Transition-state analogs as inhibitors of human and malarial hypoxanthine-guanine phosphoribosyltransferases

Caroline M. Li, Peter C. Tyler, Richard H. Furneaux, Gregory Kicska, Yiming Xu, Charles Grubmeyer, Mark E. Girvin, Vern L. Schramm

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


The proposed transition state for hypoxanthine-guanine phosphoribosyltransferases (HGPRTs) has been used to design and synthesize powerful inhibitors that contain features of the transition state. The iminoribitols (1S)-1-(9-deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D- ribitol 5-phosphate (immucillinHP) and (1S)-1-(9-deazaguanin-9-yl)-1,4- dideoxy-1,4-imino-D-ribitol 5-phosphate (immucillinGP) are the most powerful inhibitors yet reported for both human and malarial HGPRTs. Equilibrium binding constants are >1,000-fold tighter than the binding of the nucleotide substrate. The NMR spectrum of malaria HGXPRT in the Michaelis complex reveals downfield hydrogen-bonded protons. The chemical shifts move farther downfield with bound inhibitor. The inhibitors are lead compounds for species-specific antibiotics against parasitic protozoa. The high-resolution crystal structure of human HGPRT with immucillinGP is reported in the companion paper.

Original languageEnglish (US)
Pages (from-to)582-587
Number of pages6
JournalNature Structural Biology
Issue number6
StatePublished - 1999

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Genetics


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