Adenosine deaminase from Saccharomyces cerevisiae: kinetics and interaction with transition and ground state inhibitors

Lupidi, Giulio; Marmocchi, Franco; Falasca, Marco; Venardi, G; Cristalli, Gloria; Grifantini, Mario; Whitehead, Edward P.; Riva, F.

doi:10.1016/0167-4838(92)90410-f

Cited by 9 publications

(3 citation statements)

References 21 publications

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“…It has also been shown that the presence of adenosine deaminase favors AdoHC hydrolysis in vitro (119). Yeast adenosine deaminase has been purified and characterized (156,164), but its role in AdoHC metabolism has not been studied. However, the conversion of adenosine to AMP by adenosine kinase could be involved in this metabolism.…”

Section: Methyl Cyclementioning

confidence: 99%

Metabolism of sulfur amino acids in Saccharomyces cerevisiae.

Thomas¹,

Surdin-Kerjan²

1997

Microbiology and Molecular Biology Reviews : MMBR

518

333

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Section: Methyl Cyclementioning

confidence: 99%

Metabolism of sulfur amino acids in Saccharomyces cerevisiae.

Thomas¹,

Surdin-Kerjan²

1997

Microbiology and Molecular Biology Reviews : MMBR

518

333

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“…4.4) is an important enzyme [1] of the purine metabolism which catalyses the irreversible deamination of adenosine and 2 0 -deoxyadenosine to inosine and 2 0 -deoxyinosine, respectively (scheme 1). This enzyme has been found in plants, bacteria [2], invertebrates [3], vertebrates [4] and mammals [5,6], including humans [7 -9]. ADA is present in many human tissues, but the highest levels have been found in lymph nodes, spleen and thymus [1].…”

Section: Introductionmentioning

confidence: 99%

A study on the inhibition of adenosine deaminase

Alunni

Orrù

Ottavi

2008

Journal of Enzyme Inhibition and Medicinal Chemistry

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Adenosine deaminase (ADA, EC 3.5.4.4) catalyses the irreversible deamination of adenosine and 2 0 -deoxyadenosine to inosine and 2 0 -deoxyinosine, respectively. In this study the inhibition of ADA from bovine spleen by several molecules with structure related to that of the substrate or product has been quantified. The inhibitors adenine, purine, inosine, 2-aminopurine, 4-aminopyrimidine, 4-aminopyridine, 4-hydroxypyridine and phenylhydrazine are shown to be competitive inhibitors with K I (mM) values of 0.17, 1.1, 0.35, 0.33, 1.3, 1.8, 1.4 and 0.25, respectively. Synergistic inhibition by various combinations of molecules that imitate the structure of the substrate has never been observed. Some general conclusions are: i) the enzyme ADA from bovine spleen we have used is appropriate for kinetic studies of inhibition and mechanistic studies; it can be a reference catalytic system for the homogeneous comparison of various inhibitors; ii) this enzyme presents very rigid requirements for binding the substrate: variations in the structure of adenosine imply the loss of important interactions.

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“…ADA is an ubiquitous enzyme found in a wide variety of microrganisms [Lupidi et al, 1992a], plants, invertebrates [Ma and Fisher, 1968;Aikawa et al, 19771, and mammals [Lupidi et al, 1992b], including humans [ Daddona and Kelley, 1980;Daddona, 19811. The development of inhibitors, which are ground-state (erythro-9-(2-hydroxy-3-nonyl)adenine, EHNA 12, Ki = 7 X lo-' M) [Schaeffer and Schwender, 19741 and transition state (coformycin and deoxycoformycin, Ki = 10-1'-10-12 M) stable analogues of substrate, made possible a direct approach to the investigation of the factors responsible for transition-state stabilization [Frick et al, 1986;Weiss et al, 1987;Kurz et al, 1987aKurz et al, , 1992Kurz and Frieden, 1987;Kati and Wolfenden, 1989;Wilson et al, 19911. Interest in studying this enzyme has been recently stimulated by the discovery that ADA activity is related to the development of several diseases.…”

Section: Introductionmentioning

confidence: 99%

Adenosine deaminase inhibitors: Structure‐activity relationships in 1‐deazaadenosine and erythro‐9‐(2‐hydroxy‐3‐nonyl)adenine analogues

Cristalli

Eleuteri

Vittori

et al. 1993

Drug Development Research

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Adenosine deaminase (ADA) is the enzyme which catalyzes the irreversible deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. It is widely distributed in vertebrate tissues and i s thought to be essential for proper functioning of mammalian cells. ADA inhibitors may have several clinical applications (i.e., in the chemotherapy of lyrnphoproliferative disorders, in the immunosuppresive therapy, in adenosine level modulation). Modification of the purine moiety of adenosine led to ADA inhibitors. In particular, l-deazaadenosine (1, Ki = 0.66 pM) and its 2'-deoxy derivative (21, Ki = 0.19 JLM) are the most potent in the series. Substitutions on the N6 amino group did not produce a decrease in activity only when small groups, as hydroxyl or methyl, were introduced. The presence of a chlorine atom in position 2 produced a decrease in ADA inhibitory activity. All these findings are in agreement with a direct interaction of the l-deazapurine moiety with the catalytic site of ADA. Erythro-9-(2-hydroxy-3-nonyl) adenine (12, EHNA) and 3-deazaEHNA (14) are potent ADA inhibitors with Ki in the nanomolar range. Opening the pyrimidine ring of EHNA led to a series of erythro-l-(2-hydroxy-3-nonyl)imidazole derivatives which are still ADA inhibitors. In order to introduce additional simplification and to investigate the role of nitrogen atoms in the azole structure, a series of di-, tri-, and tetrazoles bearing the 2-hydroxy-3-nonyl chain have been synthesized and tested. The results indicated that the presence of N-3 in the azole ring is critical for the inhibitory activity and that the introduction of additional nitrogens led to compounds whose potency range accounts for a direct interaction with an inhibitory site of ADA. o 1993 WiIey-Liss, Inc.

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Adenosine deaminase from Saccharomyces cerevisiae: kinetics and interaction with transition and ground state inhibitors

Cited by 9 publications

References 21 publications

Metabolism of sulfur amino acids in Saccharomyces cerevisiae.

Metabolism of sulfur amino acids in Saccharomyces cerevisiae.

A study on the inhibition of adenosine deaminase

Adenosine deaminase inhibitors: Structure‐activity relationships in 1‐deazaadenosine and erythro‐9‐(2‐hydroxy‐3‐nonyl)adenine analogues

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