l-Enantiomers of Transition State Analogue Inhibitors Bound to Human Purine Nucleoside Phosphorylase
نویسندگان
چکیده
منابع مشابه
Nucleotide analogue inhibitors of purine nucleoside phosphorylase.
The diphosphate of the antiherpetic agent acyclovir [9-[(2-hydroxyethoxy)methyl]guanine] has been shown to inhibit purine nucleoside phosphorylase with unique potency (Tuttle, J. V., and Krenitsky, T. A. (1984) J. Biol. Chem. 259, 4065-4069). A major factor contributing to the superior inhibition by this diphosphate over the corresponding mono- and triphosphates is revealed here. Homologues of ...
متن کاملAchieving the ultimate physiological goal in transition state analogue inhibitors for purine nucleoside phosphorylase.
Genetic deficiency of human purine nucleoside phosphorylase (PNP) causes T-cell immunodeficiency. The enzyme is therefore a target for autoimmunity disorders, tissue transplant rejection and T-cell malignancies. Transition state analysis of bovine PNP led to the development of immucillin-H (ImmH), a powerful inhibitor of bovine PNP but less effective for human PNP. The transition state of human...
متن کاملAtomic dissection of the hydrogen bond network for transition-state analogue binding to purine nucleoside phosphorylase.
Immucillin-H (ImmH) and immucillin-G (ImmG) were previously reported as transition-state analogues for bovine purine nucleoside phosphorylase (PNP) and are the most powerful inhibitors reported for the enzyme (K(i) = 23 and 30 pM). Sixteen new immucillins are used to probe the atomic interactions that cause tight binding for bovine PNP. Eight analogues of ImmH are identified with equilibrium di...
متن کاملOne-third-the-sites transition-state inhibitors for purine nucleoside phosphorylase.
Genetic defects in human purine nucleoside phosphorylase cause T-cell deficiency as the major phenotype. It has been proposed that efficient inhibitors of the enzyme might intervene in disorders of T-cell function. Compounds with features of the transition-state structure of purine nucleoside phosphorylase were synthesized and tested as inhibitors. The transition-state structure for purine nucl...
متن کاملPurine Nucleoside Phosphorylase
Purine nucleoside phosphorylase (EC 2.4.2.1) from bovine spleen is a trimeric enzyme that readily dissociates to the monomer. Dilution of enzyme from 20 to 0.02 pg of protein/ml is accompanied by a greater than 50-fold increase in the specific activity (utrimer = 0.23 nmol/min/pg; umonomer = 12.5 nmol/min/pg). Gel permeation chromatography in the presence of the substrate phosphate shows the en...
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ژورنال
عنوان ژورنال: Journal of the American Chemical Society
سال: 2008
ISSN: 0002-7863,1520-5126
DOI: 10.1021/ja710733g