Purine and Pyrimidine Metabolism of Normal and Leukemic Lymphocytes

Marijnen, Yolanda M. T.; Korte, Dirk de; Roos, Dirk; Gennip, Albert H.

doi:10.1007/978-1-4684-5673-8_71

Cited by 6 publications

(3 citation statements)

References 7 publications

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“…The requirement for de novo CTP makes CTPS activity key to the viability of a number of cancers ( − ), viruses ( − ), pathogenic bacteria ( , ), and protozoan parasites ( − ). As a result, CTPSs are both the targets for therapeutics and responsible for resistance to them by selected mutations.…”

mentioning

confidence: 99%

Crystal Structure of Escherichia coli Cytidine Triphosphate Synthetase, a Nucleotide-Regulated Glutamine Amidotransferase/ATP-Dependent Amidoligase Fusion Protein and Homologue of Anticancer and Antiparasitic Drug Targets^,

et al. 2004

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Cytidine triphosphate synthetases (CTPSs) produce CTP from UTP and glutamine, and regulate intracellular CTP levels through interactions with the four ribonucleotide triphosphates. We solved the 2.3-Å resolution crystal structure of Escherichia coli CTPS using Hg-MAD phasing. The structure reveals a nearly symmetric 222 tetramer, in which each bifunctional monomer contains a dethiobiotin synthetase-like amidoligase N-terminal domain and a Type 1 glutamine amidotransferase C-terminal domain. For each amidoligase active site, essential ATP-and UTPbinding surfaces are contributed by three monomers, suggesting that activity requires tetramer formation, and that a nucleotide-dependent dimer-tetramer equilibrium contributes to the observed positive cooperativity. A gated channel that spans 25 Å between the glutamine hydrolysis and amidoligase active sites provides a path for ammonia diffusion. The channel is accessible to solvent at the base of a cleft adjoining the glutamine hydrolysis active site, providing an entry point for exogenous ammonia. Guanine nucleotide binding sites of structurally related GTPases superimpose on this cleft, providing insights into allosteric regulation by GTP. Mutations that confer nucleoside drug resistance and release CTP inhibition map to a pocket that neighbors the UTP-binding site and can accommodate a pyrimidine ring. Its location suggests that competitive feedback inhibition is affected via a distinct product/drug binding site that overlaps the substrate triphosphate binding site. Overall, the E. coli structure provides a framework for homology modeling of other CTPSs and structure-based design of anti-CTPS therapeutics. † This work was funded by the UC Systemwide Biotechnology Training Program Grant #2002-07, and the National Institutes of Health, General Medical Sciences, #GM63109. ‡ Protein Data Bank accession number 1S1M. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2010 June 24. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptCytidine triphosphate synthetases (CTPSs, 1 E. C. 6.4.3.2, uridine triphosphate ammonia lyases, 525-630 amino acid residues) are essential ubiquitous enzymes that catalyze the ratelimiting step of de novo CTP biosynthesis (1,2). Genes pyrG (bacteria), ctrA (some gram positive bacteria), URA7 and URA8 (Saccharomyces cerevisiae), and CTPS1 and CTPS2 (human) encode CTP synthetase enzymes, with most eukaryotes expressing two isoforms.CTPSs not only provide a key precursor for synthesis of DNA, RNA, and phospholipid (3,4), they also control the intracellular CTP concentrations that limit these processes (5-9).CTP is derived from UTP in three reaction steps catalyzed by CTPSs (Figure 1a). In one active site, the UTP O4 oxygen is activated by Mg-ATP-dependent phosphorylation, followed by displacement of the resulting 4-phosphate moiety by ammonia (10,11). In a separate site, ammonia is generated via rate-limiting glutamine hydrolysis (glutaminase) activity (12). CTPS activity was first re...

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confidence: 99%

Crystal Structure of Escherichia coli Cytidine Triphosphate Synthetase, a Nucleotide-Regulated Glutamine Amidotransferase/ATP-Dependent Amidoligase Fusion Protein and Homologue of Anticancer and Antiparasitic Drug Targets^,

et al. 2004

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“…Nevertheless, it was very recently described that the signatures of purine metabolites, including betaine metabolites, branched-chain amino acids, aromatic amino acids, acylglycine derivatives and nucleic acid metabolites, are associated with hyperglycemia or insulin resistance [49,50]. While there is no recent evidence regarding a possible role for purine and pyrimidine metabolites in leukemia, older studies support the notion that reciprocal alterations in the phenotype of specific enzymes may occur in leukemia cells [51,52].…”

Section: Discussionmentioning

confidence: 99%

Common Genetic Aberrations Associated with Metabolic Interferences in Human Type-2 Diabetes and Acute Myeloid Leukemia: A Bioinformatics Approach

Kyriakou

Papageorgis

Christodoulou

2021

IJMS

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Type-2 diabetes mellitus (T2D) is a chronic metabolic disorder, associated with an increased risk of developing solid tumors and hematological malignancies, including acute myeloid leukemia (AML). However, the genetic background underlying this predisposition remains elusive. We herein aimed at the exploration of the genetic variants, related transcriptomic changes and disturbances in metabolic pathways shared by T2D and AML, utilizing bioinformatics tools and repositories, as well as publicly available clinical datasets. Our approach revealed that rs11709077 and rs1801282, on PPARG, rs11108094 on USP44, rs6685701 on RPS6KA1 and rs7929543 on AC118942.1 comprise common SNPs susceptible to the two diseases and, together with 64 other co-inherited proxy SNPs, may affect the expression patterns of metabolic genes, such as USP44, METAP2, PPARG, TIMP4 and RPS6KA1, in adipose tissue, skeletal muscle, liver, pancreas and whole blood. Most importantly, a set of 86 AML/T2D common susceptibility genes was found to be significantly associated with metabolic cellular processes, including purine, pyrimidine, and choline metabolism, as well as insulin, AMPK, mTOR and PI3K signaling. Moreover, it was revealed that the whole blood of AML patients exhibits deregulated expression of certain T2D-related genes. Our findings support the existence of common metabolic perturbations in AML and T2D that may account for the increased risk for AML in T2D patients. Future studies may focus on the elucidation of these pathogenetic mechanisms in AML/T2D patients, as well as on the assessment of certain susceptibility variants and genes as potential biomarkers for AML development in the setting of T2D. Detection of shared therapeutic molecular targets may enforce the need for repurposing metabolic drugs in the therapeutic management of AML.

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“…Pyrimidine metabolism: Pyrimidine compounds are widely distributed in mammalian animals and provide materials for a variety of mammalian metabolism throughout life. The promotion of cell proliferation is the main function of pyrimidine metabolism [32]. Uracil is a base of RNA [33] and also appears during DNA replication [34], playing an important role in protecting host from being attacked by pathogenic microorganisms [35].…”

Section: Metabolic Pathway Analysismentioning

confidence: 99%

Comparative Immune-Related Metabonomics Analysis of Plasma from Mouse after Given Long-Term Astragalus Membranaceus and Panax Ginseng

Chen¹,

Zhang²,

Cheng³

et al. 2018

Preprint

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Astragalus membranaceus (AM) and Panax ginseng (PG) are two herbal products with a long history of clinical usage in traditional Chinese medicine (TCM), used in treating a variety of diseases especially in stimulating or inhibiting the immune system. To elucidate the immunity effect of these two traditional Chinese medicine on animal model, four pharmacodynamic indexes (spleen index, thymus index, splenic lymphocyte proliferation and cytotoxic activity of natural killer (NK) cells) were observed on mice. Furthermore, metabolic profiles of plasma were also analyzed by ultra-performance liquid chromatography quadrupole-time-of-flight mass spectrometry (UPLC-Q/TOF-MS, LC-MS) method. All mice were intragastric administrated at three doses (low dose, moderate dose and high dose) once daily for 30 days. Principal components analysis (PCA) and orthogonal projection to latent structure discriminant analysis (OPLS-DA) were performed on LC-MS spectra of plasma, showing that all administration groups developed the disturbance of internal milieu, compared to the blank control (BC) group. Besides, correlation analysis was conducted between pharmacodynamic index and metabolic index. It indicated that uracil, lysoPC(18:3(6Z,9Z,12Z)), sphinganine, LPA(0:0/16:0), UDP-glucuronate, PC(14:0/18:0) were five main endogenous substances, much closely related to four immunological indexes. Glycerophospholipid metabolism was found in both AM and PG groups. Pyrimidine metabolism and sphingolipid metabolism were closely regulated in AM groups. Energy metabolism (starch and sucrose metabolism, Pentose and glucuronate interconversions, together with glycerolipid metabolism) and glycerolipid metabolism were found in PG groups. These findings could contribute to the understanding of mice plasmatic metabolic profiling after long-term administration. Comparative immune-related metabolomic analysis of AM and PG was obtained on the base of pathway analysis of immune-related biomarkers. PG groups trended to have effect on cytotoxic activity of NK cells. AM groups trended to effect thymus index. Our work provides a detailed interpretation of immunological characteristics in different traditional Chinese medicine on metabonomic level.

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Purine and Pyrimidine Metabolism of Normal and Leukemic Lymphocytes

Cited by 6 publications

References 7 publications

Crystal Structure of Escherichia coli Cytidine Triphosphate Synthetase, a Nucleotide-Regulated Glutamine Amidotransferase/ATP-Dependent Amidoligase Fusion Protein and Homologue of Anticancer and Antiparasitic Drug Targets^,

Crystal Structure of Escherichia coli Cytidine Triphosphate Synthetase, a Nucleotide-Regulated Glutamine Amidotransferase/ATP-Dependent Amidoligase Fusion Protein and Homologue of Anticancer and Antiparasitic Drug Targets^,

Common Genetic Aberrations Associated with Metabolic Interferences in Human Type-2 Diabetes and Acute Myeloid Leukemia: A Bioinformatics Approach

Comparative Immune-Related Metabonomics Analysis of Plasma from Mouse after Given Long-Term Astragalus Membranaceus and Panax Ginseng

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Purine and Pyrimidine Metabolism of Normal and Leukemic Lymphocytes

Cited by 6 publications

References 7 publications

Crystal Structure of Escherichia coli Cytidine Triphosphate Synthetase, a Nucleotide-Regulated Glutamine Amidotransferase/ATP-Dependent Amidoligase Fusion Protein and Homologue of Anticancer and Antiparasitic Drug Targets,

Crystal Structure of Escherichia coli Cytidine Triphosphate Synthetase, a Nucleotide-Regulated Glutamine Amidotransferase/ATP-Dependent Amidoligase Fusion Protein and Homologue of Anticancer and Antiparasitic Drug Targets,

Common Genetic Aberrations Associated with Metabolic Interferences in Human Type-2 Diabetes and Acute Myeloid Leukemia: A Bioinformatics Approach

Comparative Immune-Related Metabonomics Analysis of Plasma from Mouse after Given Long-Term Astragalus Membranaceus and Panax Ginseng

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Crystal Structure of Escherichia coli Cytidine Triphosphate Synthetase, a Nucleotide-Regulated Glutamine Amidotransferase/ATP-Dependent Amidoligase Fusion Protein and Homologue of Anticancer and Antiparasitic Drug Targets^,

Crystal Structure of Escherichia coli Cytidine Triphosphate Synthetase, a Nucleotide-Regulated Glutamine Amidotransferase/ATP-Dependent Amidoligase Fusion Protein and Homologue of Anticancer and Antiparasitic Drug Targets^,