Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The crystal structure of a murine adenosine deaminase complexed with 6-hydroxyl-1,6-dihydropurine ribonucleoside, a nearly ideal transition-state analog, has been determined and refined at 2.4 angstrom resolution. The structure is folded as an eight-stranded parallel alpha/beta barrel with a deep pocket at the beta-barrel COOH-terminal end wherein the inhibitor and a zinc are bound and completely sequestered. The presence of the zinc cofactor and the precise structure of the bound analog were not previously known. The 6R isomer of the analog is very tightly held in place by the coordination of the 6-hydroxyl to the zinc and the formation of nine hydrogen bonds. On the basis of the structure of the complex a stereoselective addition-elimination or SN2 mechanism of the enzyme is proposed with the zinc atom and the Glu and Asp residues playing key roles. A molecular explanation of a hereditary disease caused by several point mutations of an enzyme is also presented.
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PMID:Atomic structure of adenosine deaminase complexed with a transition-state analog: understanding catalysis and immunodeficiency mutations. 192 39

2-Deoxy-beta-D-ribo-hexopyranosyl nucleosides with adenine (2), hypoxanthine (17), guanine (23), cytosine (13), and uracil (7) as the aglycon were synthesized by the Lewis-acid catalyzed condensation of an appropriate trimethylsilylated heterocyclic base and 2-deoxy-1,3,4,6-tetrakis-O-(4-nitrobenzoyl)-beta-D-ribo-hexopyranose+ ++ (5) to provide the desired beta anomers in good yield. When the synthesis of 7 via an SN2 displacement was attempted by reaction between silylated uracil and 2-deoxy-3,4,6-tris-O-(4-nitrobenzoyl)-alpha-D-ribo-hexopyranosyl bromide (8), the major product, 1-(2-deoxy-3,4,6-tris-O-(4-nitrobenzoyl)-alpha-D-ribo-hexopyranosyl)-2,4 - pyrimidinedione (9), had retained the alpha configuration at the anomeric carbon. The structures of both anomers of 1-(2-deoxy-D-ribo-hexopyranosyl)-2,4-pyrimidinedione were assigned by single-crystal X-ray methods. The anomeric configuration and conformation of other nucleosides were determined by proton magnetic resonance analysis of the 4-nitrobenzoylated nucleosides. Nucleoside 6'-monophosphates of 7, 13, and 2 and the 4',6'-cyclic monophosphate of 2 were also prepared. All 2'-deoxy-D-ribo-hexopyranosyl nucleosides and 6'-monophosphate derivatives were tested in vitro for antiviral and antitumor activity. The guanosine analogue 23 was moderately active against HSV-2 virus. The UMP analogue, 1-(2-deoxy-6-O-phosphono-beta-D-ribo-hexopyranosyl) -2,4-pyrimidinedione (28), demonstrated moderate activity against HSV-2 and parainfluenza 3 virus and was also active against L1210 (ID50 = 39 microM) and P388 (ID50 = 33 microM) leukemic cell lines. Two compounds, 6-amino-9-(2-deoxy-beta-D-ribo-hexopyranosyl)purine (2) and 9-(2-deoxy-beta-D-ribo-hexopyranosyl)-2,6-diaminopurine (24), were substrates for adenosine deaminase (EC 3.5.4.4) with Km values of 57 and 90 microM, respectively. 6-Amino-7-(2-deoxy-beta-D-ribo-hexopyranosyl)purine, 18, was a competitive inhibitor of ADase (Ki = 0.1 mM).
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PMID:Synthesis, structure, and biological activity of certain 2-deoxy-beta-D-ribo-hexopyranosyl nucleosides and nucleotides. 358 3