Synthesis of bis-Phosphate Iminoaltritol Enantiomers and Structural Characterization with Adenine Phosphoribosyltransferase

Lawrence D. Harris, Rajesh K. Harijan, Rodrigo G. Ducati, Gary B. Evans, Brett M. Hirsch, Vern L. Schramm

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Phosphoribosyl transferases (PRTs) are essential in nucleotide synthesis and salvage, amino acid and vitamin synthesis. Transition state analysis of several PRTs has demonstrated ribocation-like transition states with a partial positive charge residing on the pentose ring. Core chemistry for synthesis of transition state analogues related to the 5-phospho-α-D-ribosyl 1-pyrophosphate (PRPP) reactant of these enzymes could be developed by stereospecific placement of bis-phosphate groups on an iminoaltritol ring. Cationic character is provided by the imino group and the bis-phosphates anchor both the 1- and 5-phosphate binding sites. We provide a facile synthetic path to these molecules. Cyclic-nitrone redox methodology was applied to the stereo-controlled synthesis of three stereoisomers of a selectively mono-protected diol relevant to the synthesis of transition-state analogue inhibitors. These polyhydroxylated pyrrolidine natural product analogues were bis-phosphorylated to generate analogues of the ribocationic form of 5-phosphoribosyl 1-phosphate. A safe, high yielding synthesis of the key intermediate represents a new route to these transition state mimics. An enantiomeric pair of iminoaltritol bis-phosphates (L-DIAB and D-DIAB) were prepared and shown to display inhibition of Plasmodium falciparum orotate phosphoribosyltransferase and Saccharomyces cerevisiae adenine phosphoribosyltransferase (ScAPRT). Crystallographic inhibitor binding analysis of L- and D-DIAB bound to the catalytic sites of ScAPRT demonstrates accommodation of both enantiomers by altered ring geometry and bis-phosphate catalytic site contacts.

Original languageEnglish (US)
JournalACS Chemical Biology
DOIs
StateAccepted/In press - Jul 17 2017

Fingerprint

Adenine Phosphoribosyltransferase
Enantiomers
Phosphates
Transferases
Yeast
Saccharomyces cerevisiae
Catalytic Domain
Orotate Phosphoribosyltransferase
Pentoses
Salvaging
Stereoisomerism
Plasmodium falciparum
Biological Products
Anchors
Vitamins
Oxidation-Reduction
Nucleotides
Binding Sites
Amino Acids
Molecules

Keywords

  • enzyme inhibitors
  • ribocation mimics
  • stereochemical specificity
  • structure of transition state analogue complexes
  • transition state analogues

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Synthesis of bis-Phosphate Iminoaltritol Enantiomers and Structural Characterization with Adenine Phosphoribosyltransferase. / Harris, Lawrence D.; Harijan, Rajesh K.; Ducati, Rodrigo G.; Evans, Gary B.; Hirsch, Brett M.; Schramm, Vern L.

In: ACS Chemical Biology, 17.07.2017.

Research output: Contribution to journalArticle

Harris, Lawrence D. ; Harijan, Rajesh K. ; Ducati, Rodrigo G. ; Evans, Gary B. ; Hirsch, Brett M. ; Schramm, Vern L. / Synthesis of bis-Phosphate Iminoaltritol Enantiomers and Structural Characterization with Adenine Phosphoribosyltransferase. In: ACS Chemical Biology. 2017.
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AU - Hirsch, Brett M.

AU - Schramm, Vern L.

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AB - Phosphoribosyl transferases (PRTs) are essential in nucleotide synthesis and salvage, amino acid and vitamin synthesis. Transition state analysis of several PRTs has demonstrated ribocation-like transition states with a partial positive charge residing on the pentose ring. Core chemistry for synthesis of transition state analogues related to the 5-phospho-α-D-ribosyl 1-pyrophosphate (PRPP) reactant of these enzymes could be developed by stereospecific placement of bis-phosphate groups on an iminoaltritol ring. Cationic character is provided by the imino group and the bis-phosphates anchor both the 1- and 5-phosphate binding sites. We provide a facile synthetic path to these molecules. Cyclic-nitrone redox methodology was applied to the stereo-controlled synthesis of three stereoisomers of a selectively mono-protected diol relevant to the synthesis of transition-state analogue inhibitors. These polyhydroxylated pyrrolidine natural product analogues were bis-phosphorylated to generate analogues of the ribocationic form of 5-phosphoribosyl 1-phosphate. A safe, high yielding synthesis of the key intermediate represents a new route to these transition state mimics. An enantiomeric pair of iminoaltritol bis-phosphates (L-DIAB and D-DIAB) were prepared and shown to display inhibition of Plasmodium falciparum orotate phosphoribosyltransferase and Saccharomyces cerevisiae adenine phosphoribosyltransferase (ScAPRT). Crystallographic inhibitor binding analysis of L- and D-DIAB bound to the catalytic sites of ScAPRT demonstrates accommodation of both enantiomers by altered ring geometry and bis-phosphate catalytic site contacts.

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