Human purine nucleoside phosphorylase

The review articles by Schramm (1998, 2003) provide a number of examples of the successful application of this protocol to the design of enzyme-specific transition state-like inhibitors. Among these, the transition state inhibitors of human purine nucleoside phosphorylase (PNP) are particularly interesting from a medicinal chemistry perspective, as examples of these compounds have entered human clinical trials for the treatment of T-cell cancers and autoimmune disorders. 

G. B. Evans, R. H. Fumeaux, A. Lewandowicz, V. L. Schramm, and P. C. Tyler, Exploring structure-activity relationships of transition state analogues of human purine nucleoside phosphorylase, J. Med. Chem., 46 (2003) 3412-3423. 

A. S. Murkin, M. R. Birck, A. Rinaldo-Matthis, W. Shi,E. A. Taylor, S. C. Almo, and V. L. Schramm, Neighboring group participation in the transition state of human purine nucleoside phosphorylase, Biochemistry, 46 (2007) 5038-5049. 

Nunez S, Antoniou D, Schramm VL, Schwartz SD (2004) Promoting vibrations in human purine nucleoside phosphorylase. A molecular dynamics and hybrid quantum mechanical/molecular mechanical study. J. Am. Chem. Soc. 126 15720-15729... 

Lewandowicz A, Tyler PC, Evans GB, Furneaux RH, Schramm VL (2003) Achieving the ultimate goal in ttansition state analogues for human purine nucleoside phosphorylase. J. Biol. Chem. 278 31465-31468... 

To identify motifs that are effective for the inhibition of human purine nucleoside phosphorylase, Shibuya et al. have prepared numerous conforma-tionally restricted nucleotides (30) and (31) that act as multi-substrate analogue inhibitors for Preliminary results demonstrated that... 

Crystal structures of human purine nucleoside phosphorylase with several TS analogs showed an unusual geometric arrangement of three oxygens, lying in a close stack. One may question whether this geometry serves a catalytic purpose. 

Mincer, J.S., Nunez, S. and Schwartz, S.D. (2004). Coupling protein dynamics to reaction center electron density in enzymes an electronic protein promoting vibration in human purine nucleoside phosphorylase. J. Theor. Comp. Chem. 3, 501-509... 

Promoting vibrations in human purine nucleoside phosphorylase ... 

Sircar J. C, Suto M. J, Scott M. E, Dong M. K, Gilbertsen R. B. Inhibitors of human purine nucleoside phosphorylase. Synthesis, purine nucleoside phosphorylase inhibition, and T-cell cytotoxicity of 2,5-diaminothiazolo[5,4-d]pyrimidin-7(6H)-one and 2,5-diaminothiazolo[4,5-d]pyrimidin-7(6H)-one. Two thioisosteres of 8-aminogua-nine, J. Med. Chem. 1986. p. 1804 -1806. DOI 10.1021/jm00159a045... 

Rejman et al. reported the N-phosphonocarbonylpyrrolidine derivatives of guanine (67). These compounds can act as bisubstrate inhibitors that occupy both the phosphate and nucleoside binding sites of human purine nucleoside phosphorylase. 

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