Transition states and inhibitors of the purine nucleoside phosphorylase family

Erika A. Taylor Ringia, Vern L. Schramm

Research output: Contribution to journalReview article

37 Scopus citations

Abstract

Purine nucleoside phosphorylase (PNP), an enzyme involved in the catabolism and recycling of nucleosides, is under investigation for the development of novel antibiotics. One method used for the design of inhibitors is transition state analysis. Chemically stable analogues of a transition state complex are predicted to convert the energy of enzymatic rate acceleration (kcat/knon) into binding energy. Transition state structures have been reported for the bovine (Bos taurus), human (Homo sapiens), and malarial (Plasmodium falciparum) PNPs. All three enzymes proceed through SN1-like mechanisms and have transition states with substantial ribooxocarbenium ion character. Bovine PNP proceeds through an early SN1-like transition state, whereas the human and malarial PNPs proceed through more dissociative transition state. Transition state analogues developed for PNP exhibit differential inhibition specificity for these three enzymes based upon their distinct reaction rates (kcat), mechanisms, and substrate specificity. The most powerful inhibitors of these three enzymes have picomolar dissociation constants, two of which are Immucillin-H and DADMe-Immucillin-H. MT-Immucillin-H was also developed as a specific inhibitor for P. falciparum PNP by virtue of its unique utilization of 5′-methylthio substrates. Although the transition state for tuberculosis (Mycobacterium tuberculosis) PNP is yet to be determined, inhibition values support a mechanism with a dissociative transition state like those of its human and plasmodial counterparts. Comparison of the transition states and substrate specificity of various PNPs permits the design of species-specific inhibitors for use as therapeutic agents.

Original languageEnglish (US)
Pages (from-to)1237-1258
Number of pages22
JournalCurrent Topics in Medicinal Chemistry
Volume5
Issue number13
DOIs
Publication statusPublished - Dec 1 2005

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Keywords

  • DADMe-Immucillin
  • Immucillin
  • Inhibitor
  • Kinetic isotope effects
  • Malaria
  • Purine nucleoside phosphorylase
  • T-cell disorders
  • Transition state analogue

ASJC Scopus subject areas

  • Drug Discovery

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