it is linked to altered drug responses. Complete ITPase deficiency causes a severe multisystem disorder characterized by seizures and encephalopathy that is frequently associated with fatal infantile dilated cardiomyopathy. In the absence of ITPase activity, its substrate noncanonical nucleotides have the potential to accumulate and become aberrantly incorporated into DNA and RNA. Hence, the pathophysiology of ITPase deficiency could arise from metabolic imbalance, altered DNA or RNA regulation, or from a combination of these factors. Here, we review the known functions of ITPase and highlight recent work aimed at determining the molecular basis for ITPA ‐associated pathogenesis which provides evidence for RNA dysfunction.
This article is categorized under: RNA in Disease and Development > RNA in Disease
RNA in Disease and Development > RNA in Development
... ICT significantly corrected the disorder of purine metabolism in the brain tissue of MCAO/R mice. Purine metabolism disorders may cause, or reflect, defective DNA synthesis or repair, and further cause neurons to undergo apoptosis (Pang et al., 2012;Wang, 2016). ...
Background
Icaritin (ICT) has been previously demonstrated to display protective effects against cerebral ischemic reperfusion (I/R) by inhibiting oxidative stress, but the mechanism remains unclear. This study aimed to explore the mechanism from the perspective of metabolomics.
Methods
A mice cerebral artery occlusion/reperfusion (MCAO/R) model was explored to mimic cerebral ischemic reperfusion and protective effect of ICT was assessed by neurologic deficit scoring, infarct volume and brain water content. Ultra-high-performance liquid chromatography electrospray ionization orbitrap tandem mass spectrometry (UHPLC-ESI-QE-Orbitrap-MS) based metabolomic was performed to explore potential biomarkers. Brain tissue metabolic profiles were analyzed and metabolic biomarkers were identified through multivariate data analysis. The protein levels of Nrf2, HO-1 and HQO1 were assayed by western blot. The release of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were detected using corresponding assay kits.
Results
The results showed that after ICT treatment, the neurological deficit, cerebral infarction area, brain edema and the level of MDA in brain tissue of MCAO/R mice were significantly reduced. Meanwhile, ICT enhanced the activity of SOD, CAT and GSH-Px. Western blot results confirmed that ICT up-regulated the protein levels of antioxidant-related protein including Nrf2, HO-1 and NQO1. According to the metabolomic profiling of brain tissues, clear separations were observed among the Sham, Model and ICT groups. A total of 44 biomarkers were identified, and the identified biomarkers were mainly related to linoleic acid metabolism, arachidonic acid metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis, arginine and proline metabolism, D-glutamine and D-glutamate metabolism, taurine and hypotaurine metabolism and purine metabolism, respectively. At the same time, the inhibitory effect of ICT on arachidonic acid and linoleic acid in brain tissue, as well as the promoting effect on taurine, GABA, NAAG, may be the key factors for the anti-neurooxidative function of mice after MCAO/R injury.
Conclusion
Our results demonstrate that ICT has benefits for MCAO/R injury, which are partially related to the suppression of oxidative stress via stimulating the Nrf2 signaling and regulating the production of arachidonic acid, linoleic acid, taurine, GABA, NAAG in brain tissue.
