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Transition state analogues, purine salvage, cancer and malaria
Author(s) -
Schramm Vern L.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.248.3
Subject(s) - purine nucleoside phosphorylase , purine , adenosine deaminase , purine metabolism , transition state analog , chemistry , transition (genetics) , enzyme , nucleotide salvage , biochemistry , adenosine , stereochemistry , nucleotide , active site , gene
Transition state theory proposes that chemically stable mimics of the transition state will bind more tightly than substrates by the rate acceleration factor imposed by the enzyme, typically 10 10 to 10 15 fold. Transition state structures of enzymatic targets for cancer and malaria have been explored by the systematic application of kinetic isotope effects and computational chemistry. Analogues of the transition states deduced by these methods bind up to 10 7 times tighter than substrate. Using these methods, three generations of transition state analogues have been produced for human purine nucleoside phosphorylase (PNP) and two of these are in clinical trials. Transition state analogues of human 5′‐methylthioadenosine phosphorylase show promise as anticancer agents in mouse xenografts. Inhibition of S‐adenosylmethionine recycling and DNA methylation are implicated in the anti‐cancer effect. Malaria parasites are purine auxotrophs and require parasite‐specific PNP and adenosine deaminase in the purine salvage pathway. Powerful and parasite‐specific transition state analogues were designed against both malarial PNP and adenosine deaminases. These inhibitors cause purine starvation (purine‐less death) in parasites cultured in human erythrocytes. Application of kinetic isotope effects and transition state have permitted synthesis of some of the most powerful enzymatic inhibitors. Supported by GM41916 and AI49512.