-
Biochimica Et Biophysica Acta 2006Despite the enormous interest in the roles of novel uncoupling proteins, there is still great uncertainty as to their mechanism and regulation. The regulation of the... (Review)
Review
Despite the enormous interest in the roles of novel uncoupling proteins, there is still great uncertainty as to their mechanism and regulation. The regulation of the architypal uncoupling protein 1 from brown adipose tissue was elucidated more than 20 years ago. This review suggests that a number of the approaches and criteria developed for the study of UCP1 could with profit be applied to current investigations of the novel UCPs.
Topics: Adipose Tissue, Brown; Animals; Biological Transport; Carrier Proteins; Fatty Acids; Ion Channel Gating; Ion Channels; Lipid Peroxidation; Membrane Proteins; Mitochondrial Proteins; Protons; Purine Nucleotides; Uncoupling Protein 1
PubMed: 16725104
DOI: 10.1016/j.bbabio.2006.02.005 -
The Biochemical Journal Sep 1997A purine nucleoside- and nucleotide-binding protein has been isolated from extracts of rat and rabbit heart, calf aortic smooth muscle and rat liver using an affinity...
A purine nucleoside- and nucleotide-binding protein has been isolated from extracts of rat and rabbit heart, calf aortic smooth muscle and rat liver using an affinity column containing adenosine bound through the N6-position. The protein, which was eluted by adenosine, was cloned and expressed in Escherichia coli. The deduced amino acid sequence has a calculated Mr of 13693 (p13.7). The expressed protein has properties identical with the protein isolated from heart and liver, including an anomalous, apparent Mr of 15300, observed on gel electrophoresis. Gel filtration shows it to be a dimer. p13.7 differs by only three amino acids out of 125 from protein kinase C inhibitor 1 [Pearson, DeWald, Mathews, Mozier, Zürcher-Neely, Heinrikson, Morris, McCubbin, McDonald, Fraser et al. (1990) J. Biol. Chem. 265, 4583-4591]. However, we have not been able to demonstrate inhibition of protein kinase C by physiological concentrations of p13.7, regardless of whether it was isolated from tissue extracts or expressed in E. coli. p13.7 is a member of the histidine triad motif family of proteins [Séraphin (1992) J. DNA Sequencing Mapping 3, 177-179]. The affinity of p13.7 for a number of different purine nucleosides and nucleotides, as measured by fluorescence titration and gel filtration, falls within the range 5-50 microM. On the basis of these properties and its crystal structure [Brenner, Garrison, Gilmour, Peisach, Ringe, Petsko and Lowenstein (1997) Nature Struct. Biol. 4, 231-238], we have coined the acronym HINT (histidine triad nucleotide-binding motif) to describe the family of proteins of which p13.7 is a member. Other proteins that bind to the affinity column have been identified as malate and lactate dehydrogenases, cAMP-binding proteins, adenosine kinase and S-adenosylhomocysteine hydrolase.
Topics: Adenosine; Amino Acid Sequence; Animals; Base Sequence; Chromatography, Affinity; Cloning, Molecular; Hydrolases; Molecular Sequence Data; Molecular Weight; Organ Specificity; Protein Binding; Proteins; Purine Nucleosides; Purine Nucleotides; Rabbits; Rats; Spectrometry, Fluorescence; Titrimetry
PubMed: 9291120
DOI: 10.1042/bj3260471 -
Frontiers in Immunology 2022Phosphoribosyl pyrophosphate synthetase 1 (PRPS1) is the first enzyme in the purine nucleotide synthesis pathway and is essential for cell development. However, the...
Phosphoribosyl pyrophosphate synthetase 1 (PRPS1) is the first enzyme in the purine nucleotide synthesis pathway and is essential for cell development. However, the effect of PRPS1 on melanoma proliferation and metastasis remains unclear. This study aimed to investigate the regulatory mechanism of PRPS1 in the malignant progression of melanoma. Here, we found PRPS1 was upregulated in melanoma and melanoma cells. In addition, our data indicated that PRPS1 could promote the proliferation and migration and invasion of melanoma both and . PRPS1 also could inhibit melanoma cell apoptosis. Furthermore, we found NRF2 is an upstream transcription factor of PRPS1 that drive malignant progression of melanoma.
Topics: Humans; Melanoma; NF-E2-Related Factor 2; Purine Nucleotides; Ribose-Phosphate Pyrophosphokinase; Syndrome; Up-Regulation
PubMed: 36203561
DOI: 10.3389/fimmu.2022.989263 -
The Biochemical Journal Nov 19781. The contents of the major purine nucleotides in the isolated non-working perfused rat heart varied systematically during 80min of perfusion. In particular the amounts...
Systematic variations in the content of the purine nucleotides in the steady-state perfused rat heart. Evidence for the existence of controlled storage and release of adenine nucleotides.
1. The contents of the major purine nucleotides in the isolated non-working perfused rat heart varied systematically during 80min of perfusion. In particular the amounts of ATP, ADP, GTP, cyclic AMP and cyclic GMP in the well-oxygenated myocardium showed changes ranging from 25 to 60% of the mean concentrations. The apparent periodicity was about 30min for some and about 60min for other nucleotides. 2. These data are in contrast with measurements of parameters reflecting heart performance, which remained constant over this period of perfusion. 3. The ATP/ADP ratio, the cyclic AMP content, the GTP content and the GTP/GDP ratio in the tissue bore a constant relationship to one another, and all showed the same temporal variation. 4. Increasing the energy demand on the heart by administration of bovine somatotropin (1mug/ml) tended to damp the variations, and generally lower the content of all the nucleotides. 5. The total extractable adenine nucleotide pool also showed systematic temporal variations of as much as 1.3mumol/g wet wt. of tissue within 10min. 6. These variations could not be accounted for as inter-conversion with adenosine, other purine nucleotides, nucleosides or purine-degradation products either in the tissue or in the perfusion medium. No evidence was found in this preparation of the purine nucleotide oscillations described by Lowenstein and his co-workers [see Tornheim & Lowenstein (1975) J. Biol. Chem.250, 6304-6314]. 7. Further, the pool size increases cannot be satisfactorily explained by either synthesis de novo or the breakdown of any purine macromolecular species in the cell. Thus it is suggested that an unsuspected substantial storage form of purine nucleotide may exist in heart.
Topics: Adenine Nucleotides; Animals; In Vitro Techniques; Male; Myocardium; Nucleotides, Cyclic; Perfusion; Purine Nucleotides; Rats
PubMed: 743254
DOI: 10.1042/bj1760485 -
Nucleic Acids Research Nov 1989A compilation is presented of viral proteins containing the NTP-binding sequence pattern, and criteria are suggested for assessment of the functional significance of the... (Review)
Review
A compilation is presented of viral proteins containing the NTP-binding sequence pattern, and criteria are suggested for assessment of the functional significance of the occurrence of this pattern in protein sequences. It is shown that the distribution of NTP-binding pattern-containing proteins through the viral kingdom is strongly non-random. Sequence comparisons led to delineation of several families of these proteins, some of which could be brought together into superfamilies including also cellular proteins. The available biochemical evidence is compatible with the proposal that viral proteins in which the NTP-binding pattern is evolutionarily conserved might all be NTPases involved in: i) duplex unwinding during DNA and RNA replication, transcription, recombination and repair, and possibly mRNA translation; ii) DNA packaging, and iii) dNTP generation.
Topics: Amino Acid Sequence; Molecular Sequence Data; Nucleoside-Triphosphatase; Phosphoric Monoester Hydrolases; Protein Conformation; Purine Nucleotides; Viral Proteins
PubMed: 2555771
DOI: 10.1093/nar/17.21.8413 -
Proceedings of the National Academy of... Jan 1982Studies in animal models of myocardial ischemia and left ventricular hypertrophy have demonstrated a number of derangements in purine and pyrimidine nucleotide content...
Studies in animal models of myocardial ischemia and left ventricular hypertrophy have demonstrated a number of derangements in purine and pyrimidine nucleotide content of myocardium that are postulated to play a role in the pathogenesis of muscle dysfunction in these disorders. The present study examined myocardium of patients with coronary artery disease, left ventricular hypertrophy, or neither of these two abnormalities, to determine whether derangements in purine and pyrimidine nucleotide metabolism occur in humans. In patients with coronary artery disease, endocardial content of ATP, GTP, UTP, CTP, and creatine phosphate was reduced and ranged between 60% and 86% of the amount found in the epicardium. In patients without coronary artery disease or ventricular hypertrophy, endocardial content of these nucleotides was equal to or greater than that of epicardium. Endocardial and epicardial content of inosine was increased in patients with coronary artery disease, and after vein bypass grafting inosine content fell to the levels observed in myocardium of patients with normal coronary arteries. In patients with left ventricular hypertrophy, endocardial content of ATP, GTP, UTP, CTP, and creatine phosphate was also reduced and ranged between 64% and 88% of the epicardial content. In contrast to results obtained in patients without left ventricular hypertrophy, epicardial content of GTP, UTP, and CTP was increased by 131%, 123%, and 132% in hypertrophied myocardium. Thus the changes noted in myocardial nucleotide content in patients are similar to those noted in animal models of occlusive coronary disease and ventricular hypertrophy. These results suggest that the pathophysiological abnormalities in nucleotide metabolism noted in animal models also occur in human myocardium.
Topics: Adenine Nucleotides; Cardiomegaly; Coronary Disease; Guanosine Triphosphate; Humans; Myocardium; NAD; Nucleotides; Phosphocreatine; Pyrimidine Nucleotides
PubMed: 6210911
DOI: 10.1073/pnas.79.2.655 -
The Journal of Biological Chemistry Sep 2019Nucleotide synthesis is essential to proliferating cells, but the preferred precursors for biosynthesis are not defined in human cancer tissues. We have employed...
Nucleotide synthesis is essential to proliferating cells, but the preferred precursors for biosynthesis are not defined in human cancer tissues. We have employed multiplexed stable isotope-resolved metabolomics to track the metabolism of [C]glucose, D-glycine, [C]glycine, and D-serine into purine nucleotides in freshly resected cancerous and matched noncancerous lung tissues from nonsmall cell lung cancer (NSCLC) patients, and we compared the metabolism with established NSCLC PC9 and A549 cell lines Surprisingly, [C]glucose was the best carbon source for purine synthesis in human NSCLC tissues, in contrast to the noncancerous lung tissues from the same patient, which showed lower mitotic indices and MYC expression. We also observed that D-Ser was preferentially incorporated into purine rings over D-glycine in both tissues and cell lines. suppression attenuated [C]glucose, D-serine, and [C]glycine incorporation into purines and reduced proliferation in PC9 but not in A549 cells. Using detailed kinetic modeling, we showed that the preferred use of glucose as a carbon source for purine ring synthesis in NSCLC tissues involves cytoplasmic activation/compartmentation of the glucose-to-serine pathway and enhanced reversed one-carbon fluxes that attenuate exogenous serine incorporation into purines. Our findings also indicate that the substrate for nucleotide synthesis differs profoundly between cancer cell lines and fresh human lung cancer tissues; the latter preferred glucose to exogenous serine or glycine but not the former. This distinction in substrate utilization in purine synthesis in human cancer tissues should be considered when targeting one-carbon metabolism for cancer therapy.
Topics: A549 Cells; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Glycine; Humans; Lung Neoplasms; Metabolomics; Purine Nucleotides; Serine
PubMed: 31337706
DOI: 10.1074/jbc.RA119.008743 -
The Biochemical Journal Jan 19751. The metabolism of xanthine and hypoxanthine in excised shoot tips of tea was studied with micromolar amounts of [2(-14)C]xanthine or [8(-14)C]hypoxanthine. Almost all...
1. The metabolism of xanthine and hypoxanthine in excised shoot tips of tea was studied with micromolar amounts of [2(-14)C]xanthine or [8(-14)C]hypoxanthine. Almost all of the radioactive compounds supplied were utilized by tea shoot tips by 30 h after their uptake. 2. The main products of [2(-14)C]xanthine and [8(-14)C]hypoxanthine metabolism in tea shoots were urea, allantoin and allantoic acid. There was also incorporation of the label into theobromine, caffeine and RNA purine nucleotides. 3. The results indicate that tea plants can catabolize purine bases by the same pathways as animals. It is also suggested that tea plants have the ability to snythesize purine nucleotides from glycine by the pathways of purine biosynthesis de novo and from hypoxanthine and xanthine by the pathway of purine salvage. 4. The results of incorporation of more radioactivity from [8(-14)C]hypoxanthine than from [2(-14)C]xanthine into RNA purine nucleotides and caffeine suggest that hypoxanthine is a more effective precursor of caffeine biosynthesis than xanthine. The formation of caffeine from hypoxanthine is a result of nucleotide synthesis via the pathway of purine salvage.
Topics: Allantoin; Caffeine; Glycine; Hypoxanthines; Purine Nucleotides; Purines; RNA; Tea; Theobromine; Time Factors; Urea; Xanthines
PubMed: 1147906
DOI: 10.1042/bj1460079 -
In Vivo (Athens, Greece) 2006Asparaginase is a key component of the chemotherapy protocols used in the treatment of acute lymphoblastic leukemia (ALL). The current treatment protocols are remarkable... (Review)
Review
Asparaginase is a key component of the chemotherapy protocols used in the treatment of acute lymphoblastic leukemia (ALL). The current treatment protocols are remarkable in that childhood ALL cure rates are approaching 85%. As the name implies, asparaginase catalyzes the deamination of asparagine to aspartic acid. What is not generally realized is that asparaginase also catalyzes, essentially to the same extent, the removal of the amide nitrogen from glutamine to form glutamic acid. Glutamine is a required substrate for three enzymes involved in the de novo synthesis of purine nucleotides and two enzymes involved in the de novo synthesis of pyrimidine nucleotides. In this review, the specific roles of glutamine in the de novo synthesis of nucleotides are defined and an appropriate explanation for the cell cycle arrest and cytotoxicity induced in proliferating malignant lymphoblasts by asparaginase treatment is provided.
Topics: Antineoplastic Agents; Asparaginase; Cell Cycle; Glutamine; Molecular Structure; Nitrogen; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purine Nucleotides; Pyrimidine Nucleotides
PubMed: 17091764
DOI: No ID Found -
The Journal of Clinical Investigation Nov 1975We have reported previously two siblings with gout and uric acid lithiasis associated with excessive purine production. In the erythrocytes of these patients,...
Mutant feedback-resistant phosphoribosylpyrophosphate synthetase associated with purine overproduction and gout. Phosphoribosylpyrophosphate and purine metabolism in cultured fibroblasts.
We have reported previously two siblings with gout and uric acid lithiasis associated with excessive purine production. In the erythrocytes of these patients, phosphoribosylpyrophosphate (PRPP) synthetase exhibited resistance to feedback-inhibition by normal cell constituents such as guanosine-5'-diphosphate (GDP) and adenosine-5'-diphosphate (ADP), resulting in superactivity of the mutant enzyme and consequently in increased PRPP content and availability for nucleotide synthesis. Erythrocyte PRPP content and availability were normal in the propositus' parents, his healthy brother and three sons, and they all had normal serum level and urinary excretion of uric acid, except for the mother who was hyperuricosuric. To further characterize this mutation we studied PRPP and purine metabolism in cultured fibroblasts of the affected family. PRPP synthetase in dialyzed lysates of fibroblasts from the propositus and his mother exhibited increased specific activity, more markedly at low inorganic phosphate concentration, and decreased sensitivity to inhibition by ADP and GDP, PRPP content and availability and the rate of de novo purine nucleotide synthesis were markedly increased in the fibroblasts of the propositus and to a lesser extent in the fibroblasts of his mother but were normal in the fibroblasts of the other family members investigated. The fibroblast studies demonstrate the following sequence of abnormalities: feedback-resistance of PRPP synthetase; superactivity of this enzyme in normal physiological milieu; increased availability of PRPP; and increased de novo synthesis of purine nucleotides. The pattern of inheritance of this disorder is compatible with both an X-linked recessive and autosomal dominant traits.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Erythrocytes; Feedback; Female; Fibroblasts; Genes; Gout; Humans; Male; Mutation; Pentosephosphates; Phosphoribosyl Pyrophosphate; Phosphotransferases; Purine Nucleotides; Ribose-Phosphate Pyrophosphokinase; Uric Acid
PubMed: 171280
DOI: 10.1172/JCI108183