Theoretical Study of Inhibition of Adenosine Deaminase by (8<i>R</i>)-Coformycin and (8<i>R</i>)-Deoxycoformycin

Tj, Marrone; Tp, Straatsma; Briggs, James M.; Dk, Wilson; Fa, Quiocho; McCammon, J. Andrew

doi:10.1021/jm9505674

Cited by 40 publications

(16 citation statements)

References 25 publications

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“…3A). The disappearance of Ado from the medium was partially blocked by dipyridamole, an inhibitor of Ado uptake, 19) or coformycin, an inhibitor of Ado deaminase 20) (Fig. 3A).…”

Section: Metabolism Of Extracellular Ado and Atp By Pc12mentioning

confidence: 98%

“…The addition of dipyridamole, an inhibitor of Ado uptake, 19) or coformycin, an inhibitor of Ado deaminase, 20) slightly but significantly increased cellular ATP levels in PC12 cells. When coincubated with Ado 100 mM, the cellular ATP levels was further enhanced as compared with the levels induced by Ado alone (Table 4).…”

Section: Effects Of Dipyridamole Coformycin and 5-iodotubercidin Onmentioning

confidence: 99%

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Enhancement of Cellular Adenosine Triphosphate Levels in PC12 Cells by Extracellular Adenosine.

Fujimori

Yasuda

Pan-Hou

2002

Biological & Pharmaceutical Bulletin

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Extracellular adenosine (Ado), a metabolite of adenosine triphosphate (ATP), has been shown to function as an intercellular signaling molecule by interacting with specific P1 receptors.1,2) Extracellular ATP released from nerve cells, endothelial cells, chromaffin cells, or platelets can act as a transmitter or modulator via P2 receptors. 1,3) A number of cellular responses induced by Ado [4][5][6] and ATP [7][8][9][10][11] in rat pheochromocytoma PC12 cells, a neuronal model, have been demonstrated to be mediated mainly through P1 and P2 receptors. PC12 cells are known to have A2a and A2b but not A1 or A3 receptors among the P1 receptor subtypes, and P2X 2 , P2Y 1 , and P2Y 2 among the P2 receptor subtypes.2)The common responses induced by Ado and ATP in PC12 cells are to increase the cellular levels of cAMP and the activity of cAMP-regulated tyrosine hydroxylase, a rate-limiting enzyme of catecholamine biosynthesis. 4,12) It is of interest to determine whether cellular levels of ATP in PC12 cells would be affected by the addition of Ado, ATP, and related compounds.In general, extracellular ATP is known to be metabolized rapidly to Ado, and then converted to inosine and other metabolites by ecto-enyzmes on cell surfaces or soluble enzymes in extracellular fluids. 3,13,14) Extracellular ATP was rapidly degraded to adenosine 5Ј-monophosphate (AMP) by PC12 cells, but the formation of Ado from AMP was slow, 4,15) despite having ecto-5Ј-nucleotidase, which catalyzes the conversion of AMP to Ado.16) It is of interest to examine whether PC12 cells have the ability to metabolize Ado, and to know whether extracellular Ado influences the cellular contents of adenine compounds, especially ATP.In this investigation, we examined the effects of Ado and adenine nucleotides on cellular levels of adenine compounds, especially ATP, in PC12 cells. We showed that extracellular Ado enhanced the cellular ATP level, probably via the salvage pathway of adenine nucleotides, but not P1 and P2 receptors of Ado and ATP, respectively. MATERIALS AND METHODSMaterials Ado, AMP, adenosine 5Ј-diphosphate (ADP), and ATP were purchased from Yamasa Shouyu (Japan). 2-Chloro-N 6 -cyclopentyladenosine (CCPA), N 6 -cyclohexyladenosine (CHA), 5Ј-N-ethylcarboxaminoadenosine (NECA), dipyridamole, and reactive blue 2 were obtained from Sigma Chemical (U.S.A.). 2[p-(2-Carboxyethyl)phenethylamino]-5Ј-N-ethylcarboxamidoadenosine (CGS 21680) and coformycin were from Funakoshi Chemical (Japan) and Nakarai Tesque (Japan), respectively. Theophylline and chloroacetaldehyde were from Wako Chemicals (Japan). Fetal calf serum and inactivated horse serum were from IS Japan (Japan) and Gibco BRL (U.S.A.), respectively. Other chemicals of reagent grade were commercially obtained.Cell Culture Rat pheochromocytoma PC12 cells were kindly supplied by Professor K. Miura (Wako University, Tokyo, Japan). Cells were grown at 37°C in Dulbecco's modified Eagle's medium supplemented with 10% fetal calf serum, 5% heat-inactivated horse serum, glutamine 30 mg/ ml, and kanamycin 60 ...

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“…3A). The disappearance of Ado from the medium was partially blocked by dipyridamole, an inhibitor of Ado uptake, 19) or coformycin, an inhibitor of Ado deaminase 20) (Fig. 3A).…”

Section: Metabolism Of Extracellular Ado and Atp By Pc12mentioning

confidence: 98%

Section: Effects Of Dipyridamole Coformycin and 5-iodotubercidin Onmentioning

confidence: 99%

Enhancement of Cellular Adenosine Triphosphate Levels in PC12 Cells by Extracellular Adenosine.

Fujimori

Yasuda

Pan-Hou

2002

Biological & Pharmaceutical Bulletin

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“…[25]. As reported [15,17,25,33] in the reaction mechanism of mammalian adenosine deaminase the histidine bridge formed between a His residue (His-17 in the murine ADA) and the 5'-OH group of the ribose mojety of substrate play a key role in the deamination process where this bound is an essential conditions to align the substrate in the active site. In fact substrates modified on the 5'-OH as 5'-deoxyadenosine, were deaminated by mammalian ADA with a rate of deamination 103 fold lower than that reported for adenosine, in contrast to the fungal enzyme that shows the same affinity for adenosine and 5'-deoxyadenosine [25].…”

Section: Data Inmentioning

confidence: 85%

Photoinactivation studies on adenosine deaminase

et al. 1998

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Reinvestigation of direct modification of histidine residues in calf intestine adenosin deaminase resulted in loss of the activity towards substrates as adenosine, 2′‐deoxyadenosine and 6‐hydroxyl‐aminopurin riboside. Photo‐oxidation of the enzyme in the presence of methylene blue led to a complete loss of enzymatic activity and the presence of inhibitors such as purin riboside, EHNA, coformycin, showed protection against methylene blue oxidation. Kinetic analysis of the inactivation by diethylpyrocarbonate, indicated that enzyme inactivation results from the modification of at most one essential histidine residue. Photoinactivation of adenosine deaminase from Aspergillus Orizae reduces the activity of the enzyme but the accessibility of histidine residues in the active site seems to be lower as compared to that shown from mammalian adenosine deaminase. The results obtained are in agreement with the important role played by the “bridge” between an enzyme histidine residue and the 5′‐OH of the ribose mojety of substrate in the transition state stabilization in the two enzymatic forms observed. Upon ultraviolet irradiation of calf intestine adenosine deaminase in the presence of 2,2,2‐thrichloroethanol, the trasformation of fluorescent tryptophan residues occurs with the reduced enzymatic catalytical activity and confirms the likely location of tryptophans near the binding site of the enzyme.

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“…This method has been used extensively to study the relative binding energies of drugs and inhibitors for enzymes (van Gunsteren and Weiner 1989;Marrone et al 1997;Plaxco and Goddard 1994) and inhibitors. Here we describe brieºy one of the recent applications (Marrone et al 1996) of the free energy perturbation simulations to the study of inhibition of the enzyme adenosine deaminase by 8R-coformycin and (8R)-deoxycoformycin. The inhibition of the enzyme adenosine deaminase, which deaminates the base adenosine, could provide an effective treatment of some immunological disorders.…”

Section: Calculation Of Binding Energy Using Free Energy Perturbationmentioning

confidence: 99%

Atomic-Level Simulation and Modeling of Biomacromolecules

2001

Computational Modeling of Genetic and Biochemical Networks

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Figure 6.1 The hierarchy of biomolecular simulations. It is necesary to predict reliable properties before starting an experiment. The foundation is quantum mechanics. This allows prediction in advance, but is not practical for time and distance scales of molecular engineering. Thus one must extend from QM to large-scale, cellular-level dynamics by a succession of scales, where at each scale the parameters are determined by averaging over the finer scale.

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Theoretical Study of Inhibition of Adenosine Deaminase by (8R)-Coformycin and (8R)-Deoxycoformycin

Cited by 40 publications

References 25 publications

Enhancement of Cellular Adenosine Triphosphate Levels in PC12 Cells by Extracellular Adenosine.

Enhancement of Cellular Adenosine Triphosphate Levels in PC12 Cells by Extracellular Adenosine.

Photoinactivation studies on adenosine deaminase

Atomic-Level Simulation and Modeling of Biomacromolecules

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