Transition-State Variation in Human, Bovine, and <i>Plasmodium falciparum</i> Adenosine Deaminases

Singh, Vipender; Taylor, Erika A.; Schramm, Vern L.

doi:10.1021/ja072122y

Cited by 33 publications

(86 citation statements)

References 50 publications

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“…The nucleophilic addition shows large normal 13 C 6 KIEs, in contrast to the relatively small 13 C 6 KIEs from Schramm's experiments. 6 The elongation of the C 6 -N 6 bond, participation of Zn-coordinated hydroxyl, and the protonation of N 1 at the transition state all contribute to the primary 13 C 6 KIEs for the nucleophilic addition.…”

Section: Kinetic Isotope Effectcontrasting

confidence: 56%

A theoretical study on the catalytic mechanism of Mus musculus adenosine deaminase

Zou

Quan

et al. 2010

J Comput Chem

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The catalytic mechanism of Mus musculus adenosine deaminase (ADA) has been studied by quantum mechanics and two-layered ONIOM calculations. Our calculations show that the previously proposed mechanism, involving His238 as the general base to activate the Zn-bound water, has a high activation barrier of about 28 kcal/mol at the proposed rate-determining nucleophilic addition step, and the corresponding calculated kinetic isotope effects are significantly different from the recent experimental observations. We propose a revised mechanism based on calculations, in which Glu217 serves as the general base to abstract the proton of the Zn-bound water, and the protonated Glu217 then activates the substrate for the subsequent nucleophilic addition. The rate-determining step is the proton transfer from Zn-OH to 6-NH(2) of the tetrahedral intermediate, in which His238 serves as a proton shuttle for the proton transfer. The calculated kinetic isotope effects agree well with the experimental data, and calculated activation energy is also consistent with the experimental reaction rate.

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Section: Kinetic Isotope Effectcontrasting

confidence: 56%

A theoretical study on the catalytic mechanism of Mus musculus adenosine deaminase

Zou

Quan

et al. 2010

J Comput Chem

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“…The reaction was initiated by addition of an enzyme mixture of 0.01 unit of ribokinase, 0.01 unit of adenine phosphoribosyltransferase, 0.01 unit of phospho-D-ribosyl-1-pyrophosphate synthase, 1 unit of adenylate kinase (Sigma), and 1 unit of pyruvate kinase (Sigma). Ribokinase, phospho-D-ribosyl-1-pyrophosphatesynthase, and adenine phosphoribosyltransferase were purified according to the methods reported previously (17,18 …”

Section: [1-3 H]adenosine Synthesismentioning

confidence: 99%

Erythrocytic Adenosine Monophosphate as an Alternative Purine Source in Plasmodium falciparum

Cassera

Hazleton

Riegelhaupt

et al. 2008

Journal of Biological Chemistry

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Plasmodium falciparum is a purine auxotroph, salvaging purines from erythrocytes for synthesis of RNA and DNA. Hypoxanthine is the key precursor for purine metabolism in Plasmodium. Inhibition of hypoxanthine-forming reactions in both erythrocytes and parasites is lethal to cultured P. falciparum. We observed that high concentrations of adenosine can rescue cultured parasites from purine nucleoside phosphorylase and adenosine deaminase blockade but not when erythrocyte adenosine kinase is also inhibited. P. falciparum lacks adenosine kinase but can salvage AMP synthesized in the erythrocyte cytoplasm to provide purines when both human and Plasmodium purine nucleoside phosphorylases and adenosine deaminases are inhibited. Transport studies in Xenopus laevis oocytes expressing the P. falciparum nucleoside transporter PfNT1 established that this transporter does not transport AMP. These metabolic patterns establish the existence of a novel nucleoside monophosphate transport pathway in P. falciparum.Malaria is one of the leading causes of morbidity and mortality in the tropics with 300 -500 million clinical cases and 1.5-2.7 million deaths per year (1). Malaria is caused by protozoan parasites of the Plasmodium genus of which Plasmodium falciparum is responsible for most of the fatal cases. The parasite is transmitted between human hosts by Anopheles mosquitoes. Malaria has been treated for many years through chemotherapeutic and vector control strategies, but these have not prevented widespread occurrence. An alarming increase in both the resistance of malaria parasites to drug treatment and in mosquito vectors to insecticides has renewed the demand for the development of new chemotherapeutic strategies (2, 3). Advances in the knowledge of the metabolic and nutritional needs of the parasite offer new potential routes for chemotherapy. Because of the rapid rate of DNA synthesis during the 48-h intraerythrocytic growth phase, targeting purine metabolic pathways is a promising route for novel drug development.P. falciparum is a purine auxotroph, salvaging host cell purines for synthesis of cofactors and nucleic acids (4, 5). Purine nucleosides and nucleobases can be transported across the parasite plasma membrane by the PfNT1 2 transporter (Fig. 1). The mechanisms by which Plasmodium salvages purines during the intraerythrocytic cycle are diverse both with regard to primary sources and to routes of interconversion (Fig. 1). Hypoxanthine is the key precursor of other purines in Plasmodium metabolism and is commonly used as a nutritional supplement in malarial culture media. A key source of hypoxanthine in vivo is from the erythrocyte purine pool where ATP is in dynamic metabolic exchange with hypoxanthine via ADP, AMP, IMP, inosine, and adenosine (5). In human erythrocytes, adenosine is efficiently salvaged by adenosine kinase (hAK). This allows human erythrocytes to utilize serum adenosine to maintain erythrocyte ATP levels. In P. falciparum, adenosine is salvaged by conversion to hypoxanthine using adenosine deaminas...

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“…[5][6][7][8][9][10][11] In biochemistry, Meisenheimer intermediates are involved in enzymatic pathways, the inhibition of which can lead to the treatment of widespread and important diseases. [12][13][14][15][16] Although a large amount of detailed knowledge has been gathered on Meisenheimer complexes in condensed phases, relatively few studies have addressed the issue of anion binding to aromatic rings in the absence of solvation. [17][18][19][20][21][22][23][24][25] Recently, renewed interest has been devoted to aromatic nucleophilic substitution reactions effected by halide ions in the gas phase, and the dynamics have been examined with femtosecond resolution on an overall neutral system.…”

Section: Introductionmentioning

confidence: 99%

Molecular Complexes of Simple Anions with Electron‐Deficient Arenes: Spectroscopic Evidence for Two Types of Structural Motifs for Anion–Arene Interactions

Chiavarino

Crestoni

Fornarini

et al. 2009

Chemistry A European J

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Anion-pi interactions between a pi-acidic aromatic system and an anion are gaining increasing recognition in chemistry and biology. Herein, the binding features of an electron-deficient aromatic system (1,3,5-trinitrobenzene (TNB)) and selected anions (OH-, Br-, and I-) are examined in the gas phase by using the combined information derived from collision-induced dissociation experiments at variable energy, infrared multiple-photon dissociation spectroscopy, and quantum chemical calculations. We provide spectroscopic evidence for two different structural motifs of anion-arene complexes depending on the nature of the anion. The TNB-OR- complexes (R=H, or alkyl groups which were studied earlier) adopt an anionic sigma-complex structure whereby RO- attacks the aromatic ring with covalent bond formation, and develops a tetrahedral ring carbon bound to H and OR. The halide complexes rather conform to a structure in which the TNB moiety is hardly altered, and the halogen is placed on an unsubstituted carbon atom over the periphery of the ring at a C-X distance that is appreciably longer than a typical covalent bond length. The ensuing structural motif, previously characterized in the solid state and named weak sigma interaction, is now confirmed by an IR spectroscopic assay in the gas phase, in which the sampled species are unperturbed by crystal packing or solvation effects.

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Transition-State Variation in Human, Bovine, and Plasmodium falciparum Adenosine Deaminases

Cited by 33 publications

References 50 publications

A theoretical study on the catalytic mechanism of Mus musculus adenosine deaminase

A theoretical study on the catalytic mechanism of Mus musculus adenosine deaminase

Erythrocytic Adenosine Monophosphate as an Alternative Purine Source in Plasmodium falciparum

Molecular Complexes of Simple Anions with Electron‐Deficient Arenes: Spectroscopic Evidence for Two Types of Structural Motifs for Anion–Arene Interactions

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