Transition state analogue discrimination by related purine nucleoside phosphorylases.
Transition state analogues of PNP, the Immucillins and DADMe-Immucillins, were designed to match transition state features of bovine and human PNPs, respectively. The inhibitors with or without the hydroxyl and hydroxymethyl groups of the substrate demonstrate that inhibitor geometry mimicking that of the transition state confers binding affinity discrimination. This finding is remarkable since crystallographic analysis indicates complete conservation of active site residues and contacts to ligands in human and bovine PNPs.
Taylor Ringia
Erika A
EA
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Tyler
Peter C
PC
Evans
Gary B
GB
Furneaux
Richard H
RH
Murkin
Andrew S
AS
Schramm
Vern L
VL
D000818:Animals; D001149:Arsenates / Q000737:chemistry; D002417:Cattle; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011485:Protein Binding; D011684:Purine Nucleosides / Q000737:chemistry; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011744:Pyrimidinones / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry
D001149:Arsenates; C508755:DADMe-immucillin H; D004791:Enzyme Inhibitors; D011684:Purine Nucleosides; D011744:Pyrimidinones; D011759:Pyrrolidines; C113101:forodesine; D011683:Purine-Nucleoside Phosphorylase