Adenine ribo- and deoxyribonucleotide metabolism in human erythrocytes, B- and T-lymphocyte cell lines, and monocyte-macrophages.

Valentine, William N.; Paglia, Donald E.; Clarke, Steven; Morimoto, Bruce H.; Nakatani, Misae; Brockway, Richard A.

doi:10.1073/pnas.82.19.6682

Cited by 8 publications

(3 citation statements)

References 34 publications

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“…Conversely, ADA can efficiently deaminate dAMP because the 2Ј-OH of adenosine is not essential for substrate binding (15,16). This ribonucleotide substrate preference of AMPD has a significant clinical consequence because it promotes deoxyadenosine nucleotide accumulation that produces a severe combined immunodeficiency in an inherited ADA deficiency in man (49).…”

Section: Discussionmentioning

confidence: 99%

Membrane Association, Mechanism of Action, and Structure of Arabidopsis Embryonic Factor 1 (FAC1)

Han

Bingman

Mahnke

et al. 2006

Journal of Biological Chemistry

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Embryonic factor 1 (FAC1) is one of the earliest expressed plant genes and encodes an AMP deaminase (AMPD), which is also an identified herbicide target. This report identifies an N-terminal transmembrane domain in Arabidopsis FAC1, explores subcellular fractionation, and presents a 3.3-Å globular catalytic domain x-ray crystal structure with a bound herbicide-based transition state inhibitor that provides the first glimpse of a complete AMPD active site. FAC1 contains an (␣/␤) 8 -barrel characterized by loops in place of strands 5 and 6 that places it in a small subset of the amidohydrolase superfamily with imperfect folds. Unlike tetrameric animal orthologs, FAC1 is a dimer and each subunit contains an exposed Walker A motif that may be involved in the dramatic combined K m (25-80-fold lower) and V max (5-6-fold higher) activation by ATP. Normal mode analysis predicts a hinge motion that flattens basic surfaces on each monomer that flank the dimer interface, which suggests a reversible association between the FAC1 globular catalytic domain and intracellular membranes, with N-terminal transmembrane and disordered linker regions serving as the anchor and attachment to the globular catalytic domain, respectively.Embryonic factor 1 (FAC1) 5 was recently identified as one of the earliest expressed plant genes and is essential for the zygote to embryo transition in Arabidopsis thaliana (1). The zygote-lethal phenotype is characterized by developmental arrest at the 8 -16-cell stage and mutant embryo shriveling 2-3 days after fertilization. The Arabidopsis FAC1 locus encodes an AMP deaminase (AMPD; EC 3.5.4.6), which is a eukaryotic enzyme that catalyzes the hydrolytic deamination of AMP to IMP. AMPD has also been identified as the intracellular target for a class of herbicides that are produced by fungal pathogens. Carbocyclic coformycin was initially discovered in Saccharothrix (2), and plant cells can take up this diffusible nucleoside and 5Ј-phosphorylate it to produce a potent transition state inhibitor of AMPD (3). Exposure to carbocyclic coformycin results in cessation of seedling growth, followed by paling and necrosis at the apical meristem (3). Coformycin, a structurally related compound produced by a number of microbes (4, 5), also has herbicidal properties (5). Although the intracellular metabolism of this compound in plants has not been examined, its mode of action is presumably similar because coformycin 5Ј-phosphate is a transition state inhibitor of rabbit muscle AMPD (6). Both herbicides are inhibitors of mammalian adenosine deaminase (ADA) (3, 6), but the lack of this enzyme in plants (3, 7-9) supports the argument that AMPD is the intracellular target for their nucleotide derivatives. Taken together, these observations suggest that AMPD is essential throughout the plant life cycle. However, the underlying basis for lethality of a FAC1 null phenotype and for herbicidal toxicity related to the catalytic inhibition of this enzyme is not known.AMPD catalyzes the initial step in adenine to guanine ribon...

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Section: Discussionmentioning

confidence: 99%

Membrane Association, Mechanism of Action, and Structure of Arabidopsis Embryonic Factor 1 (FAC1)

Han

Bingman

Mahnke

et al. 2006

Journal of Biological Chemistry

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“…It cannot even be excluded that in determining haemolysis, under the conditions of oxidative stress used here, a critical role was played by the profound changes of energy metabolism, in great part due to the loss of regulation of AMP-deaminase. It has been suggested that this enzymatic activity might be accelerated in dying erythrocytes with the specific purpose of depleting the energy state of the erythrocyte and facilitating haemolysis [22].…”

Section: Discussionmentioning

confidence: 99%

Energy metabolism and lipid peroxidation of human erythrocytes as a function of increased oxidative stress

Tavazzi

Pierro

Amorini

et al. 2000

European Journal of Biochemistry

140

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To study the influence of oxidative stress on energy metabolism and lipid peroxidation in erythrocytes, cells were incubated with increasing concentrations (0.5±10 mm) of hydrogen peroxide for 1 h at 37 8C and the main substances of energy metabolism (ATP, AMP, GTP and IMP) and one index of lipid peroxidation (malondialdehyde) were determined by HPLC on cell extracts. Using the same incubation conditions, the activity of AMP-deaminase was also determined. Under nonhaemolysing conditions (at up to 4 mm H 2 O 2 ), oxidative stress produced, starting from 1 mm H 2 O 2 , progressive ATP depletion and a net decrease in the intracellular sum of adenine nucleotides (ATP + ADP + AMP), which were not paralleled by AMP formation. Concomitantly, the IMP level increased by up to 20-fold with respect to the value determined in control erythrocytes, when cells were challenged with the highest nonhaemolysing H 2 O 2 concentration (4 mm). Efflux of inosine, hypoxanthine, xanthine and uric acid towards the extracellular medium was observed. The metabolic imbalance of erythrocytes following oxidative stress was due to a dramatic and unexpected activation of AMPdeaminase (a twofold increase of activity with respect to controls) that was already evident at the lowest dose of H 2 O 2 used; this enzymatic activity increased with increasing H 2 O 2 in the medium, and reached its maximum at 4 mm H 2 O 2 -treated erythrocytes (10-fold higher activity than controls). Generation of malondialdehyde was strictly related to the dose of H 2 O 2 , being detectable at the lowest H 2 O 2 concentration and increasing without appreciable haemolysis up to 4 mm H 2 O 2 . Besides demonstrating a close relationship between lipid peroxidation and haemolysis, these data suggest that glycolytic enzymes are moderately affected by oxygen radical action and strongly indicate, in the change of AMP-deaminase activity, a highly sensitive enzymatic site responsible for a profound modification of erythrocyte energy metabolism during oxidative stress.Keywords: AMP-deaminase; energy metabolism; human erythrocytes; IMP; oxidative stress.Reactive oxygen species (ROS) are produced in living organisms from the partial reduction of molecular oxygen under physiological and pathological conditions. Because ROS has the capability of reacting nonspecifically with a vast number of compounds, all living organisms contain several enzymatic (superoxide dismutase, catalase, glutathione peroxidase) and nonenzymatic (a-tocopherol, ascorbic and uric acids, glutathione and other thiol protein groups) antioxidants with the specific purpose of protecting the functional and structural integrity of biologically fundamental macromolecules (nucleic acids, proteins, phospholipids). Imbalance between ROS production and antioxidant cell defences has been reported to occur in several physiopathological conditions of both animals and man: for example tissue ischemia and reperfusion Many in vitro and in vivo studies showed that several parameters of red blood cell function and integrity are ne...

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“…In vitro treatment of human red cells with deoxycoformycin and then provided with deoxyadenosine and D-glucose similarly resulted in a marked decline of ATP and concomitant dATP accumulation (Koller et al, 1984;Buc et al, 1986). The mechanism of induced ATP breakdown in human hemopoietic cells accumulating dATP is the subject of three excellent recent reviews (Bagnara and Hershfield, 1982;Valentine et al, 1985;Bontemps et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

Studies on the energy metabolism of opossum (Didelphis virginiana) erythrocytes: V. Utilization of hypoxanthine for the synthesis of adenine and guanine nucleotides in vitro

Bethlenfalvay

White

Chadwick

et al. 1990

Journal Cellular Physiology

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High pressure liquid radiochromatography was used to test the ability of opossum erythrocytes to incorporate tracer amounts of [G-3H] hypoxanthine (Hy) into [3H] labelled triphosphates of adenine and guanine. In the presence of supraphysiologic (30 mM) phosphate which is optimal for PRPP synthesis, both ATP and GTP are extensively labelled. When physiologic (1 mM) medium phosphate is used, red cells incubated under an atmosphere of nitrogen accumulate [3H] ATP in a linear fashion suggesting ongoing PRPP synthesis in red cells whose hemoglobin is deoxygenated. In contrast, a lesser increase of labelled ATP is observed in cells incubated under oxygen, suggesting that conditions for purine nucleotide formation from ambient Hy are more favorable in the venous circulation.

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Adenine ribo- and deoxyribonucleotide metabolism in human erythrocytes, B- and T-lymphocyte cell lines, and monocyte-macrophages.

Cited by 8 publications

References 34 publications

Membrane Association, Mechanism of Action, and Structure of Arabidopsis Embryonic Factor 1 (FAC1)

Membrane Association, Mechanism of Action, and Structure of Arabidopsis Embryonic Factor 1 (FAC1)

Energy metabolism and lipid peroxidation of human erythrocytes as a function of increased oxidative stress

Studies on the energy metabolism of opossum (Didelphis virginiana) erythrocytes: V. Utilization of hypoxanthine for the synthesis of adenine and guanine nucleotides in vitro

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